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1
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DeFranciscis V, Amabile G, Kortylewski M. Clinical applications of oligonucleotides for cancer therapy. Mol Ther 2025:S1525-0016(25)00172-8. [PMID: 40045578 DOI: 10.1016/j.ymthe.2025.02.045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 02/21/2025] [Accepted: 02/28/2025] [Indexed: 03/17/2025] Open
Abstract
Oligonucleotide therapeutics (ONTs) represent a rapidly evolving modality for cancer treatment, capitalizing on their ability to modulate gene expression with high specificity. With more than 20 nucleic acid-based therapies that gained regulatory approval, advances in chemical modifications, sequence optimization, and novel delivery systems have propelled ONTs from research tools to clinical realities. ONTs, including siRNAs, antisense oligonucleotides, saRNA, miRNA, aptamers, and decoys, offer promising solutions for targeting previously "undruggable" molecules, such as transcription factors, and enhancing cancer immunotherapy by overcoming tumor immune evasion. The promise of ONT application in cancer treatment is exemplified by the recent FDA approval of the first oligonucleotide-based treatment to myeloproliferative disease. At the same time, there are challenges in delivering ONTs to specific tissues, mitigating off-target effects, and improving cellular uptake and endosomal release. This review provides a comprehensive overview of ONTs in clinical trials, emerging delivery strategies, and innovative therapeutic approaches, emphasizing the role of ONTs in immunotherapy and addressing hurdles that hinder their clinical translation. By examining advances and remaining challenges, we highlight opportunities for ONTs to revolutionize oncology and enhance patient outcomes.
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Affiliation(s)
- Vittorio DeFranciscis
- National Research Council, Institute of Genetic and Biomedical Research, Milan, Italy
| | | | - Marcin Kortylewski
- Department of Immuno-Oncology, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USA.
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2
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Chen F, Zhao D, Xu Y, Zhang Y, Chen MH, Pathak KV, Hansen N, Lovell B, Liang Y, Estrella K, Wang WL, Ghoda L, Rockne R, Wu X, Ali H, Yu J, Caligiuri MA, Forman SJ, Trent JM, Kuo YH, Li L, Swiderski P, Zhang J, Kortylewski M, Nguyen LXT, Pirrotte P, Boldin M, Marcucci G, Zhang B. miR-142 deficit in T cells during blast crisis promotes chronic myeloid leukemia immune escape. Nat Commun 2025; 16:1253. [PMID: 39893171 PMCID: PMC11787332 DOI: 10.1038/s41467-025-56383-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 01/14/2025] [Indexed: 02/04/2025] Open
Abstract
We reported that an acquired miR-142 deficit transforms chronic phase (CP) chronic myeloid leukemia (CML) leukemic stem cells (LSCs) into blast crisis (BC) LSCs. Given the role of miR-142 in the development and activity of the immune system, we postulated that this deficit also promotes LSC immune escape. Herein, we report on IL-6-driven miR-142 deficit occurring in T cells during BC transformation. In CML murine models, miR-142 deficit impairs thymic differentiation of lymphoid-primed multipotent progenitors (LMPP) into T cells and prevents T cells' metabolic reprogramming, thereby leading to loss of T cells and leukemia immune escape. Correcting miR-142 deficit with a miR-142 mimic compound (M-miR-142), alone or in combination with immune checkpoint antibodies, restores T cell number and immune activity, leading to LSC elimination and prolonged survival of BC CML murine and patient-derived xenograft models. These observations may open new therapeutic opportunities for BC CML and other myeloid malignancies.
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MESH Headings
- MicroRNAs/genetics
- MicroRNAs/metabolism
- MicroRNAs/immunology
- Animals
- Blast Crisis/immunology
- Blast Crisis/genetics
- Blast Crisis/pathology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Humans
- Mice
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Neoplastic Stem Cells/immunology
- Neoplastic Stem Cells/pathology
- Neoplastic Stem Cells/metabolism
- Tumor Escape/genetics
- Tumor Escape/immunology
- Interleukin-6/metabolism
- Female
- Cell Differentiation
- Disease Models, Animal
- Mice, Inbred C57BL
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Affiliation(s)
- Fang Chen
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Dandan Zhao
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Yongfang Xu
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Yi Zhang
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Min-Hsuan Chen
- Integrative Genomics Core, City of Hope Beckman Research Institute, Duarte, CA, USA
- Department of Computational and Quantitative Medicine, City of Hope Beckman Research Institute, Duarte, CA, USA
| | - Khyatiben V Pathak
- Cancer & Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA
- Integrated Mass Spectrometry Shared Resource, City of Hope, Duarte, CA, USA
| | - Nate Hansen
- Cancer & Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA
- Integrated Mass Spectrometry Shared Resource, City of Hope, Duarte, CA, USA
| | - Brooke Lovell
- Cancer & Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA
- Integrated Mass Spectrometry Shared Resource, City of Hope, Duarte, CA, USA
| | - Yong Liang
- DNA/RNA Peptide Shared Resources, City of Hope Beckman Research Institute, Duarte, CA, USA
| | - Katrina Estrella
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Wei-Le Wang
- Department of Systems Biology, City of Hope Beckman Research Institute, Duarte, CA, USA
| | - Lucy Ghoda
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Russell Rockne
- Department of Computational and Quantitative Medicine, City of Hope Beckman Research Institute, Duarte, CA, USA
| | - Xiwei Wu
- Integrative Genomics Core, City of Hope Beckman Research Institute, Duarte, CA, USA
- Department of Computational and Quantitative Medicine, City of Hope Beckman Research Institute, Duarte, CA, USA
| | - Haris Ali
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Jianhua Yu
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA
| | - Michael A Caligiuri
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA
| | - Stephen J Forman
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA
| | - Jeff M Trent
- Cancer & Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Ya-Huei Kuo
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Ling Li
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Piotr Swiderski
- DNA/RNA Peptide Shared Resources, City of Hope Beckman Research Institute, Duarte, CA, USA
| | - Jianying Zhang
- Department of Computational and Quantitative Medicine, City of Hope Beckman Research Institute, Duarte, CA, USA
| | - Marcin Kortylewski
- Department of Immuno-Oncology, City of Hope Beckman Research Institute, Duarte, CA, USA
| | - Le Xuan Truong Nguyen
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Patrick Pirrotte
- Cancer & Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA
- Integrated Mass Spectrometry Shared Resource, City of Hope, Duarte, CA, USA
| | - Mark Boldin
- Department of Systems Biology, City of Hope Beckman Research Institute, Duarte, CA, USA
| | - Guido Marcucci
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA.
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA.
| | - Bin Zhang
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA.
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3
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Hamamoto K, Zhu G, Lai Q, Lesperance J, Luo H, Li Y, Nigam N, Sharma A, Yang FC, Claxton D, Qiu Y, Aplan PD, Xu M, Huang S. HoxBlinc lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98-rearranged leukemia. J Clin Invest 2025; 135:e184743. [PMID: 39883527 PMCID: PMC11957699 DOI: 10.1172/jci184743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 01/24/2025] [Indexed: 01/31/2025] Open
Abstract
Although nucleoporin 98 (NUP98) fusion oncogenes often drive aggressive pediatric leukemia by altering chromatin structure and expression of homeobox (HOX) genes, underlying mechanisms remain elusive. Here, we report that the Hoxb-associated lncRNA HoxBlinc was aberrantly activated in NUP98-PHF23 fusion-driven leukemias. HoxBlinc chromatin occupancies led to elevated mixed-lineage leukemia 1 (MLL1) recruitment and aberrant homeotic topologically associated domains (TADs) that enhanced chromatin accessibilities and activated homeotic/hematopoietic oncogenes. HoxBlinc depletion in NUP98 fusion-driven leukemia impaired HoxBlinc binding, TAD integrity, MLL1 recruitment, and the MLL1-driven chromatin signature within HoxBlinc-defined TADs in a CCCTC-binding factor-independent (CTCF-independent) manner, leading to inhibited homeotic/leukemic oncogenes that mitigated NUP98 fusion-driven leukemogenesis in xenografted mouse models. Mechanistically, HoxBlinc overexpression in the mouse hematopoietic compartment induced leukemias resembling those in NUP98-PHF23-knockin (KI) mice via enhancement of HoxBlinc chromatin binding, TAD formation, and Hox gene aberration, leading to expansion of hematopoietic stem and progenitor cell and myeloid/lymphoid cell subpopulations. Thus, our studies reveal a CTCF-independent role of HoxBlinc in leukemic TAD organization and oncogene-regulatory networks.
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Affiliation(s)
- Karina Hamamoto
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Ganqian Zhu
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Qian Lai
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Julia Lesperance
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Huacheng Luo
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Ying Li
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Nupur Nigam
- Genetics Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Arati Sharma
- Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Feng-Chun Yang
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - David Claxton
- Division of Hematology/Oncology, Department of Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
- Penn State Cancer Institute, Hershey, Pennsylvania, USA
| | - Yi Qiu
- Penn State Cancer Institute, Hershey, Pennsylvania, USA
- Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Peter D. Aplan
- Genetics Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Mingjiang Xu
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Suming Huang
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
- Penn State Cancer Institute, Hershey, Pennsylvania, USA
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4
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Khiabani NA, Doustvandi MA, Story D, Nobari SA, Hajizadeh M, Petersen R, Dunbar G, Rossignol J. Glioblastoma therapy: State of the field and future prospects. Life Sci 2024; 359:123227. [PMID: 39537100 DOI: 10.1016/j.lfs.2024.123227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/03/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Glioblastoma (GB) is a cancerous brain tumor that originates from glial cells and leads to thousands of deaths each year and a five-year survival of only 6.8 %. Treatments for GB include surgery, chemotherapy, radiation, and immunotherapy. GB is an incurable fatal disease, necessitating the development of innovative strategies to find a developing effective therapy. Genetic therapies may be crucial in treating GB by identifying the mutations and amplifications of multiple genes, which drive its proliferation and spread. Use of small interfering RNAs (siRNAs) provides a novel technology used to suppress the genes associated with disease, which forms a basis for targeted therapy in GB and its stem cell population, which are recognized for their ability to develop resistance to chemotherapy and tumorigenic capabilities. This review examines the use of siRNAs in GB, emphasizing their effectiveness in suppressing key oncogenes and signaling pathways associated with tumor development, invasion, stemness, and resistance to standard treatments. siRNA-based gene silencing is a promising approach for developing targeted therapeutics against GB and associated stem cell populations, potentially enhancing patient outcomes and survival rates in this devastating disease.
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Affiliation(s)
- Nadia Allahyarzadeh Khiabani
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, USA; Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, USA; College of Medicine, Central Michigan University, Mount Pleasant, MI, USA
| | | | - Darren Story
- Department of Psychology, Saginaw Valley State University, University Center, MI 48710, USA
| | | | | | - Robert Petersen
- College of Medicine, Central Michigan University, Mount Pleasant, MI, USA
| | - Gary Dunbar
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, USA; Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, USA; Department of Psychology, Central Michigan University, Mount Pleasant, MI, USA
| | - Julien Rossignol
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, USA; Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, USA; College of Medicine, Central Michigan University, Mount Pleasant, MI, USA.
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5
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Zhang C, Huang R, Ren L, Martincuks A, Song J, Kortylewski M, Swiderski P, Forman SJ, Yu H. Local CpG- Stat3 siRNA treatment improves antitumor effects of immune checkpoint inhibitors. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102357. [PMID: 39618825 PMCID: PMC11605413 DOI: 10.1016/j.omtn.2024.102357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 10/04/2024] [Indexed: 12/11/2024]
Abstract
Immune checkpoint blockade (ICB) therapy has significantly benefited patients with several types of solid tumors and some lymphomas. However, many of the treated patients do not have a durable clinical response. It has been demonstrated that rescuing exhausted CD8+ T cells is required for ICB-mediated antitumor effects. We recently developed an immunostimulatory strategy based on silencing STAT3 while stimulating immune responses by CpG, a ligand for Toll-like receptor 9 (TLR9). The CpG-small interfering RNA (siRNA) conjugates efficiently enter immune cells, silencing STAT3 and activating innate immunity to enhance T cell-mediated antitumor immune responses. In the present study, we demonstrate that blocking STAT3 through locally delivered CpG-Stat3 siRNA enhances the efficacies of the systemic PD-1 and CTLA4 blockade against mouse A20 B cell lymphoma. In addition, locally delivered CpG-Stat3 siRNA combined with systemic administration of PD-1 antibody significantly augmented both local and systemic antitumor effects against mouse B16 melanoma tumors, with enhanced tumor-associated T cell activation. Furthermore, locally delivered CpG-Stat3 siRNA enhanced CD8+ T cell tumor infiltration and antitumor activity in a xenograft tumor model. Overall, our studies in both B cell lymphoma and melanoma mouse models demonstrate the potential of combinatory immunotherapy with CpG-Stat3 siRNA and checkpoint inhibitors as a therapeutic strategy for B cell lymphoma and melanoma.
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Affiliation(s)
- Chunyan Zhang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Rui Huang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Lyuzhi Ren
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Antons Martincuks
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - JiEun Song
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Marcin Kortylewski
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Piotr Swiderski
- DNA/RNA Synthesis Core Facility, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Stephen J. Forman
- Department of Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Hua Yu
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA
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Wang Z, Cortez-Jugo C, Yang Y, Chen J, Wang T, De Rose R, Cui J, Caruso F. A Metal-Phenolic Network-Enabled Nanoadjuvant to Modulate Immune Responses. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2401776. [PMID: 39031853 DOI: 10.1002/smll.202401776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 05/19/2024] [Indexed: 07/22/2024]
Abstract
The presence of hierarchical suppressive pathways in the immune system combined with poor delivery efficiencies of adjuvants and antigens to antigen-presenting cells are major challenges in developing advanced vaccines. The present study reports a nanoadjuvant constructed using aluminosilicate nanoparticles (as particle templates), incorporating cytosine-phosphate-guanosine (CpG) oligonucleotides and small-interfering RNA (siRNA) to counteract immune suppression in antigen-presenting cells. Furthermore, the application of a metal-phenolic network (MPN) coating, which can endow the nanoparticles with protective and bioadhesive properties, is assessed with regard to the stability and immune function of the resulting nanoadjuvant in vitro and in vivo. Combining the adjuvanticity of aluminum and CpG with RNA interference and MPN coating results in a nanoadjuvant that exhibits greater accumulation in lymph nodes and elicits improved maturation of dendritic cells in comparison to a formulation without siRNA or MPN, and with no observable organ toxicity. The incorporation of a model antigen, ovalbumin, within the MPN coating demonstrates the capacity of MPNs to load functional biomolecules as well as the ability of the nanoadjuvant to trigger enhanced antigen-specific responses. The present template-assisted fabrication strategy for engineering nanoadjuvants holds promise in the design of delivery systems for disease prevention, as well as therapeutics.
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Affiliation(s)
- Zhaoran Wang
- Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Christina Cortez-Jugo
- Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Yang Yang
- Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong, 250100, China
| | - Jingqu Chen
- Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Tianzheng Wang
- Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Robert De Rose
- Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Jiwei Cui
- Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong, 250100, China
| | - Frank Caruso
- Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria, 3010, Australia
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Binder AK, Bremm F, Dörrie J, Schaft N. Non-Coding RNA in Tumor Cells and Tumor-Associated Myeloid Cells-Function and Therapeutic Potential. Int J Mol Sci 2024; 25:7275. [PMID: 39000381 PMCID: PMC11242727 DOI: 10.3390/ijms25137275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/19/2024] [Accepted: 06/29/2024] [Indexed: 07/16/2024] Open
Abstract
The RNA world is wide, and besides mRNA, there is a variety of other RNA types, such as non-coding (nc)RNAs, which harbor various intracellular regulatory functions. This review focuses on small interfering (si)RNA and micro (mi)RNA, which form a complex network regulating mRNA translation and, consequently, gene expression. In fact, these RNAs are critically involved in the function and phenotype of all cells in the human body, including malignant cells. In cancer, the two main targets for therapy are dysregulated cancer cells and dysfunctional immune cells. To exploit the potential of mi- or siRNA therapeutics in cancer therapy, a profound understanding of the regulatory mechanisms of RNAs and following targeted intervention is needed to re-program cancer cells and immune cell functions in vivo. The first part focuses on the function of less well-known RNAs, including siRNA and miRNA, and presents RNA-based technologies. In the second part, the therapeutic potential of these technologies in treating cancer is discussed, with particular attention on manipulating tumor-associated immune cells, especially tumor-associated myeloid cells.
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Affiliation(s)
- Amanda Katharina Binder
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (A.K.B.); (F.B.); (J.D.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Franziska Bremm
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (A.K.B.); (F.B.); (J.D.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Jan Dörrie
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (A.K.B.); (F.B.); (J.D.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Niels Schaft
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (A.K.B.); (F.B.); (J.D.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
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8
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Bao Q, Bao M, Xiao H, Ganbold T, Han S, Baigude H. Tumor-Targeted Codelivery of CpG and siRNA by a Dual-Ligand-Functionalized Curdlan Nanoparticle. Biomacromolecules 2024; 25:3360-3372. [PMID: 38771665 DOI: 10.1021/acs.biomac.4c00025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2024]
Abstract
The simultaneous delivery of CpG oligonucleotide along with short interfering RNA (siRNA) has the potential to significantly boost the anticancer impact of siRNA medications. Our previous research demonstrated that Curdlan nanoparticles functionalized with adenosine are capable of selectively delivering therapeutic siRNA to cancerous cells through endocytosis mediated by adenosine receptors. Herein, we synthesized a dual-ligand-functionalized Curdlan polymer (denoted by CuMAN) to simultaneously target tumor cells and tumor-associated macrophages (TAMs). CuMAN nanoparticles containing CpG and siRNA demonstrated enhanced uptake by B16F10 tumor cells and bone marrow-derived macrophages, which are facilitated by AR on tumor cells and mannose receptor on macrophages. This led to increased release of pro-inflammatory cytokines in both in vitro and in vivo settings. The synergistic effect of CpG on TAMs and RNAi on tumor cells mediated by the CuMAN nanoparticle not only suppressed the tumor growth but also strongly inhibited the lung metastasis. Our findings indicate that the CuMAN nanoparticle has potential as an effective dual-targeting delivery system for nucleic acid therapeutics.
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Affiliation(s)
- Qingming Bao
- School of Chemistry & Chemical Engineering, Inner Mongolia University, Hohhot, Inner Mongolia 010020, P. R. China
| | - Mingming Bao
- School of Chemistry & Chemical Engineering, Inner Mongolia University, Hohhot, Inner Mongolia 010020, P. R. China
| | - Hai Xiao
- School of Chemistry & Chemical Engineering, Inner Mongolia University, Hohhot, Inner Mongolia 010020, P. R. China
| | - Tsogzolmaa Ganbold
- School of Chemistry & Chemical Engineering, Inner Mongolia University, Hohhot, Inner Mongolia 010020, P. R. China
| | - Shuqin Han
- School of Chemistry & Chemical Engineering, Inner Mongolia University, Hohhot, Inner Mongolia 010020, P. R. China
| | - Huricha Baigude
- School of Chemistry & Chemical Engineering, Inner Mongolia University, Hohhot, Inner Mongolia 010020, P. R. China
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9
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Wang KN, Zhou K, Zhong NN, Cao LM, Li ZZ, Xiao Y, Wang GR, Huo FY, Zhou JJ, Liu B, Bu LL. Enhancing cancer therapy: The role of drug delivery systems in STAT3 inhibitor efficacy and safety. Life Sci 2024; 346:122635. [PMID: 38615745 DOI: 10.1016/j.lfs.2024.122635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/14/2024] [Accepted: 04/10/2024] [Indexed: 04/16/2024]
Abstract
The signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, resides in the nucleus to regulate genes essential for vital cellular functions, including survival, proliferation, self-renewal, angiogenesis, and immune response. However, continuous STAT3 activation in tumor cells promotes their initiation, progression, and metastasis, rendering STAT3 pathway inhibitors a promising avenue for cancer therapy. Nonetheless, these inhibitors frequently encounter challenges such as cytotoxicity and suboptimal biocompatibility in clinical trials. A viable strategy to mitigate these issues involves delivering STAT3 inhibitors via drug delivery systems (DDSs). This review delineates the regulatory mechanisms of the STAT3 signaling pathway and its association with cancer. It offers a comprehensive overview of the current application of DDSs for anti-STAT3 inhibitors and investigates the role of DDSs in cancer treatment. The conclusion posits that DDSs for anti-STAT3 inhibitors exhibit enhanced efficacy and reduced adverse effects in tumor therapy compared to anti-STAT3 inhibitors alone. This paper aims to provide an outline of the ongoing research and future prospects of DDSs for STAT3 inhibitors. Additionally, it presents our insights on the merits and future outlook of DDSs in cancer treatment.
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Affiliation(s)
- Kang-Ning Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Kan Zhou
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Nian-Nian Zhong
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Lei-Ming Cao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Zi-Zhan Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Yao Xiao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Guang-Rui Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Fang-Yi Huo
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Jun-Jie Zhou
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Oral & Maxillofacial, Anyang Sixth People's Hospital, Anyang 45500, China.
| | - Bing Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Oral & Maxillofacial - Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
| | - Lin-Lin Bu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Oral & Maxillofacial - Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
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10
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Chen J, Liu Z, Fang H, Su Q, Fan Y, Song L, He S. Therapeutic efficacy of a novel self-assembled immunostimulatory siRNA combining apoptosis promotion with RIG-I activation in gliomas. J Transl Med 2024; 22:395. [PMID: 38685028 PMCID: PMC11057130 DOI: 10.1186/s12967-024-05151-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 03/30/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND Current cancer therapies often fall short in addressing the complexities of malignancies, underscoring the urgent need for innovative treatment strategies. RNA interference technology, which specifically suppresses gene expression, offers a promising new approach in the fight against tumors. Recent studies have identified a novel immunostimulatory small-interfering RNA (siRNA) with a unique sequence (sense strand, 5'-C; antisense strand, 3'-GGG) capable of activating the RIG-I/IRF3 signaling pathway. This activation induces the release of type I and III interferons, leading to an effective antiviral immune response. However, this class of immunostimulatory siRNA has not yet been explored in cancer therapy. METHODS IsiBCL-2, an innovative immunostimulatory siRNA designed to suppress the levels of B-cell lymphoma 2 (BCL-2), contains a distinctive motif (sense strand, 5'-C; antisense strand, 3'-GGG). Glioblastoma cells were subjected to 100 nM isiBCL-2 treatment in vitro for 48 h. Morphological changes, cell viability (CCK-8 assay), proliferation (colony formation assay), migration/invasion (scratch test and Transwell assay), apoptosis rate, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were evaluated. Western blotting and immunofluorescence analyses were performed to assess RIG-I and MHC-I molecule levels, and ELISA was utilized to measure the levels of cytokines (IFN-β and CXCL10). In vivo heterogeneous tumor models were established, and the anti-tumor effect of isiBCL-2 was confirmed through intratumoral injection. RESULTS IsiBCL-2 exhibited significant inhibitory effects on glioblastoma cell growth and induced apoptosis. BCL-2 mRNA levels were significantly decreased by 67.52%. IsiBCL-2 treatment resulted in an apoptotic rate of approximately 51.96%, accompanied by a 71.76% reduction in MMP and a 41.87% increase in ROS accumulation. Western blotting and immunofluorescence analyses demonstrated increased levels of RIG-I, MAVS, and MHC-I following isiBCL-2 treatment. ELISA tests indicated a significant increase in IFN-β and CXCL10 levels. In vivo studies using nude mice confirmed that isiBCL-2 effectively impeded the growth and progression of glioblastoma tumors. CONCLUSIONS This study introduces an innovative method to induce innate signaling by incorporating an immunostimulatory sequence (sense strand, 5'-C; antisense strand, 3'-GGG) into siRNA, resulting in the formation of RNA dimers through Hoogsteen base-pairing. This activation triggers the RIG-I signaling pathway in tumor cells, causing further damage and inducing a potent immune response. This inventive design and application of immunostimulatory siRNA offer a novel perspective on tumor immunotherapy, holding significant implications for the field.
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Affiliation(s)
- Junxiao Chen
- Department of Pharmacy, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Ziyuan Liu
- Department of Pharmacy, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Haiting Fang
- Department of Pharmacy, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Qing Su
- Department of Pharmacy, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Yiqi Fan
- Department of Pharmacy, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Luyao Song
- Department of Pharmacy, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, Guangdong, China.
| | - Shuai He
- Department of Pharmacy, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, Guangdong, China.
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11
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Hall J, Zhang Z, Bhattacharya S, Wang D, Alcantara M, Liang Y, Swiderski P, Forman S, Kwak L, Vaidehi N, Kortylewski M. Oligo-PROTAC strategy for cell-selective and targeted degradation of activated STAT3. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102137. [PMID: 38384444 PMCID: PMC10879796 DOI: 10.1016/j.omtn.2024.102137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 01/31/2024] [Indexed: 02/23/2024]
Abstract
Decoy oligodeoxynucleotides (ODNs) allow targeting undruggable transcription factors, such as STAT3, but their limited potency and lack of delivery methods hampered translation. To overcome these challenges, we conjugated a STAT3-specific decoy to thalidomide, a ligand to cereblon in E3 ubiquitin ligase complex, to generate a proteolysis-targeting chimera (STAT3DPROTAC). STAT3DPROTAC downregulated STAT3 in target cells, but not STAT1 or STAT5. Computational modeling of the STAT3DPROTAC ternary complex predicted two surface lysines, K601 and K626, in STAT3 as potential ubiquitination sites. Accordingly, K601/K626 point mutations in STAT3, as well as proteasome inhibition or cereblon deletion, alleviated STAT3DPROTAC effect. Next, we conjugated STAT3DPROTAC to a CpG oligonucleotide targeting Toll-like receptor 9 (TLR9) to generate myeloid/B cell-selective C-STAT3DPROTAC. Naked C-STAT3DPROTAC was spontaneously internalized by TLR9+ myeloid cells, B cells, and human and mouse lymphoma cells but not by T cells. C-STAT3DPROTAC effectively decreased STAT3 protein levels and also STAT3-regulated target genes critical for lymphoma cell proliferation and/or survival (BCL2L1, CCND2, and MYC). Finally, local C-STAT3DPROTAC administration to human Ly3 lymphoma-bearing mice triggered tumor regression, while control C-STAT3D and C-SCR treatments had limited effects. Our results underscore the feasibility of using a PROTAC strategy for cell-selective, decoy oligonucleotide-based STAT3 targeting of and potentially other tumorigenic transcription factors for cancer therapy.
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Affiliation(s)
- Jeremy Hall
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Zhuoran Zhang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Supriyo Bhattacharya
- Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Dongfang Wang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Marice Alcantara
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Yong Liang
- DNA/RNA Synthesis Core Facility, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Piotr Swiderski
- DNA/RNA Synthesis Core Facility, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Stephen Forman
- Department of Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Larry Kwak
- Department of Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Nagarajan Vaidehi
- Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Marcin Kortylewski
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
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12
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Sun F, Xiao Y, Shapiro SD, Qu Z, Xiao G. Critical and distinct roles of cell type-specific NF-κB2 in lung cancer. JCI Insight 2024; 9:e164188. [PMID: 38385745 DOI: 10.1172/jci.insight.164188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 01/17/2024] [Indexed: 02/23/2024] Open
Abstract
Different from the well-studied canonical NF-κB member RelA, the role of the noncanonical NF-κB member NF-κB2 in solid tumors, and lung cancer in particular, is poorly understood. Here we report that in contrast to the tumor-promoting role of RelA, NF-κB2 intrinsic to lung epithelial and tumor cells had no marked effect on lung tumorigenesis and progression. On the other hand, NF-κB2 limited dendritic cell number and activation in the lung but protected lung macrophages and drove them to promote lung cancer through controlling activation of noncanonical and canonical NF-κB, respectively. NF-κB2 was also required for B cell maintenance and T cell activation. The antitumor activity of lymphocyte NF-κB2 was dominated by the protumor function of myeloid NF-κB2; thus, NF-κB2 has an overall tumor-promoting activity. These studies reveal a cell type-dependent role for NF-κB2 in lung cancer and help understand the complexity of NF-κB action and lung cancer pathogenesis for better design of NF-κB-targeted therapy against this deadliest cancer.
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Affiliation(s)
- Fan Sun
- UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Yadong Xiao
- UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Norris Comprehensive Cancer Center, Hastings Center for Pulmonary Research, Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, California, USA
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - Steven D Shapiro
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - Zhaoxia Qu
- UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Norris Comprehensive Cancer Center, Hastings Center for Pulmonary Research, Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - Gutian Xiao
- UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Norris Comprehensive Cancer Center, Hastings Center for Pulmonary Research, Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, California, USA
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13
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Zhuang Q, Chao T, Wu Y, Wei T, Ren J, Cao Z, Peng R, Liu Z. Fluorocarbon Modified Chitosan to Enable Transdermal Immunotherapy for Melanoma Treatment. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2303634. [PMID: 37467294 DOI: 10.1002/smll.202303634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 07/03/2023] [Indexed: 07/21/2023]
Abstract
Despite the rapid development of the immune checkpoint blockade (ICB) in melanoma treatment, the immunosuppressive tumor microenvironment (TME) still hinders the efficacy of immunotherapy. Recently, using agonists to modulate the TME have presented promising clinical responses in combination with ICB therapies. However, local intratumoral injection as the commonly used administration route for immune agonists would lead to low patient compliance. Herein, it is demonstrated that fluorocarbon modified chitosan (FCS) can self-assemble with immune adjuvant polyriboinosinic:polyribocytidylic acid (poly(I:C)), forming nanoparticles that can penetrate through cutaneous barriers to enable transdermal delivery. FCS/poly(I:C) can efficiently activate various types of cells presented on the transdermal route (through the skin into the TME), leading to IRF3-mediated IFN-β induction in the activated cells for tumor repression. Furthermore, transdermal FCS/poly(I:C) treatment can significantly magnify the efficacy of the programmed cell death protein 1 (PD-1) blockade in melanoma treatment through activating the immunosuppressive TME. This study approach offered an attractive transdermal approach in combined with ICB therapy for combined immunotherapy, particularly suitable for melanoma treatment.
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Affiliation(s)
- Qi Zhuang
- Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu, 215123, China
- Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren'ai Rd, Suzhou, Jiangsu, 215123, China
| | - Ting Chao
- Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu, 215123, China
- Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren'ai Rd, Suzhou, Jiangsu, 215123, China
| | - Yuanyuan Wu
- Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu, 215123, China
- Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren'ai Rd, Suzhou, Jiangsu, 215123, China
| | - Ting Wei
- Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu, 215123, China
- InnoBM Pharmaceuticals, Suzhou, Jiangsu, 215123, China
| | - Jiacheng Ren
- Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu, 215123, China
- Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren'ai Rd, Suzhou, Jiangsu, 215123, China
| | - Zhiqing Cao
- Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu, 215123, China
- Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren'ai Rd, Suzhou, Jiangsu, 215123, China
| | - Rui Peng
- Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu, 215123, China
- Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren'ai Rd, Suzhou, Jiangsu, 215123, China
| | - Zhuang Liu
- Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu, 215123, China
- Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren'ai Rd, Suzhou, Jiangsu, 215123, China
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14
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Kim S, Kang YG, Kim J, Dua P, Lee DK. Development of Long Asymmetric siRNA Structure for Target Gene Silencing and Immune Stimulation in Mammalian Cells. Nucleic Acid Ther 2023; 33:329-337. [PMID: 37797162 DOI: 10.1089/nat.2023.0003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/07/2023] Open
Abstract
Post-transcriptional regulation of transcript abundances by RNA interference (RNAi) is a widely conserved regulatory mechanism to control cellular processes. We previously introduced an alternative siRNA structure called asymmetric siRNA (asiRNA), and showed that asiRNA exhibits comparable gene-silencing efficiency with reduced off-target effects compared with conventional siRNAs. However, to what extent the length of the guide strand affects the gene-silencing efficiency of asiRNAs is still elusive. In this study, we analyzed in detail the gene-silencing ability of asiRNAs along the guide strand length and immunostimulatory capacity of asiRNAs. We generated asiRNAs containing various guide strand lengths ranging from 25 to 29 nt, called long asiRNA (lasiRNA). We found that the gene-silencing activity of lasiRNAs decreased as the length of the guide strand increased. Nonetheless, the 3'-end overhangs that are complementary to the target gene have higher efficiency for gene silencing compared with mismatched overhangs. In addition, we found that the silencing efficiency of lasiRNAs correlates with their Ago2-binding affinity. Finally, replacing the mismatched overhang with a TLR7- or TLR9-associated immune response motif induced a toll-like receptor (TLR)-specific immune response and retained gene-silencing activity. Our findings demonstrate that lasiRNA structures can be tailored to function as bifunctional siRNA, which trigger a specific immune response combined with target gene silencing. Taken together, we anticipate that our findings provide a road map for the subsequent development of immune-stimulating lasiRNA, which bear the potential to be applied for therapeutic benefits.
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Affiliation(s)
- Soonkap Kim
- Department of Chemistry, Sungkyunkwan University, Suwon, Korea
| | - Young Gyu Kang
- Department of Chemistry, Sungkyunkwan University, Suwon, Korea
- Department of Platform Technology Unit2, OliX Pharmaceuticals, Inc., Suwon, Korea
| | - Jaejin Kim
- Department of Chemistry, Sungkyunkwan University, Suwon, Korea
| | - Pooja Dua
- Department of Platform Technology Unit2, OliX Pharmaceuticals, Inc., Suwon, Korea
| | - Dong-Ki Lee
- Department of Chemistry, Sungkyunkwan University, Suwon, Korea
- Department of Platform Technology Unit2, OliX Pharmaceuticals, Inc., Suwon, Korea
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15
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Li W, Li M, Huang Q, He X, Shen C, Hou X, Xue F, Deng Z, Luo Y. Advancement of regulating cellular signaling pathways in NSCLC target therapy via nanodrug. Front Chem 2023; 11:1251986. [PMID: 37744063 PMCID: PMC10512551 DOI: 10.3389/fchem.2023.1251986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 08/29/2023] [Indexed: 09/26/2023] Open
Abstract
Lung cancer (LC) is one of the leading causes of high cancer-associated mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common type of LC. The mechanisms of NSCLC evolution involve the alterations of multiple complex signaling pathways. Even with advances in biological understanding, early diagnosis, therapy, and mechanisms of drug resistance, many dilemmas still need to face in NSCLC treatments. However, many efforts have been made to explore the pathological changes of tumor cells based on specific molecular signals for drug therapy and targeted delivery. Nano-delivery has great potential in the diagnosis and treatment of tumors. In recent years, many studies have focused on different combinations of drugs and nanoparticles (NPs) to constitute nano-based drug delivery systems (NDDS), which deliver drugs regulating specific molecular signaling pathways in tumor cells, and most of them have positive implications. This review summarized the recent advances of therapeutic targets discovered in signaling pathways in NSCLC as well as the related NDDS, and presented the future prospects and challenges.
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Affiliation(s)
- Wenqiang Li
- Zigong First People’s Hospital, Zigong, Sichuan, China
| | - Mei Li
- West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qian Huang
- Sichuan North Medical College, Nanchong, Sichuan, China
| | - Xiaoyu He
- Sichuan North Medical College, Nanchong, Sichuan, China
| | - Chen Shen
- West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaoming Hou
- West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Fulai Xue
- West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhiping Deng
- Zigong First People’s Hospital, Zigong, Sichuan, China
| | - Yao Luo
- Zigong First People’s Hospital, Zigong, Sichuan, China
- West China Hospital, Sichuan University, Chengdu, Sichuan, China
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16
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Zhang B, Zhao D, Chen F, Frankhouser D, Wang H, Pathak KV, Dong L, Torres A, Garcia-Mansfield K, Zhang Y, Hoang DH, Chen MH, Tao S, Cho H, Liang Y, Perrotti D, Branciamore S, Rockne R, Wu X, Ghoda L, Li L, Jin J, Chen J, Yu J, Caligiuri MA, Kuo YH, Boldin M, Su R, Swiderski P, Kortylewski M, Pirrotte P, Nguyen LXT, Marcucci G. Acquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis. Nat Commun 2023; 14:5325. [PMID: 37658085 PMCID: PMC10474062 DOI: 10.1038/s41467-023-41167-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 08/23/2023] [Indexed: 09/03/2023] Open
Abstract
The mechanisms underlying the transformation of chronic myeloid leukemia (CML) from chronic phase (CP) to blast crisis (BC) are not fully elucidated. Here, we show lower levels of miR-142 in CD34+CD38- blasts from BC CML patients than in those from CP CML patients, suggesting that miR-142 deficit is implicated in BC evolution. Thus, we create miR-142 knockout CML (i.e., miR-142-/-BCR-ABL) mice, which develop BC and die sooner than miR-142 wt CML (i.e., miR-142+/+BCR-ABL) mice, which instead remain in CP CML. Leukemic stem cells (LSCs) from miR-142-/-BCR-ABL mice recapitulate the BC phenotype in congenic recipients, supporting LSC transformation by miR-142 deficit. State-transition and mutual information analyses of "bulk" and single cell RNA-seq data, metabolomic profiling and functional metabolic assays identify enhanced fatty acid β-oxidation, oxidative phosphorylation and mitochondrial fusion in LSCs as key steps in miR-142-driven BC evolution. A synthetic CpG-miR-142 mimic oligodeoxynucleotide rescues the BC phenotype in miR-142-/-BCR-ABL mice and patient-derived xenografts.
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Affiliation(s)
- Bin Zhang
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA.
| | - Dandan Zhao
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Fang Chen
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - David Frankhouser
- Department of Computational and Quantitative Medicine, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Huafeng Wang
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Khyatiben V Pathak
- Cancer & Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA
- Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Lei Dong
- Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, USA
| | - Anakaren Torres
- Cancer & Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA
- Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Krystine Garcia-Mansfield
- Cancer & Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA
- Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Yi Zhang
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Dinh Hoa Hoang
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Min-Hsuan Chen
- City of Hope National Medical Center, Integrative Genomics Core, Department of Computational and Quantitative Medicine, Beckman Research Institute, Duarte, CA, USA
| | - Shu Tao
- City of Hope National Medical Center, Integrative Genomics Core, Department of Computational and Quantitative Medicine, Beckman Research Institute, Duarte, CA, USA
| | - Hyejin Cho
- City of Hope National Medical Center, Integrative Genomics Core, Department of Computational and Quantitative Medicine, Beckman Research Institute, Duarte, CA, USA
| | - Yong Liang
- DNA/RNA Peptide Shared Resources, Beckman Research Institute, Duarte, CA, USA
| | - Danilo Perrotti
- Department of Medicine and Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine Baltimore, Baltimore, MD, USA
- Department of Immunology and Inflammation, Centre of Hematology, Imperial College of London, London, UK
| | - Sergio Branciamore
- Department of Computational and Quantitative Medicine, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Russell Rockne
- Department of Computational and Quantitative Medicine, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Xiwei Wu
- City of Hope National Medical Center, Integrative Genomics Core, Department of Computational and Quantitative Medicine, Beckman Research Institute, Duarte, CA, USA
| | - Lucy Ghoda
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Ling Li
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Jie Jin
- Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Jianjun Chen
- Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, USA
| | - Jianhua Yu
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA
| | - Michael A Caligiuri
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA
| | - Ya-Huei Kuo
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA
| | - Mark Boldin
- Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, USA
| | - Rui Su
- Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, USA
| | - Piotr Swiderski
- DNA/RNA Peptide Shared Resources, Beckman Research Institute, Duarte, CA, USA
| | - Marcin Kortylewski
- Department of Immuno-Oncology, Beckman Research Institute, Duarte, CA, USA
| | - Patrick Pirrotte
- Cancer & Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA
- Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Le Xuan Truong Nguyen
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA.
- Cancer & Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
| | - Guido Marcucci
- Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA.
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17
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Zhang C, Huang R, Ren L, Song J, Kortylewski M, Swiderski P, Forman S, Yu H. Local CpG- Stat3 siRNA treatment improves antitumor effects of immune checkpoint inhibitors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.17.553571. [PMID: 37645787 PMCID: PMC10462083 DOI: 10.1101/2023.08.17.553571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Immune checkpoint blockade (ICB) therapy has significantly benefited patients with several types of solid tumors and some lymphomas. However, many of the treated patients do not have durable clinical response. It has been demonstrated that rescuing exhausted CD8 + T cells is required for ICB-mediated antitumor effects. We recently developed an immunostimulatory strategy based on silencing STAT3 while stimulating immune responses by CpG, ligand for Toll-like receptor 9 (TLR9). The CpG-small interfering RNA (siRNA) conjugates efficiently enter immune cells, silencing STAT3 and activating innate immunity to enhance T-cell mediated antitumor immune responses. In the present study, we demonstrate that blocking STAT3 through locally delivered CpG- Stat3 siRNA enhances the efficacies of the systemic PD-1 and CTLA4 blockade against mouse A20 B cell lymphoma. In addition, locally delivered CpG- Stat3 siRNA combined with systemic administration of PD-1 antibody significantly augmented both local and systemic antitumor effects against mouse B16 melanoma tumors, with enhanced tumor-associated T cell activation. Overall, our studies in both B cell lymphoma and melanoma mouse models demonstrate the potential of combinatory immunotherapy with CpG- Stat3 siRNA and checkpoint inhibitors as a therapeutic strategy for B cell lymphoma and melanoma.
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18
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Hall J, Zhang Z, Wang D, Bhattacharya S, Alcantara M, Liang Y, Swiderski P, Forman S, Kwak L, Vaidehi N, Kortylewski M. Oligo-PROTAC strategy for cell-selective and targeted degradation of activated STAT3. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.01.551552. [PMID: 37577590 PMCID: PMC10418257 DOI: 10.1101/2023.08.01.551552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
Decoy-oligodeoxynucleotides (D-ODNs) can target undruggable transcription factors, such as STAT3. However, challenges in D-ODN delivery and potency hampered their translation. To overcome these limitations, we conjugated STAT3-specific D-ODN to thalidomide (Tha), a known ligand to cereblon (CRBN, a component of E3 ubiquitin ligase) to generate a proteolysis-targeting chimera (STAT3D PROTAC ). STAT3D PROTAC downregulated STAT3, but not STAT1 or STAT5, in target cells. Computational modeling of the STAT3D PROTAC ternary complex predicted two surface lysines on STAT3, K601 and K626 as potential ubiquitination sites for the PROTAC bound E3 ligase. Accordingly, K601/K626 point mutations in STAT3, as well as proteasome inhibitors, and CRBN deletion alleviated STAT3D PROTAC effect. Next, we conjugated STAT3D PROTAC to a CpG ligand targeting Toll-like receptor 9 (TLR9) to generate myeloid/B-cell-selective C-STAT3D PROTAC conjugate. Naked C-STAT3D PROTAC was spontaneously internalized by TLR9 + myeloid cells, B cells as well as human Ly18 and mouse A20 lymphoma cells, but not by T cells. C-STAT3D PROTAC decreased STAT3 levels to 50% at 250 nM and over 85% at 2 µM dosing in myeloid cells. We also observed significantly improved downregulation of STAT3 target genes involved in lymphoma cell proliferation and/or survival ( BCL2L1, CCND2, MYC ). Finally, we assessed the antitumor efficacy of C-STAT3D PROTAC compared to C-STAT3D or scrambled control (C-SCR) against human lymphoma xenotransplants. Local C-STAT3D PROTAC administration triggered lymphoma regression while control treatments had limited effects. Our results underscore feasibility of using PROTAC strategy for cell-selective, decoy oligonucleotide-based targeting of STAT3 and potentially other tumorigenic transcription factors for cancer therapy.
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19
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Yang MY, Zheng MH, Meng XT, Ma LW, Liang HY, Fan HY. Role of toll-like receptors in the pathogenesis of COVID-19: Current and future perspectives. Scand J Immunol 2023; 98:e13275. [PMID: 38441378 DOI: 10.1111/sji.13275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 04/21/2023] [Accepted: 04/24/2023] [Indexed: 03/07/2024]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic underlines a persistent threat of respiratory tract infectious diseases and warrants preparedness for a rapid response. At present, COVID-19 has had a serious social impact and imposed a heavy global burden on public health. The exact pathogenesis of COVID-19 has not been fully elucidated. Since the outbreak of COVID-19, a renewed attention has been brought to Toll-like receptors (TLRs). Available data and new findings have demonstrated that the interaction of human TLRs and SARS-CoV-2 is a vital mediator of COVID-19 immunopathogenesis. TLRs such as TLR2, 4, 7 and 8 are potentially important in viral combat and activation of immunity in patients with COVID-19. Therapeutics targeting TLRs are currently considered promising options against the pandemic. A number of TLR-targeting immunotherapeutics are now being investigated in preclinical studies and different phases of clinical trials. In addition, innovative vaccines based on TLRs under development could be a promising approach for building a new generation of vaccines to solve the current challenges. In this review, we summarize recent progress in the role of TLRs in COVID-19, focusing the new candidate drugs targeting TLRs, the current technology and potential paths forward for employing TLR agonists as vaccine adjuvants.
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Affiliation(s)
- Ming-Yan Yang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Mei-Hua Zheng
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Xiang-Ting Meng
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
| | - Le-Wei Ma
- Ruikang Pharmaceutical Group Co. Ltd., Yantai, China
| | - Hai-Yue Liang
- Yantai Center for Food and Drug Control, Yantai, China
| | - Hua-Ying Fan
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
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20
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Ma S, Sun B, Duan S, Han J, Barr T, Zhang J, Bissonnette MB, Kortylewski M, He C, Chen J, Caligiuri MA, Yu J. YTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8 + T cells. Nat Immunol 2023; 24:255-266. [PMID: 36658237 PMCID: PMC10150872 DOI: 10.1038/s41590-022-01398-6] [Citation(s) in RCA: 109] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 12/02/2022] [Indexed: 01/21/2023]
Abstract
Despite tumor-associated macrophages (TAMs) playing a key role in shaping the tumor microenvironment (TME), the mechanisms by which TAMs influence the TME and contribute to cancer progression remain unclear. Here, we show that the N6-methyladenosine reader YTHDF2 regulates the antitumor functions of TAMs. YTHDF2 deficiency in TAMs suppressed tumor growth by reprogramming TAMs toward an antitumoral phenotype and increasing their antigen cross-presentation ability, which in turn enhanced CD8+ T cell-mediated antitumor immunity. YTHDF2 deficiency facilitated the reprogramming of TAMs by targeting interferon-γ-STAT1 signaling. The expression of YTHDF2 in TAMs was regulated by interleukin-10-STAT3 signaling. Selectively targeting YTHDF2 in TAMs using a Toll-like receptor 9 agonist-conjugated small interfering RNA reprogrammed TAMs toward an antitumoral phenotype, restrained tumor growth and enhanced the efficacy of PD-L1 antibody therapy. Collectively, our findings describe the role of YTHDF2 in orchestrating TAMs and suggest that YTHDF2 inhibition is an effective approach to enhance cancer immunotherapy.
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Affiliation(s)
- Shoubao Ma
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA
- Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, USA
| | - Baofa Sun
- College of Life Sciences, Nankai University, Tianjin, China
| | - Songqi Duan
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Jingjing Han
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA
- Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, USA
| | - Tasha Barr
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA
- Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, USA
| | - Jianying Zhang
- Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA, USA
| | | | - Marcin Kortylewski
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Los Angeles, CA, USA
| | - Chuan He
- Departments of Chemistry and Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA
- Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, USA
| | - Jianjun Chen
- Department of Systems Biology, Beckman Research Institute, City of Hope, Los Angeles, CA, USA
- Comprehensive Cancer Center, City of Hope, Los Angeles, CA, USA
| | - Michael A Caligiuri
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA.
- Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, USA.
- Comprehensive Cancer Center, City of Hope, Los Angeles, CA, USA.
| | - Jianhua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA.
- Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, USA.
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Los Angeles, CA, USA.
- Comprehensive Cancer Center, City of Hope, Los Angeles, CA, USA.
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21
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Ma S, Barr T, Yu J. Recent Advances of RNA m 6A Modifications in Cancer Immunoediting and Immunotherapy. Cancer Treat Res 2023; 190:49-94. [PMID: 38112999 DOI: 10.1007/978-3-031-45654-1_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2023]
Abstract
Cancer immunotherapy, which modulates immune responses against tumors using immune-checkpoint inhibitors or adoptive cell transfer, has emerged as a novel and promising therapy for tumors. However, only a minority of patients demonstrate durable responses, while the majority of patients are resistant to immunotherapy. The immune system can paradoxically constrain and promote tumor development and progression. This process is referred to as cancer immunoediting. The mechanisms of resistance to immunotherapy seem to be that cancer cells undergo immunoediting to evade recognition and elimination by the immune system. RNA modifications, specifically N6-methyladenosine (m6A) methylation, have emerged as a key regulator of various post-transcriptional gene regulatory processes, such as RNA export, splicing, stability, and degradation, which play unappreciated roles in various physiological and pathological processes, including immune system development and cancer pathogenesis. Therefore, a deeper understanding of the mechanisms by which RNA modifications impact the cancer immunoediting process can provide insight into the mechanisms of resistance to immunotherapies and the strategies that can be used to overcome such resistance. In this chapter, we briefly introduce the background of cancer immunoediting and immunotherapy. We also review and discuss the roles and mechanisms of RNA m6A modifications in fine-tuning the innate and adaptive immune responses, as well as in regulating tumor escape from immunosurveillance. Finally, we summarize the current strategies targeting m6A regulators for cancer immunotherapy.
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Affiliation(s)
- Shoubao Ma
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA
| | - Tasha Barr
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA
| | - Jianhua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Los Angeles, CA, 91010, USA.
- Comprehensive Cancer Center, City of Hope, Los Angeles, CA, 91010, USA.
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Abstract
Accumulating evidence indicates that Toll-like receptor (TLR) agonists proficiently (re)instore cancer immunosurveillance as immunological adjuvants. So far, three TLR agonists have been approved by regulatory agencies for use in oncological applications. Additionally, these immunotherapeutics have been extensively investigated over the past few years. Multiple clinical trials are currently evaluating the combination of TLR agonists with chemotherapy, radiotherapy, or different immunotherapies. Moreover, antibodies targeting tumor-enriched surface proteins that have been conjugated to TLR agonists are being developed to stimulate anticancer immune responses specifically within the tumor microenvironment. Solid preclinical and translational results support the favorable immune-activating effects of TLR agonists. Here, we summarize recent preclinical and clinical advances in the development of TLR agonists for anticancer immunotherapy.
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Affiliation(s)
- Julie Le Naour
- Centre de Recherche Des Cordeliers, Equipe Labellisée Par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.,Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France
| | - Guido Kroemer
- Centre de Recherche Des Cordeliers, Equipe Labellisée Par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.,Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
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23
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PA-MSHA induces inflamed tumor microenvironment and sensitizes tumor to anti-PD-1 therapy. Cell Death Dis 2022; 13:931. [PMID: 36344505 PMCID: PMC9640707 DOI: 10.1038/s41419-022-05368-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 07/08/2022] [Accepted: 10/21/2022] [Indexed: 11/09/2022]
Abstract
A low response rate to immune checkpoint inhibitor (ICI) therapy has impeded its clinical use. As reported previously, an inflamed tumor microenvironment (TME) was directly correlated with patients' response to immune checkpoint blockade (ICB). Thus, restoring the cytotoxic effect of immune cells in the TME is a promising way to improve the efficacy of ICB and overcome primary resistance to immunotherapy. The effect of Pseudomonas aeruginosa mannose-sensitive-hemagglutinin (PA-MSHA) in facilitating T cell activation was determined in vitro and in vivo. Subsets of immune cells were analyzed by flow cytometry. Proteomics was carried out to comprehensively analyze the discriminated cellular kinases and transcription factors. The combinational efficacy of PA-MSHA and αPD-1 therapy was studied in vivo. In this study we demonstrated that PA-MSHA, which is a clinically used immune adjuvant, effectively induced the anti-tumor immune response and suppressed the growth of non-small cell lung cancer (NSCLC) cells. PA-MSHA showed great potential to sensitize refractory "cold" tumors to immunotherapy. It effectively enhanced macrophage M1 polarization and induced T cell activation. In vivo, in combination with αPD-1, PA-MSHA suppressed tumor growth and prolonged the survival time of allograft model mice. These results indicate that PA-MSHA is a potent agent to stimulate immune cells infiltration into the TME and consequently induces inflammation in tumors. The combination of PA-MSHA with αPD-1 is a potential strategy to enhance the clinical response rate to ICI therapy.
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24
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Sharma RK, Sharma J, Kumar R, Badal D, Pattekar A, Sehgal S, Gupta A, Jain P, Sachdeva N. TLR9 signalling activation via direct ligation and its functional consequences in CD4 + T cells. Scand J Immunol 2022; 96:e13214. [PMID: 37406035 PMCID: PMC9788197 DOI: 10.1111/sji.13214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 08/11/2022] [Accepted: 08/23/2022] [Indexed: 11/29/2022]
Abstract
CpG Oligodeoxynucleotides (ODNs) are established TLR9 ligands; however, their functional responses in CD4+ T cells are believed to be independent of TLR9 and MyD88. We studied ligand-receptor interactions of ODN 2216 and TLR9 in human CD4+ T cells and assessed their consequences in terms of TLR9 signalling and cell phenotype. We demonstrated that the uptake of ODN 2216, a synthetic TLR9 agonist, is controlled by TLR9 signalling molecules and results in an increase in the expression of TLR9 signalling molecules, regulated via a feedback mechanism. Next, the uptake of ODN 2216 resulted in TLR9 signalling dependent but MyD88 independent increase in expression of TGF-β. Finally, ODN 2216 treated CD4+ T cells showed an anti-inflammatory phenotype that was similar to Th3 type of regulatory T cells. These Th3-like cells were able to suppress the proliferation of untreated CD4+ T cells. Collectively, our results demonstrate a direct and interdependent relationship between ODN 2216 uptake and TLR9 signalling in CD4+ T cells. Our findings thus pave the way for future research to explore direct modulation of adaptive immune cells, using innate immune ligands, to subvert exaggerated inflammatory responses.
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Affiliation(s)
- Ravi Kumar Sharma
- Advanced Eye CentrePost Graduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
- Department of Microbiology and Immunology and the Institute for Molecular Medicine and Infectious DiseaseDrexel University College of MedicinePhiladelphiaPennsylvaniaUSA
- Division of Rheumatology, Department of MedicineKarolinska InstitutetSolnaSweden
| | - Jyoti Sharma
- Advanced Eye CentrePost Graduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
| | - Rajendra Kumar
- Division of Biological SciencesIndian Institute of Science Education and ResearchMohaliPunjabIndia
- Department of OncologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Darshan Badal
- Department of EndocrinologyPost Graduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
| | - Ajinkya Pattekar
- Department of Microbiology and Immunology and the Institute for Molecular Medicine and Infectious DiseaseDrexel University College of MedicinePhiladelphiaPennsylvaniaUSA
| | - Shobha Sehgal
- Department of ImmunopathologyPost Graduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
| | - Amod Gupta
- Advanced Eye CentrePost Graduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
| | - Pooja Jain
- Department of Microbiology and Immunology and the Institute for Molecular Medicine and Infectious DiseaseDrexel University College of MedicinePhiladelphiaPennsylvaniaUSA
| | - Naresh Sachdeva
- Department of EndocrinologyPost Graduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
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25
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Abosalha AK, Boyajian J, Ahmad W, Islam P, Ghebretatios M, Schaly S, Thareja R, Arora K, Prakash S. Clinical pharmacology of siRNA therapeutics: current status and future prospects. Expert Rev Clin Pharmacol 2022; 15:1327-1341. [PMID: 36251525 DOI: 10.1080/17512433.2022.2136166] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Small interfering RNA (siRNA) has emerged as a powerful tool for post-transcriptional downregulation of multiple genes for various therapies. Naked siRNA molecules are surrounded by several barriers that tackle their optimum delivery to target tissues such as limited cellular uptake, short circulation time, degradation by endonucleases, glomerular filtration, and capturing by the reticuloendothelial system (RES). AREAS COVERED This review provides insights into studies that investigate various siRNA-based therapies, focusing on the mechanism, delivery strategies, bioavailability, pharmacokinetic, and pharmacodynamics of naked and modified siRNA molecules. The clinical pharmacology of currently approved siRNA products is also discussed. EXPERT OPINION Few siRNA-based products have been approved recently by the Food and Drug Administration (FDA) and other regulatory agencies after approximately twenty years following its discovery due to the associated limitations. The absorption, distribution, metabolism, and excretion of siRNA therapeutics are highly restricted by several obstacles, resulting in rapid clearance of siRNA-based therapeutic products from systemic circulation before reaching the cytosol of targeted cells. The siRNA therapeutics however are very promising in many diseases, including gene therapy and SARS-COV-2 viral infection. The design of suitable delivery vehicles and developing strategies toward better pharmacokinetic parameters may solve the challenges of siRNA therapies.
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Affiliation(s)
- Ahmed Khaled Abosalha
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada.,Pharmaceutical Technology Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Jacqueline Boyajian
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Waqar Ahmad
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Paromita Islam
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Merry Ghebretatios
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Sabrina Schaly
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Rahul Thareja
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Karan Arora
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Satya Prakash
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, Canada
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26
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Kim YA, Gu H, Gwon MG, An HJ, Bae S, Leem J, Jung HJ, Park KK, Lee SJ. Synthetic Non-Coding RNA for Suppressing mTOR Translation to Prevent Renal Fibrosis Related to Autophagy in UUO Mouse Model. Int J Mol Sci 2022; 23:11365. [PMID: 36232665 PMCID: PMC9569483 DOI: 10.3390/ijms231911365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/23/2022] [Accepted: 09/24/2022] [Indexed: 11/16/2022] Open
Abstract
The global burden of chronic kidney disease is increasing, and the majority of these diseases are progressive. Special site-targeted drugs are emerging as alternatives to traditional drugs. Oligonucleotides (ODNs) have been proposed as effective therapeutic tools in specific molecular target therapies for several diseases. We designed ring-type non-coding RNAs (ncRNAs), also called mTOR ODNs to suppress mammalian target rapamycin (mTOR) translation. mTOR signaling is associated with excessive cell proliferation and fibrogenesis. In this study, we examined the effects of mTOR suppression on chronic renal injury. To explore the regulation of fibrosis and inflammation in unilateral ureteral obstruction (UUO)-induced injury, we injected synthesized ODNs via the tail vein of mice. The expression of inflammatory-related markers (interleukin-1β, tumor necrosis factor-α), and that of fibrosis (α-smooth muscle actin, fibronectin), was decreased by synthetic ODNs. Additionally, ODN administration inhibited the expression of autophagy-related markers, microtubule-associated protein light chain 3, Beclin1, and autophagy-related gene 5-12. We confirmed that ring-type ODNs inhibited fibrosis, inflammation, and autophagy in a UUO mouse model. These results suggest that mTOR may be involved in the regulation of autophagy and fibrosis and that regulating mTOR signaling may be a therapeutic strategy against chronic renal injury.
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Affiliation(s)
- Young-Ah Kim
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| | - Hyemin Gu
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| | - Mi-Gyeong Gwon
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| | - Hyun-Jin An
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| | - Seongjae Bae
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| | - Jaechan Leem
- Department of Immunology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| | - Hyun Jin Jung
- Department of Urology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| | - Kwan-Kyu Park
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| | - Sun-Jae Lee
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
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27
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Wang Y, Chen-Mayfield TJ, Li Z, Younis MH, Cai W, Hu Q. Harnessing DNA for immunotherapy: Cancer, infectious diseases, and beyond. ADVANCED FUNCTIONAL MATERIALS 2022; 32:2112273. [PMID: 36304724 PMCID: PMC9595111 DOI: 10.1002/adfm.202112273] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Indexed: 05/03/2023]
Abstract
Despite the rapid development of immunotherapy, low response rates, poor therapeutic outcomes and severe side effects still limit their implementation, making the augmentation of immunotherapy an important goal for current research. DNA, which has principally been recognized for its functions of encoding genetic information, has recently attracted research interest due to its emerging role in immune modulation. Inspired by the intrinsic DNA-sensing signaling that triggers the host defense in response to foreign DNA, DNA or nucleic acid-based immune stimulators have been used in the prevention and treatment of various diseases. Besides that, DNA vaccines allow the synthesis of target proteins in host cells, subsequently inducing recognition of these antigens to provoke immune responses. On this basis, researchers have designed numerous vehicles for DNA and nucleic acid delivery to regulate immune systems. Additionally, DNA nanostructures have also been implemented as vaccine delivery systems to elicit strong immune responses against pathogens and diseased cells. This review will introduce the mechanism of harnessing DNA-mediated immunity for the prevention and treatment of diseases, summarize recent progress, and envisage their future applications and challenges.
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Affiliation(s)
- Yixin Wang
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705
- Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53705
| | - Ting-Jing Chen-Mayfield
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705
- Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53705
| | - Zhaoting Li
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705
- Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53705
| | - Muhsin H. Younis
- Department of Radiology and Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin 53705
| | - Weibo Cai
- Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53705
- Department of Radiology and Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin 53705
| | - Quanyin Hu
- Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705
- Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53705
- Wisconsin Center for NanoBioSystems, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA
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Bartolucci D, Pession A, Hrelia P, Tonelli R. Precision Anti-Cancer Medicines by Oligonucleotide Therapeutics in Clinical Research Targeting Undruggable Proteins and Non-Coding RNAs. Pharmaceutics 2022; 14:pharmaceutics14071453. [PMID: 35890348 PMCID: PMC9315662 DOI: 10.3390/pharmaceutics14071453] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/24/2022] [Accepted: 07/08/2022] [Indexed: 12/23/2022] Open
Abstract
Cancer incidence and mortality continue to increase, while the conventional chemotherapeutic drugs confer limited efficacy and relevant toxic side effects. Novel strategies are urgently needed for more effective and safe therapeutics in oncology. However, a large number of proteins are considered undruggable by conventional drugs, such as the small molecules. Moreover, the mRNA itself retains oncological functions, and its targeting offers the double advantage of blocking the tumorigenic activities of the mRNA and the translation into protein. Finally, a large family of non-coding RNAs (ncRNAs) has recently emerged that are also dysregulated in cancer, but they could not be targeted by drugs directed against the proteins. In this context, this review describes how the oligonucleotide therapeutics targeting RNA or DNA sequences, are emerging as a new class of drugs, able to tackle the limitations described above. Numerous clinical trials are evaluating oligonucleotides for tumor treatment, and in the next few years some of them are expected to reach the market. We describe the oligonucleotide therapeutics targeting undruggable proteins (focusing on the most relevant, such as those originating from the MYC and RAS gene families), and for ncRNAs, in particular on those that are under clinical trial evaluation in oncology. We highlight the challenges and solutions for the clinical success of oligonucleotide therapeutics, with particular emphasis on the peculiar challenges that render it arduous to treat tumors, such as heterogeneity and the high mutation rate. In the review are presented these and other advantages offered by the oligonucleotide as an emerging class of biotherapeutics for a new era of precision anti-cancer medicine.
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Affiliation(s)
| | - Andrea Pession
- Pediatric Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Patrizia Hrelia
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy;
| | - Roberto Tonelli
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy;
- Correspondence:
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Antisense Oligonucleotides and Small Interfering RNA for the Treatment of Dyslipidemias. J Clin Med 2022; 11:jcm11133884. [PMID: 35807171 PMCID: PMC9267663 DOI: 10.3390/jcm11133884] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/21/2022] [Accepted: 07/01/2022] [Indexed: 12/12/2022] Open
Abstract
The burden of atherosclerotic disease worldwide necessitates implementing the treatment of its risk factors. Among them, hypercholesterolemia has a central role. In addition to conventional small organic compounds and the recently introduced monoclonal antibodies, new technologies are arising such as the antisense oligonucleotides and small interfering RNAs (siRNAs) that operate upstream, blocking the mRNA translation of the proteins specifically involved in lipid metabolism. In this review, we briefly explain the mechanisms of action of these molecules and discuss the difficulties related to their in vivo use as therapeutical agents. We go over the oligonucleotides tested in clinical trials that could potentially revolutionize the care of patients by acting on proteins involved in the lipoprotein metabolism and regulation, namely: angiopoietin-like protein 3 (ANGPTL3); lipoprotein a (Lp(a)); apolipoprotein B (Apo B); apolipoprotein C III (Apo C-III); and proprotein convertase subtilisin–kexin type 9 (PCSK9). Finally, the differences between ASOs and siRNAs, their future possible clinical applications, and the role of Inclisiran, a siRNA direct against PCSK9 to reduce LDL-C, were reviewed in detail.
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Yan J, Wang J, He JC, Zhong Y. Sirtuin 1 in Chronic Kidney Disease and Therapeutic Potential of Targeting Sirtuin 1. Front Endocrinol (Lausanne) 2022; 13:917773. [PMID: 35795148 PMCID: PMC9251114 DOI: 10.3389/fendo.2022.917773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 05/12/2022] [Indexed: 11/13/2022] Open
Abstract
The incidence and prevalence of chronic kidney disease (CKD) continue to increase worldwide remaining as a major public health burden. CKD eventually progresses to end-stage kidney failure and patients with CKD have high morbidity and mortality. Sirtuin 1 (SIRT1), a NAD+-dependent deacetylases, has significant renal protective effects through its regulation of fibrosis, apoptosis, and senescence, oxidative stress, inflammation and aging process. The renal protective effects of Sirt1 have been described in many kidney diseases such as diabetic kidney disease and HIV-related kidney disease. SIRT1 also has protective effects against vascular calcification and therefore could be developed as a therapy for both CKD and CKD complications. In this narrative review, we will give an overview of the recent progress on the role of SIRT1 and its downstream pathways in CKD. We will also discuss potential therapeutic approach by activating SIRT1-related pathway in patients with CKD. The purpose is to hope to provide some insights on the future direction of the research in the field of SIRT1 for CKD.
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Affiliation(s)
- Jiayi Yan
- Division of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jue Wang
- Division of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - John Cijiang He
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Yifei Zhong
- Division of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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31
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Munir MU. Nanomedicine Penetration to Tumor: Challenges, and Advanced Strategies to Tackle This Issue. Cancers (Basel) 2022; 14:cancers14122904. [PMID: 35740570 PMCID: PMC9221319 DOI: 10.3390/cancers14122904] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/06/2022] [Accepted: 06/07/2022] [Indexed: 02/01/2023] Open
Abstract
Nanomedicine has been under investigation for several years to improve the efficiency of chemotherapeutics, having minimal pharmacological effects clinically. Ineffective tumor penetration is mediated by tumor environments, including limited vascular system, rising cancer cells, higher interstitial pressure, and extra-cellular matrix, among other things. Thus far, numerous methods to increase nanomedicine access to tumors have been described, including the manipulation of tumor micro-environments and the improvement of nanomedicine characteristics; however, such outdated approaches still have shortcomings. Multi-functional convertible nanocarriers have recently been developed as an innovative nanomedicine generation with excellent tumor infiltration abilities, such as tumor-penetrating peptide-mediated transcellular transport. The developments and limitations of nanomedicines, as well as expectations for better outcomes of tumor penetration, are discussed in this review.
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Affiliation(s)
- Muhammad Usman Munir
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72388, Aljouf, Saudi Arabia
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32
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Hoang DH, Zhao D, Branciamore S, Maestrini D, Rodriguez IR, Kuo YH, Rockne R, Khaled SK, Zhang B, Nguyen LXT, Marcucci G. MicroRNA networks in FLT3-ITD acute myeloid leukemia. Proc Natl Acad Sci U S A 2022; 119:e2112482119. [PMID: 35412895 PMCID: PMC9169767 DOI: 10.1073/pnas.2112482119] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 03/11/2022] [Indexed: 12/29/2022] Open
Abstract
MiR-126 and miR-155 are key microRNAs (miRNAs) that regulate, respectively, hematopoietic cell quiescence and proliferation. Herein we showed that in acute myeloid leukemia (AML), the biogenesis of these two miRNAs is interconnected through a network of regulatory loops driven by the FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD). In fact, FLT3-ITD induces the expression of miR-155 through a noncanonical mechanism of miRNA biogenesis that implicates cytoplasmic Drosha ribonuclease III (DROSHA). In turn, miR-155 down-regulates SH2-containing inositol phosphatase 1 (SHIP1), thereby increasing phosphor-protein kinase B (AKT) that in turn serine-phosphorylates, stabilizes, and activates Sprouty related EVH1 domain containing 1 (SPRED1). Activated SPRED1 inhibits the RAN/XPO5 complex and blocks the nucleus-to-cytoplasm transport of pre-miR-126, which cannot then complete the last steps of biogenesis. The net result is aberrantly low levels of mature miR-126 that allow quiescent leukemia blasts to be recruited into the cell cycle and proliferate. Thus, miR-126 down-regulation in proliferating AML blasts is downstream of FLT3-ITD–dependent miR-155 expression that initiates a complex circuit of concatenated regulatory feedback (i.e., miR-126/SPRED1, miR-155/human dead-box protein 3 [DDX3X]) and feed-forward (i.e., miR-155/SHIP1/AKT/miR-126) regulatory loops that eventually converge into an output signal for leukemic growth.
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Affiliation(s)
- Dinh Hoa Hoang
- Gehr Family Center for Leukemia Research, City of Hope Medical Center, Hematologic Malignancies Research Institute and Center for Stem Cell Transplantation, Duarte, CA 91010
| | - Dandan Zhao
- Gehr Family Center for Leukemia Research, City of Hope Medical Center, Hematologic Malignancies Research Institute and Center for Stem Cell Transplantation, Duarte, CA 91010
| | - Sergio Branciamore
- Department of Computational and Quantitative Medicine, Division of Mathematical Oncology and Computational Systems Biology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010
| | - Davide Maestrini
- Department of Computational and Quantitative Medicine, Division of Mathematical Oncology and Computational Systems Biology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010
| | - Ivan R. Rodriguez
- Gehr Family Center for Leukemia Research, City of Hope Medical Center, Hematologic Malignancies Research Institute and Center for Stem Cell Transplantation, Duarte, CA 91010
| | - Ya-Huei Kuo
- Gehr Family Center for Leukemia Research, City of Hope Medical Center, Hematologic Malignancies Research Institute and Center for Stem Cell Transplantation, Duarte, CA 91010
| | - Russell Rockne
- Department of Computational and Quantitative Medicine, Division of Mathematical Oncology and Computational Systems Biology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010
| | - Samer K. Khaled
- Gehr Family Center for Leukemia Research, City of Hope Medical Center, Hematologic Malignancies Research Institute and Center for Stem Cell Transplantation, Duarte, CA 91010
| | - Bin Zhang
- Gehr Family Center for Leukemia Research, City of Hope Medical Center, Hematologic Malignancies Research Institute and Center for Stem Cell Transplantation, Duarte, CA 91010
| | - Le Xuan Truong Nguyen
- Gehr Family Center for Leukemia Research, City of Hope Medical Center, Hematologic Malignancies Research Institute and Center for Stem Cell Transplantation, Duarte, CA 91010
| | - Guido Marcucci
- Gehr Family Center for Leukemia Research, City of Hope Medical Center, Hematologic Malignancies Research Institute and Center for Stem Cell Transplantation, Duarte, CA 91010
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA 91010
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Adamus T, Hung CY, Yu C, Kang E, Hammad M, Flores L, Nechaev S, Zhang Q, Gonzaga JM, Muthaiyah K, Swiderski P, Aboody KS, Kortylewski M. Glioma-targeted delivery of exosome-encapsulated antisense oligonucleotides using neural stem cells. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 27:611-620. [PMID: 35036069 PMCID: PMC8752899 DOI: 10.1016/j.omtn.2021.12.029] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 12/17/2021] [Indexed: 12/20/2022]
Abstract
Tropism of neural stem cells (NSCs) to hypoxic tumor areas provides an opportunity for the drug delivery. Here, we demonstrate that NSCs effectively transport antisense oligonucleotides (ASOs) targeting oncogenic and tolerogenic signal transducer and activator of transcription 3 (STAT3) protein into glioma microenvironment. To enable spontaneous, scavenger receptor-mediated endocytosis by NSCs, we used previously described CpG-STAT3ASO conjugates. Following uptake and endosomal escape, CpG-STAT3ASO colocalized with CD63+ vesicles and later with CD63+CD81+ exosomes. Over 3 days, NSCs secreted exosomes loaded up to 80% with CpG-STAT3ASO. Compared to native NSC exosomes, the CpG-STAT3ASO-loaded exosomes potently stimulated immune activity of human dendritic cells or mouse macrophages, inducing nuclear factor κB (NF-κB) signaling and interleukin-12 (IL-12) production. Using orthotopic GL261 tumors, we confirmed that NSC-mediated delivery improved oligonucleotide transfer from a distant injection site into the glioma microenvironment versus naked oligonucleotides. Correspondingly, the NSC-delivered CpG-STAT3ASO enhanced activation of glioma-associated microglia. Finally, we demonstrated that NSC-mediated CpG-STAT3ASO delivery resulted in enhanced antitumor effects against GL261 glioma in mice. Peritumoral injections of 5 × 105 NSCs loaded ex vivo with CpG-STAT3ASO inhibited subcutaneous tumor growth more effectively than the equivalent amount of oligonucleotide alone. Based on these results, we anticipate that NSCs and NSC-derived exosomes will provide a clinically relevant strategy to improve delivery and safety of oligonucleotide therapeutics for glioma treatment.
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Affiliation(s)
- Tomasz Adamus
- Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Chia-Yang Hung
- Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Chunsong Yu
- Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Elaine Kang
- Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Mohamed Hammad
- Department of Developmental and Stem Cell Biology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Linda Flores
- Department of Developmental and Stem Cell Biology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Sergey Nechaev
- Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Qifang Zhang
- Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Joanna Marie Gonzaga
- Department of Developmental and Stem Cell Biology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Kokilah Muthaiyah
- DNA/RNA Synthesis Laboratory, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Piotr Swiderski
- DNA/RNA Synthesis Laboratory, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Karen S Aboody
- Department of Developmental and Stem Cell Biology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Marcin Kortylewski
- Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
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Qian H, Zhou T, Fu Y, Guo M, Yang W, Zhang D, Fang W, Yao M, Shi H, Chai C, Cheng W, Ding S, Chen T. Self-assembled tetrahedral framework nucleic acid mediates tumor-associated macrophage reprogramming and restores antitumor immunity. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 27:763-773. [PMID: 35116188 PMCID: PMC8783116 DOI: 10.1016/j.omtn.2021.12.036] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 12/31/2021] [Indexed: 12/20/2022]
Abstract
There is increasing interest in depleting or repolarizing tumor-associated macrophages (TAMs) to generate a proinflammatory effect. However, TAMs usually display an immunosuppressive M2-like phenotype in the tumor microenvironment. Apparently, developing a macrophage-targeting delivery system with immunomodulatory agents is urgent. In this study, an efficient siRNA and CpG ODNs delivery system (CpG-siRNA-tFNA) was prepared with nucleic acid stepwise self-assembled. The tFNA composed of CpG ODNs and siRNA showed a higher stability and an enhanced cellular uptake efficiency. Moreover, the CpG-siRNA-tFNA effectively reprogrammed TAMs toward M1 phenotype polarization with increased proinflammatory cytokine secretion and NF-κB signal pathway activation, which triggers dramatic antitumor immune responses. Additionally, the CpG-siRNA-tFNA exhibited superior antitumor efficacy in a breast cancer xenograft mouse model without obvious systemic side effects. Taken together, CpG-siRNA-tFNA displayed greatly antitumor effect by facilitating TAM polarization toward M1 phenotypes in favor of immunotherapy. Hence, we have developed an efficient therapeutic strategy with immunomodulatory agents for clinical applications.
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Affiliation(s)
- Husun Qian
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Ting Zhou
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yixin Fu
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Minkang Guo
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wu Yang
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Dian Zhang
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Wenli Fang
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Mengli Yao
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - He Shi
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Chengsen Chai
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Wei Cheng
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Shijia Ding
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Tingmei Chen
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
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Tarab-Ravski D, Stotsky-Oterin L, Peer D. Delivery strategies of RNA therapeutics to leukocytes. J Control Release 2022; 342:362-371. [PMID: 35041904 DOI: 10.1016/j.jconrel.2022.01.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/31/2021] [Accepted: 01/10/2022] [Indexed: 12/27/2022]
Abstract
Harnessing RNA-based therapeutics for cancer, inflammation, and viral diseases is hindered by poor delivery of therapeutic RNA molecules. Targeting leukocytes to treat these conditions holds great promise, as they are key participants in their initiation, drug response, and treatment. The various extra- and intra-cellular obstacles that impediment the clinical implementation of therapeutic RNA can be overcome by utilizing drug delivery systems. However, delivery of therapeutic RNA to leukocytes poses an even greater challenge as these cells are difficult to reach and transfect upon systemic administration. This review briefly describes the existing successful delivery strategies that efficiently target leukocytes in vivo and discuss their potential clinical applicability.
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Affiliation(s)
- Dana Tarab-Ravski
- Laboratory of Precision NanoMedicine, Tel Aviv University, Tel Aviv, Israel; Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Department of Materials Sciences & Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel
| | - Lior Stotsky-Oterin
- Laboratory of Precision NanoMedicine, Tel Aviv University, Tel Aviv, Israel; Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Department of Materials Sciences & Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel; Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel
| | - Dan Peer
- Laboratory of Precision NanoMedicine, Tel Aviv University, Tel Aviv, Israel; Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Department of Materials Sciences & Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel; Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel.
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36
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Activation of Innate Immunity by Therapeutic Nucleic Acids. Int J Mol Sci 2021; 22:ijms222413360. [PMID: 34948156 PMCID: PMC8704878 DOI: 10.3390/ijms222413360] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/07/2021] [Accepted: 12/09/2021] [Indexed: 12/24/2022] Open
Abstract
Nucleic acid-based therapeutics have gained increased attention during recent decades because of their wide range of application prospects. Immunostimulatory nucleic acids represent a promising class of potential drugs for the treatment of tumoral and viral diseases due to their low toxicity and stimulation of the body’s own innate immunity by acting on the natural mechanisms of its activation. The repertoire of nucleic acids that directly interact with the components of the immune system is expanding with the improvement of both analytical methods and methods for the synthesis of nucleic acids and their derivatives. Despite the obvious progress in this area, the problem of delivering therapeutic acids to target cells as well as the unresolved issue of achieving a specific therapeutic effect based on activating the mechanism of interferon and anti-inflammatory cytokine synthesis. Minimizing the undesirable effects of excessive secretion of inflammatory cytokines remains an unsolved task. This review examines recent data on the types of immunostimulatory nucleic acids, the receptors interacting with them, and the mechanisms of immunity activation under the action of these molecules. Finally, data on immunostimulatory nucleic acids in ongoing and completed clinical trials will be summarized.
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Antisense Oligonucleotide-Based Therapy of Viral Infections. Pharmaceutics 2021; 13:pharmaceutics13122015. [PMID: 34959297 PMCID: PMC8707165 DOI: 10.3390/pharmaceutics13122015] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/23/2021] [Accepted: 11/23/2021] [Indexed: 02/07/2023] Open
Abstract
Nucleic acid-based therapeutics have demonstrated their efficacy in the treatment of various diseases and vaccine development. Antisense oligonucleotide (ASO) technology exploits a single-strand short oligonucleotide to either cause target RNA degradation or sterically block the binding of cellular factors or machineries to the target RNA. Chemical modification or bioconjugation of ASOs can enhance both its pharmacokinetic and pharmacodynamic performance, and it enables customization for a specific clinical purpose. ASO-based therapies have been used for treatment of genetic disorders, cancer and viral infections. In particular, ASOs can be rapidly developed for newly emerging virus and their reemerging variants. This review discusses ASO modifications and delivery options as well as the design of antiviral ASOs. A better understanding of the viral life cycle and virus-host interactions as well as advances in oligonucleotide technology will benefit the development of ASO-based antiviral therapies.
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Wei J, Gilboa E, Calin GA, Heimberger AB. Immune Modulatory Short Noncoding RNAs Targeting the Glioblastoma Microenvironment. Front Oncol 2021; 11:682129. [PMID: 34532286 PMCID: PMC8438301 DOI: 10.3389/fonc.2021.682129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 08/11/2021] [Indexed: 12/22/2022] Open
Abstract
Glioblastomas are heterogeneous and have a poor prognosis. Glioblastoma cells interact with their neighbors to form a tumor-permissive and immunosuppressive microenvironment. Short noncoding RNAs are relevant mediators of the dynamic crosstalk among cancer, stromal, and immune cells in establishing the glioblastoma microenvironment. In addition to the ease of combinatorial strategies that are capable of multimodal modulation for both reversing immune suppression and enhancing antitumor immunity, their small size provides an opportunity to overcome the limitations of blood-brain-barrier (BBB) permeability. To enhance glioblastoma delivery, these RNAs have been conjugated with various molecules or packed within delivery vehicles for enhanced tissue-specific delivery and increased payload. Here, we focus on the role of RNA therapeutics by appraising which types of nucleotides are most effective in immune modulation, lead therapeutic candidates, and clarify how to optimize delivery of the therapeutic RNAs and their conjugates specifically to the glioblastoma microenvironment.
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Affiliation(s)
- Jun Wei
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Eli Gilboa
- Department of Microbiology & Immunology, Dodson Interdisciplinary Immunotherapy Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, United States
| | - George A Calin
- Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Amy B Heimberger
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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Ngamcherdtrakul W, Reda M, Nelson MA, Wang R, Zaidan HY, Bejan DS, Hoang NH, Lane RS, Luoh SW, Leachman SA, Mills GB, Gray JW, Lund AW, Yantasee W. In Situ Tumor Vaccination with Nanoparticle Co-Delivering CpG and STAT3 siRNA to Effectively Induce Whole-Body Antitumor Immune Response. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2021; 33:e2100628. [PMID: 34118167 PMCID: PMC8424660 DOI: 10.1002/adma.202100628] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/26/2021] [Indexed: 05/03/2023]
Abstract
The success of immunotherapy with immune checkpoint inhibitors (ICIs) in a subset of individuals has been very exciting. However, in many cancers, responses to current ICIs are modest and are seen only in a small subsets of patients. Herein, a widely applicable approach that increases the benefit of ICIs is reported. Intratumoral administration of augmenting immune response and inhibiting suppressive environment of tumors-AIRISE-02 nanotherapeutic that co-delivers CpG and STAT3 siRNA-results in not only regression of the injected tumor, but also tumors at distant sites in multiple tumor model systems. In particular, three doses of AIRISE-02 in combination with systemic ICIs completely cure both treated and untreated aggressive melanoma tumors in 63% of mice, while ICIs alone do not cure any mice. A long-term memory immune effect is also reported. AIRISE-02 is effective in breast and colon tumor models as well. Lastly, AIRISE-02 is well tolerated in mice and nonhuman primates. This approach combines multiple therapeutic agents into a single nanoconstruct to create whole-body immune responses across multiple cancer types. Being a local therapeutic, AIRISE-02 circumvents regulatory challenges of systemic nanoparticle delivery, facilitating rapid translation to the clinic. AIRISE-02 is under investigational new drug (IND)-enabling studies, and clinical trials will soon follow.
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Affiliation(s)
| | - Moataz Reda
- PDX Pharmaceuticals, Inc., Portland, OR, 97239, USA
| | | | - Ruijie Wang
- PDX Pharmaceuticals, Inc., Portland, OR, 97239, USA
| | | | | | - Ngoc Ha Hoang
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Ryan S Lane
- Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Shiuh-Wen Luoh
- VA Portland Health Care System, Portland, OR, 97239, USA
- Knight Cancer Institute, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Sancy A Leachman
- Knight Cancer Institute, Oregon Health and Science University, Portland, OR, 97239, USA
- Department of Dermatology, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Gordon B Mills
- Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, 97239, USA
- Knight Cancer Institute, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Joe W Gray
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, 97239, USA
- Knight Cancer Institute, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Amanda W Lund
- Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Wassana Yantasee
- PDX Pharmaceuticals, Inc., Portland, OR, 97239, USA
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, 97239, USA
- Knight Cancer Institute, Oregon Health and Science University, Portland, OR, 97239, USA
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40
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Abdelaal AM, Kasinski AL. Ligand-mediated delivery of RNAi-based therapeutics for the treatment of oncological diseases. NAR Cancer 2021; 3:zcab030. [PMID: 34316717 PMCID: PMC8291076 DOI: 10.1093/narcan/zcab030] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 06/21/2021] [Accepted: 06/28/2021] [Indexed: 12/19/2022] Open
Abstract
RNA interference (RNAi)-based therapeutics (miRNAs, siRNAs) have great potential for treating various human diseases through their ability to downregulate proteins associated with disease progression. However, the development of RNAi-based therapeutics is limited by lack of safe and specific delivery strategies. A great effort has been made to overcome some of these challenges resulting in development of N-acetylgalactosamine (GalNAc) ligands that are being used for delivery of siRNAs for the treatment of diseases that affect the liver. The successes achieved using GalNAc-siRNAs have paved the way for developing RNAi-based delivery strategies that can target extrahepatic diseases including cancer. This includes targeting survival signals directly in the cancer cells and indirectly through targeting cancer-associated immunosuppressive cells. To achieve targeting specificity, RNAi molecules are being directly conjugated to a targeting ligand or being packaged into a delivery vehicle engineered to overexpress a targeting ligand on its surface. In both cases, the ligand binds to a cell surface receptor that is highly upregulated by the target cells, while not expressed, or expressed at low levels on normal cells. In this review, we summarize the most recent RNAi delivery strategies, including extracellular vesicles, that use a ligand-mediated approach for targeting various oncological diseases.
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Affiliation(s)
- Ahmed M Abdelaal
- Department of Biological Sciences, Purdue University, West Lafayette, IN 47906, USA
| | - Andrea L Kasinski
- Department of Biological Sciences, Purdue University, West Lafayette, IN 47906, USA
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41
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Kadekar S, Nawale GN, Rangasami VK, Le Joncour V, Laakkonen P, Hilborn J, Varghese OP, Oommen OP. Redox responsive Pluronic micelle mediated delivery of functional siRNA: a modular nano-assembly for targeted delivery. Biomater Sci 2021; 9:3939-3944. [PMID: 34002185 DOI: 10.1039/d1bm00428j] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
There is an unmet need to develop strategies that allow site-specific delivery of short interfering RNA (siRNA) without any associated toxicity. To address this challenge, we have developed a novel siRNA delivery platform using chemically modified pluronic F108 as an amphiphilic polymer with a releasable bioactive disulfide functionality. The micelles exhibited thermoresponsive properties and showed a hydrodynamic size of ∼291 nm in DLS and ∼200-250 nm in SEM at 37 °C. The grafting of free disulfide pyridyl groups enhanced the transfection efficiency and was successfully demonstrated in human colon carcinoma (HCT116; 88%) and glioma cell lines (U87; 90%), non-cancerous human dermal fibroblast (HDF; 90%) cells as well as in mouse embryonic stem (mES; 54%) cells. To demonstrate the versatility of our modular nanocarrier design, we conjugated the MDGI receptor targeting COOP peptide on the particle surface that allowed the targeted delivery of the cargo molecules to human patent-derived primary BT-13 gliospheres. Transfection experiments with this design resulted in ∼65% silencing of STAT3 mRNA in BT-13 gliospheres, while only ∼20% of gene silencing was observed in the absence of the peptide. We believe that our delivery method solves current problems related to the targeted delivery of RNAi drugs for potential in vivo applications.
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Affiliation(s)
- Sandeep Kadekar
- Translational Chemical Biology Laboratory, Polymer Chemistry Division, Department of Chemistry - Ångström Laboratory, Uppsala University, 751 21, Uppsala, Sweden.
| | - Ganesh N Nawale
- Translational Chemical Biology Laboratory, Polymer Chemistry Division, Department of Chemistry - Ångström Laboratory, Uppsala University, 751 21, Uppsala, Sweden.
| | - Vignesh K Rangasami
- Translational Chemical Biology Laboratory, Polymer Chemistry Division, Department of Chemistry - Ångström Laboratory, Uppsala University, 751 21, Uppsala, Sweden. and Bioengineering and Nanomedicine Group, Faculty of Medicine and Health Technologies, Tampere University, 33720, Tampere, Finland.
| | - Vadim Le Joncour
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Pirjo Laakkonen
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Jöns Hilborn
- Polymer Chemistry, Department of Chemistry - Ångström Laboratory, Uppsala University, 751 21, Uppsala, Sweden
| | - Oommen P Varghese
- Translational Chemical Biology Laboratory, Polymer Chemistry Division, Department of Chemistry - Ångström Laboratory, Uppsala University, 751 21, Uppsala, Sweden.
| | - Oommen P Oommen
- Bioengineering and Nanomedicine Group, Faculty of Medicine and Health Technologies, Tampere University, 33720, Tampere, Finland.
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42
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Subhan MA, Attia SA, Torchilin VP. Advances in siRNA delivery strategies for the treatment of MDR cancer. Life Sci 2021; 274:119337. [PMID: 33713664 DOI: 10.1016/j.lfs.2021.119337] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/02/2021] [Accepted: 03/04/2021] [Indexed: 12/18/2022]
Abstract
RNA interference (RNAi) represents a promising therapeutic method that uses siRNA for cancer treatment. Although the RNAi technique has been increasingly used for clinical trials, systemic siRNA delivery into targeted cells is still challenging. The barriers impeding siRNA therapeutics delivery and impacting the treatment outcome must overcome with negligible systemic toxicity for a desirable and successful delivery of siRNA to MDR cancer cells. Nano delivery strategies have been investigated for nanocarrier functionalization, cancer immunotherapy and cancer targeting. Lipid nanoparticles (LNPs), dynamic polyconjugates (DPC™), GalNAc-siRNA conjugates, exosome and RBC systems have shown potential for efficient delivery of siRNA to cancer cells. Delivery of siRNA to tumor cells, immune cells to regulate T cell functions for immunotherapy are promising approaches.
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Affiliation(s)
- Md Abdus Subhan
- Department of Chemistry, ShahJalal University of Science and Technology, Sylhet 3114, Bangladesh.
| | - Sara Aly Attia
- CPBN, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
| | - Vladimir P Torchilin
- CPBN, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA; Department of Oncology, Radiotherapy and Plastic Surgery I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.
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43
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Manuel ER, Blache CA, Ellenhorn JDI, Diamond DJ. Survivin the battle against immunosuppression. Oncoimmunology 2021; 1:240-241. [PMID: 22720256 PMCID: PMC3377007 DOI: 10.4161/onci.1.2.18180] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Improving on the limited success of cancer immunotherapy requires new approaches to inhibit immunosuppressive pathways initiated by tumor cells to "escape" protective immunity. One unique approach utilizes Salmonella for systemic delivery of inhibitory RNA, targeting the immunosuppressive molecule Stat3, and a Survivin vaccine to suppress growth of aggressive murine tumors.
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Affiliation(s)
- Edwin R Manuel
- Division of Translational Vaccine Research; City of Hope; Duarte, CA USA
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44
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Aftabizadeh M, Li YJ, Zhao Q, Zhang C, Ambaye N, Song J, Nagao T, Lahtz C, Fakih M, Ann DK, Yu H, Herrmann A. Potent antitumor effects of cell-penetrating peptides targeting STAT3 axis. JCI Insight 2021; 6:136176. [PMID: 33491667 PMCID: PMC7934871 DOI: 10.1172/jci.insight.136176] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 12/09/2020] [Indexed: 01/05/2023] Open
Abstract
To date, there are no inhibitors that directly and specifically target activated STAT3 and c-Myc in the clinic. Although peptide-based inhibitors can selectively block activated targets, their clinical usage is limited because of low cell penetration and/or serum stability. Here, we generated cell-penetrating acetylated (acet.) STAT3, c-Myc, and Gp130 targeting peptides by attaching phosphorothioated (PS) polymer backbone to peptides. The cell-penetrating peptides efficiently penetrated cells and inhibited activation of the intended targets and their downstream genes. Locally or systemically treating tumor-bearing mice with PS-acet.-STAT3 peptide at low concentrations effectively blocked STAT3 in vivo, resulting in significant antitumor effects in 2 human xenograft models. Moreover, PS-acet.-STAT3 peptide penetrated and activated splenic CD8+ T cells in vitro. Treating immune-competent mice bearing mouse melanoma with PS-acet.-STAT3 peptide inhibited STAT3 in tumor-infiltrating T cells, downregulating tumor-infiltrating CD4+ T regulatory cells while activating CD8+ T effector cells. Similarly, systemic injections of the cell-penetrating c-Myc and Gp130 peptides prevented pancreatic tumor growth and induced antitumor immune responses. Taken together, we have developed therapeutic peptides that effectively and specifically block challenging cancer targets, resulting in antitumor effects through both direct tumor cell killing and indirectly through antitumor immune responses.
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Affiliation(s)
| | | | - Qianqian Zhao
- Department of Immuno-Oncology and
- Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, California, USA
| | | | | | | | | | - Christoph Lahtz
- Department of Immuno-Oncology and
- Sorrento Therapeutics, San Diego, California, USA
| | - Marwan Fakih
- Department of Medical Oncology and Therapeutics and
| | - David K. Ann
- Diabetes & Metabolism Research Institute, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, California, USA
| | - Hua Yu
- Department of Immuno-Oncology and
| | - Andreas Herrmann
- Department of Immuno-Oncology and
- Sorrento Therapeutics, San Diego, California, USA
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45
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Ou A, Ott M, Fang D, Heimberger AB. The Role and Therapeutic Targeting of JAK/STAT Signaling in Glioblastoma. Cancers (Basel) 2021; 13:437. [PMID: 33498872 PMCID: PMC7865703 DOI: 10.3390/cancers13030437] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 12/17/2022] Open
Abstract
Glioblastoma remains one of the deadliest and treatment-refractory human malignancies in large part due to its diffusely infiltrative nature, molecular heterogeneity, and capacity for immune escape. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway contributes substantively to a wide variety of protumorigenic functions, including proliferation, anti-apoptosis, angiogenesis, stem cell maintenance, and immune suppression. We review the current state of knowledge regarding the biological role of JAK/STAT signaling in glioblastoma, therapeutic strategies, and future directions for the field.
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Affiliation(s)
- Alexander Ou
- Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA;
| | - Martina Ott
- Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; (M.O.); (D.F.)
| | - Dexing Fang
- Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; (M.O.); (D.F.)
| | - Amy B. Heimberger
- Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; (M.O.); (D.F.)
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46
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Kubo T, Nishimura Y, Sato Y, Yanagihara K, Seyama T. Sixteen Different Types of Lipid-Conjugated siRNAs Containing Saturated and Unsaturated Fatty Acids and Exhibiting Enhanced RNAi Potency. ACS Chem Biol 2021; 16:150-164. [PMID: 33346648 DOI: 10.1021/acschembio.0c00847] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
SiRNAs are strong gene-silencing agents that function in a target sequence-specific manner. Although siRNAs might one day be used in therapy for intractable diseases such as cancers, a number of problems with siRNAs must first be overcome. In this study, we developed 16 different types of lipid-conjugated siRNAs (lipid-siRNAs) that could effectively inhibit the expression of target genes. We determined the hybridization properties, cellular uptake efficacies, and RNAi potencies of the resulting lipid-siRNAs. The lipid-siRNAs exhibited a mild interaction with Lipofectamine RNAiMAX (LFRNAi) as a transfection reagent, and a high membrane permeability was observed in all lipid-siRNAs-LFRNAi complexes; the conjugate siRNAs composed of 16-18 carbon chains as fatty acids showed an especially good cellular uptake efficacy. The in vitro RNAi effect of lipid-siRNAs targeted to a β-catenin gene exhibited a strong RNAi potency compared with those of unmodified siRNAs. In particular, the conjugate siRNAs composed of 16-18 carbon chains as fatty acids showed excellent RNAi potencies with prolonged effectivities. Interestingly, the RNAi potencies of conjugate siRNAs containing 18 carbon chains with a trans-form (elaidic acid and trans-vaccenic acid) were inferior to those of the carbon chains with a cis-form (oleic acid and cis-vaccenic acid). These lipid-siRNAs can solve the many problems hindering the clinical application of siRNAs.
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Affiliation(s)
| | | | | | - Kazuyoshi Yanagihara
- Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba 277-8577, Japan
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Abstract
Small interfering RNA (siRNA) is a clinically approved therapeutic modality, which has attracted widespread attention not only from basic research but also from pharmaceutical industry. As siRNA can theoretically modulate any disease-related gene's expression, plenty of siRNA therapeutic pipelines have been established by tens of biotechnology companies. The drug performance of siRNA heavily depends on the sequence, the chemical modification, and the delivery of siRNA. Here, we describe the rational design protocol of siRNA, and provide some modification patterns that can enhance siRNA's stability and reduce its off-target effect. Also, the delivery method based on N-acetylgalactosamine (GalNAc)-siRNA conjugate that is widely employed to develop therapeutic regimens for liver-related diseases is also recapitulated.
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Affiliation(s)
- Mei Lu
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, and Institute of Engineering Medicine, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing, China
| | - Mengjie Zhang
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, and Institute of Engineering Medicine, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing, China
| | - Bo Hu
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, and Institute of Engineering Medicine, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing, China
| | - Yuanyu Huang
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, and Institute of Engineering Medicine, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing, China.
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48
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Ning Y, Hu J, Lu F. Aptamers used for biosensors and targeted therapy. Biomed Pharmacother 2020; 132:110902. [PMID: 33096353 PMCID: PMC7574901 DOI: 10.1016/j.biopha.2020.110902] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 10/12/2020] [Accepted: 10/14/2020] [Indexed: 01/07/2023] Open
Abstract
Aptamers are single-stranded nucleic acid sequences that can bind to target molecules with high selectivity and affinity. Most aptamers are screened in vitro by a combinatorial biology technique called systematic evolution of ligands by exponential enrichment (SELEX). Since aptamers were discovered in the 1990s, they have attracted considerable attention and have been widely used in many fields owing to their unique advantages. In this review, we present an overview of the advancements made in aptamers used for biosensors and targeted therapy. For the former, we will discuss multiple aptamer-based biosensors with different principles detected by various signaling methods. For the latter, we will focus on aptamer-based targeted therapy using aptamers as both biotechnological tools for targeted drug delivery and as targeted therapeutic agents. Finally, challenges and new perspectives associated with these two regions were further discussed. We hope that this review will help researchers interested in aptamer-related biosensing and targeted therapy research.
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Affiliation(s)
- Yi Ning
- Department of Microbiology, The Medicine School of Hunan University of Chinese Medicine, Changsha, Hunan, 410208, PR China
| | - Jue Hu
- Department of Microbiology, The Medicine School of Hunan University of Chinese Medicine, Changsha, Hunan, 410208, PR China
| | - Fangguo Lu
- Department of Microbiology, The Medicine School of Hunan University of Chinese Medicine, Changsha, Hunan, 410208, PR China.
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Targeted In Vivo Delivery of NF-κB Decoy Inhibitor Augments Sensitivity of B Cell Lymphoma to Therapy. Mol Ther 2020; 29:1214-1225. [PMID: 33248246 DOI: 10.1016/j.ymthe.2020.11.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 10/17/2020] [Accepted: 11/18/2020] [Indexed: 12/16/2022] Open
Abstract
Despite recent advances, non-Hodgkin's B cell lymphoma patients often relapse or remain refractory to therapy. Therapeutic resistance is often associated with survival signaling via nuclear factor κB (NF-κB) transcription factor, an attractive but undruggable molecular target. In this study, we describe a bipartite inhibitor comprising a NF-κB-specific decoy DNA tethered to a CpG oligodeoxynucleotide (ODN) targeting Toll-like receptor-9-expressing B cell lymphoma cells. The Bc-NFκBdODN showed efficient uptake by human diffuse large B cell (U2932, OCI-Ly3), Burkitt (RaJi), and mantle cell (Jeko1) lymphomas, respectively. We confirmed that Bc-NFκBdODN inhibited NF-κB nuclear translocation and DNA binding, resulting in CCND2 and MYC downregulation. Bc-NFκBdODN enhanced radiosensitivity of lymphoma cells in vitro. In xenotransplanted human lymphoma, local injections of Bc-NFκBdODN reduced NF-κB activity in whole tumors. When combined with a local 3-Gy dose of radiation, Bc-NFκBdODN effectively arrested OCI-Ly3 lymphoma progression. In immunocompetent mice, intratumoral injections of Bc-NFκBdODN suppressed growth of directly treated and distant A20 lymphomas, as a result of systemic CD8 T cell-dependent immune responses. Finally, systemic administration of Bc-NFκBdODN to mice bearing disseminated A20 lymphoma induced complete regression and extended survival of most of the treated mice. Our results underscore clinical relevance of this strategy as monotherapy and in support of radiation therapy to benefit patients with resistant or relapsed B cell lymphoma.
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Charbe NB, Amnerkar ND, Ramesh B, Tambuwala MM, Bakshi HA, Aljabali AA, Khadse SC, Satheeshkumar R, Satija S, Metha M, Chellappan DK, Shrivastava G, Gupta G, Negi P, Dua K, Zacconi FC. Small interfering RNA for cancer treatment: overcoming hurdles in delivery. Acta Pharm Sin B 2020; 10:2075-2109. [PMID: 33304780 PMCID: PMC7714980 DOI: 10.1016/j.apsb.2020.10.005] [Citation(s) in RCA: 131] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/24/2020] [Accepted: 10/08/2020] [Indexed: 12/11/2022] Open
Abstract
In many ways, cancer cells are different from healthy cells. A lot of tactical nano-based drug delivery systems are based on the difference between cancer and healthy cells. Currently, nanotechnology-based delivery systems are the most promising tool to deliver DNA-based products to cancer cells. This review aims to highlight the latest development in the lipids and polymeric nanocarrier for siRNA delivery to the cancer cells. It also provides the necessary information about siRNA development and its mechanism of action. Overall, this review gives us a clear picture of lipid and polymer-based drug delivery systems, which in the future could form the base to translate the basic siRNA biology into siRNA-based cancer therapies.
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Key Words
- 1,3-propanediol, PEG-b-PDMAEMA-b-Ppy
- 2-propylacrylicacid, PAH-b-PDMAPMA-b-PAH
- APOB, apolipoprotein B
- AQP-5, aquaporin-5
- AZEMA, azidoethyl methacrylate
- Atufect01, β-l-arginyl-2,3-l-diaminopropionicacid-N-palmityl-N-oleyl-amide trihydrochloride
- AuNPs, gold nanoparticles
- B-PEI, branched polyethlenimine
- BMA, butyl methacrylate
- CFTR, cystic fibrosis transmembrane conductance regulator gene
- CHEMS, cholesteryl hemisuccinate
- CHOL, cholesterol
- CMC, critical micelles concentration
- Cancer
- DC-Chol, 3β-[N-(N′,N′-dimethylaminoethane)carbamoyl]cholesterol
- DMAEMA, 2-dimethylaminoethyl methacrylate
- DNA, deoxyribonucleic acid
- DOPC, dioleylphosphatidyl choline
- DOPE, dioleylphosphatidyl ethanolamine
- DOTAP, N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate
- DOTMA, N-[1-(2,3-dioleyloxy)propy]-N,N,N-trimethylammoniumchloride
- DOX, doxorubicin
- DSGLA, N,N-dis-tearyl-N-methyl-N-2[N′-(N2-guanidino-l-lysinyl)] aminoethylammonium chloride
- DSPC, 1,2-distearoyl-sn-glycero-3-phosphocholine
- DSPE, 1,2-distearoyl-sn-glycero-3-phosphorylethanolamine
- DSPE-MPEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (ammonium salt)
- DSPE-PEG-Mal: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)-2000] (mmmonium salt), EPR
- Liposomes
- Micelles
- N-acetylgalactosamine, HIF-1α
- Nanomedicine
- PE-PCL-b-PNVCL, pentaerythritol polycaprolactone-block-poly(N-vinylcaprolactam)
- PLA, poly-l-arginine
- PLGA, poly lactic-co-glycolic acid
- PLK-1, polo-like kinase 1
- PLL, poly-l-lysine
- PPES-b-PEO-b-PPES, poly(4-(phenylethynyl)styrene)-block-PEO-block-poly(4-(phenylethynyl)styrene)
- PTX, paclitaxel
- PiRNA, piwi-interacting RNA
- Polymer
- RES, reticuloendothelial system
- RGD, Arg-Gly-Asp peptide
- RISC, RNA-induced silencing complex
- RNA, ribonucleic acid
- RNAi, RNA interference
- RNAse III, ribonuclease III enzyme
- SEM, scanning electron microscope
- SNALP, stable nucleic acid-lipid particles
- SiRNA, short interfering rNA
- Small interfering RNA (siRNA)
- S–Au, thio‒gold
- TCC, transitional cell carcinoma
- TEM, transmission electron microscopy
- Tf, transferrin
- Trka, tropomyosin receptor kinase A
- USPIO, ultra-small superparamagnetic iron oxide nanoparticles
- UV, ultraviolet
- VEGF, vascular endothelial growth factor
- ZEBOV, Zaire ebola virus
- enhanced permeability and retention, Galnac
- hypoxia-inducible factor-1α, KSP
- kinesin spindle protein, LDI
- lipid-protamine-DNA/hyaluronic acid, MDR
- lysine ethyl ester diisocyanate, LPD/LPH
- messenger RNA, MTX
- methotrexate, NIR
- methoxy polyethylene glycol-polycaprolactone, mRNA
- methoxypoly(ethylene glycol), MPEG-PCL
- micro RNA, MPEG
- multiple drug resistance, MiRNA
- nanoparticle, NRP-1
- near-infrared, NP
- neuropilin-1, PAA
- poly(N,N-dimethylacrylamide), PDO
- poly(N-isopropyl acrylamide), pentaerythritol polycaprolactone-block-poly(N-isopropylacrylamide)
- poly(acrylhydrazine)-block-poly(3-dimethylaminopropyl methacrylamide)-block-poly(acrylhydrazine), PCL
- poly(ethylene glycol)-block-poly(2-dimethylaminoethyl methacrylate)-block poly(pyrenylmethyl methacrylate), PEG-b-PLL
- poly(ethylene glycol)-block-poly(l-lysine), PEI
- poly(ethylene oxide)-block-poly(2-(diethylamino)ethyl methacrylate)-stat-poly(methoxyethyl methacrylate), PEO-b-PCL
- poly(ethylene oxide)-block-poly(Ε-caprolactone), PE-PCL-b-PNIPAM
- poly(Ε-caprolactone), PCL-PEG
- poly(Ε-caprolactone)-polyethyleneglycol-poly(l-histidine), PCL-PEI
- polycaprolactone-polyethyleneglycol, PCL-PEG-PHIS
- polycaprolactone-polyethylenimine, PDMA
- polyethylenimine, PEO-b-P(DEA-Stat-MEMA
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Affiliation(s)
- Nitin Bharat Charbe
- Departamento de Quimica Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile
- Sri Adichunchunagiri College of Pharmacy, Sri Adichunchunagiri University, BG Nagar, Karnataka 571418, India
| | - Nikhil D. Amnerkar
- Adv V. R. Manohar Institute of Diploma in Pharmacy, Nagpur, Maharashtra 441110, India
| | - B. Ramesh
- Sri Adichunchunagiri College of Pharmacy, Sri Adichunchunagiri University, BG Nagar, Karnataka 571418, India
| | - Murtaza M. Tambuwala
- School of Pharmacy and Pharmaceutical Science, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
| | - Hamid A. Bakshi
- School of Pharmacy and Pharmaceutical Science, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
| | - Alaa A.A. Aljabali
- Faculty of Pharmacy, Department of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Irbid 21163, Jordan
| | - Saurabh C. Khadse
- Department of Pharmaceutical Chemistry, R.C. Patel Institute of Pharmaceutical Education and Research, Dist. Dhule, Maharashtra 425 405, India
| | - Rajendran Satheeshkumar
- Departamento de Quimica Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile
| | - Saurabh Satija
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411 Punjab, India
| | - Meenu Metha
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411 Punjab, India
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Garima Shrivastava
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Delhi, New Delhi 110016, India
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Jaipur 302017, India
| | - Poonam Negi
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Solan 173229, India
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Solan 173229, India
- Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI) and School of Biomedical Sciences and Pharmacy, University of Newcastle, NSW 2308, Australia
| | - Flavia C. Zacconi
- Departamento de Quimica Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile
- Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 4860, Chile
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