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Fatma M, Parveen S, Mir SS. Unraveling the kinase code: Role of protein kinase in lung cancer pathogenesis and therapeutic strategies. Biochim Biophys Acta Rev Cancer 2025; 1880:189309. [PMID: 40169080 DOI: 10.1016/j.bbcan.2025.189309] [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: 08/09/2024] [Revised: 02/05/2025] [Accepted: 03/28/2025] [Indexed: 04/03/2025]
Abstract
Lung cancer is a prominent cause of cancer-related deaths globally, prompting exploration into the molecular pathways governing cancer cell signaling. Recent insights highlight the critical role of kinases in carcinogenesis and metastasis, particularly in non-small cell lung cancer (NSCLC), where protein kinases significantly contribute to drug resistance. These diverse enzymes catalyze protein phosphorylation and are implicated in cancer through misregulated expression, amplification, aberrant phosphorylation, mutations, and chromosomal translocations. Amplifications of kinases serve as important diagnostic, prognostic, and predictive biomarkers across various cancers. Notably, the Phosphatidylinositol 3-kinase (PI3K)/AKT pathway is crucial for the survival and proliferation of tumor cells. Novel therapeutic approaches are being explored to precisely target these pathways. Peptide-based therapies offer specificity and reduced toxicity compared to conventional treatments, while gene therapy targets abnormal genetic expressions. Advances in nanotechnology and CRISPR/Cas9 systems enhance gene delivery methods, holding promise for targeting specific molecular pathways in lung cancer treatment and minimizing systemic toxicity.
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Affiliation(s)
- Mariyam Fatma
- Molecular Cell Biology Laboratory, Integral Centre of Excellence for Interdisciplinary Research-4 (ICEIR-4) Integral University, Kursi Road, Lucknow 226026, India; Department of Biosciences, Faculty of Science, Integral University, Kursi Road, Lucknow 226026, India
| | - Sana Parveen
- Molecular Cell Biology Laboratory, Integral Centre of Excellence for Interdisciplinary Research-4 (ICEIR-4) Integral University, Kursi Road, Lucknow 226026, India; Department of Biosciences, Faculty of Science, Integral University, Kursi Road, Lucknow 226026, India
| | - Snober S Mir
- Molecular Cell Biology Laboratory, Integral Centre of Excellence for Interdisciplinary Research-4 (ICEIR-4) Integral University, Kursi Road, Lucknow 226026, India; Department of Biosciences, Faculty of Science, Integral University, Kursi Road, Lucknow 226026, India.
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2
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Jeon J, Kang TH. Transcription-Coupled Repair and R-Loop Crosstalk in Genome Stability. Int J Mol Sci 2025; 26:3744. [PMID: 40332372 PMCID: PMC12027824 DOI: 10.3390/ijms26083744] [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: 03/19/2025] [Revised: 04/11/2025] [Accepted: 04/14/2025] [Indexed: 05/08/2025] Open
Abstract
Transcription-coupled repair (TCR) and R-loops are two interrelated processes critical to the maintenance of genome stability during transcription. TCR, a specialized sub-pathway of nucleotide excision repair, rapidly removes transcription-blocking lesions from the transcribed strand of active genes, thereby safeguarding transcription fidelity and cellular homeostasis. In contrast, R-loops, RNA-DNA hybrid structures formed co-transcriptionally, play not only regulatory roles in gene expression and replication but can also contribute to genome instability when persistently accumulated. Recent experimental evidence has revealed dynamic crosstalk between TCR and R-loop resolution pathways. This review highlights current molecular and cellular insights into TCR and R-loop biology, discusses the impact of their crosstalk, and explores emerging therapeutic strategies aimed at optimizing DNA repair and reducing disease risk in conditions such as cancer and neurodegenerative disorders.
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Affiliation(s)
| | - Tae-Hong Kang
- Department of Biomedical Sciences, Dong-A University, Busan 49315, Republic of Korea;
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3
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Bandara S, Raveendran S. Current Landscape and Future Directions in Cancer Immunotherapy: Therapies, Trials, and Challenges. Cancers (Basel) 2025; 17:821. [PMID: 40075668 PMCID: PMC11899461 DOI: 10.3390/cancers17050821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/15/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
Cancer remains a leading global health challenge, placing immense burdens on individuals and healthcare systems. Despite advancements in traditional treatments, significant limitations persist, including treatment resistance, severe side effects, and disease recurrence. Immunotherapy has emerged as a promising alternative, leveraging the immune system to target and eliminate tumour cells. However, challenges such as immunotherapy resistance, patient response variability, and the need for improved biomarkers limit its widespread success. This review provides a comprehensive analysis of the current landscape of cancer immunotherapy, highlighting both FDA-approved therapies and novel approaches in clinical development. It explores immune checkpoint inhibitors, cell and gene therapies, monoclonal antibodies, and nanotechnology-driven strategies, offering insights into their mechanisms, efficacy, and limitations. By integrating emerging research and clinical advancements, this review underscores the need for continued innovation to optimise cancer immunotherapy and overcome existing treatment barriers.
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Affiliation(s)
- Shehani Bandara
- School of Health and Life Sciences, Teesside University, Middlesbrough TS1 3BX, UK
- National Horizons Centre, Teesside University, Darlington DL1 1HG, UK
| | - Sreejith Raveendran
- School of Health and Life Sciences, Teesside University, Middlesbrough TS1 3BX, UK
- National Horizons Centre, Teesside University, Darlington DL1 1HG, UK
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4
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Oprea M, Ionita M. Antisense oligonucleotides-based approaches for the treatment of multiple myeloma. Int J Biol Macromol 2025; 291:139186. [PMID: 39732226 DOI: 10.1016/j.ijbiomac.2024.139186] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 12/23/2024] [Accepted: 12/23/2024] [Indexed: 12/30/2024]
Abstract
Multiple myeloma (MM), a hematological malignancy which affects the monoclonal plasma cells in the bone marrow, is in rising incidence around the world, accounting for approximately 2 % of newly diagnosed cancer cases in the US, Australia, and Western Europe. Despite the progress made in the last few years in the available therapeutic options (e.g. proteasome inhibitors, immunomodulatory drugs, tumor cell-targeting monoclonal antibodies, autologous stem cell transplantation, etc.), multiple myeloma is still regarded as incurable, and the prognosis for most patients is poor, as the disease becomes refractory to treatment throughout time. Antisense oligonucleotides (ASOs), designed to be complementary to selected messenger RNA (mRNA) sequences of specific genes involved in the pathogenesis of multiple myeloma (e.g. Bcl-2, Mcl-1, STAT3, IRF4, IL6, ILF2, HK2, c-MYC, etc.), represent a promising alternative to conventional treatments, and can be tailored according to the individual requirements of each patient. The main goal of antisense therapy for multiple myeloma consists in silencing the specific genes participating in the proliferation and survival of tumor cells via RNA cleavage or RNA blockage, thus preventing mRNA interactions with ribosomes and altering the process of protein translation. So far, pre-clinical and clinical studies showed promising results when Bcl-2 (Genasense), Mcl-1 (ISIS2048), STAT3 (ISIS345794) and IRF4 (ION251) were targeted using ASOs-based formulations. However, FDA approval has not been obtained yet for these products, mainly due to ethical and financial issues posed by customized therapies and insufficient information regarding their long-term toxicity. This review aims to provide a comprehensive insight into antisense oligonucleotides-based therapies, their potential chemical modifications, the mechanisms involved in ASOs-mediated gene silencing, potential systems for ASOs delivery, and the applications of ASOs in the treatment of multiple myeloma. The relevant genetic targets in ASOs-based MM therapies were described, and the research results obtained in the studies conducted so far were analyzed, with a focus on the ASOs formulations that were already included in clinical trials. In the end, current challenges, and future perspectives of antisense therapy for MM were also discussed.
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Affiliation(s)
- Madalina Oprea
- Faculty of Medical Engineering, National University of Science and Technology Politehnica Bucharest, Gheorghe Polizu 1-7, 011061 Bucharest, Romania; Advanced Polymer Materials Group, National University of Science and Technology Politehnica Bucharest, Gheorghe Polizu 1-7, 011061 Bucharest, Romania
| | - Mariana Ionita
- Faculty of Medical Engineering, National University of Science and Technology Politehnica Bucharest, Gheorghe Polizu 1-7, 011061 Bucharest, Romania; Advanced Polymer Materials Group, National University of Science and Technology Politehnica Bucharest, Gheorghe Polizu 1-7, 011061 Bucharest, Romania; ebio-Hub Research Centre, National University of Science and Technology Politehnica Bucharest-Campus, Iuliu Maniu 6, 061344 Bucharest, Romania.
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5
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Maksoud S, Schweiger MW, Tabet EI, Xiao T, Hokayem JE, Zinter M, Carvalho LA, Breyne K, Noske DP, Chiocca EA, Tannous BA. Arming AAV9 with a Single-Chain Fragment Variable Antibody Against PD-1 for Systemic Glioblastoma Therapy. Mol Neurobiol 2025; 62:2617-2625. [PMID: 39138760 PMCID: PMC11772126 DOI: 10.1007/s12035-024-04406-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: 01/04/2024] [Accepted: 07/28/2024] [Indexed: 08/15/2024]
Abstract
Glioblastoma (GBM) is a highly aggressive brain cancer with a low survival rate, prompting the exploration of novel therapeutic strategies. Immune checkpoint inhibitors have shown promise in cancer treatment but are associated with immune-related toxicities and brain penetration. Here, we present a targeted approach using an adeno-associated virus serotype 9 (AAV9) to systemically deliver a single-chain fragment variable antibody against PD-1 (scFv-PD-1) into the tumor microenvironment (TME). Single-cell RNA sequencing analysis revealed robust PD-1 expression in GBM TME, predominantly on T cells. AAV9-scFv-PD-1 expressed and secreted scFv-PD-1, which effectively binds to PD-1. Systemic administration of AAV9-scFv-PD-1 in an immunocompetent GBM mouse model resulted in a robust cytolytic T-cell activation at the tumor site, marked by accumulation of IFN-γ and Granzyme B, leading to a significant reduction in tumor growth. Importantly, AAV9-scFv-PD-1 treatment conferred a survival benefit, highlighting its therapeutic potential. This study demonstrates the feasibility of systemically delivered AAV9-mediated local expression of scFv-PD-1 for targeted immunotherapy in GBM and warrants further investigation for clinical translation.
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Affiliation(s)
- Semer Maksoud
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA.
- Neuroscience Program, Harvard Medical School, Boston, MA, 02129, USA.
- Present Address: Early Oncology R&D, ICC, AstraZeneca, Waltham, MA, 02451, USA.
| | - Markus W Schweiger
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA
- Neuroscience Program, Harvard Medical School, Boston, MA, 02129, USA
- Department of Neurosurgery, Amsterdam , UMC Location Vrije Universiteit Amsterdam, 1081 HV, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Brain Tumor Center and Liquid Biopsy Center, 1081 HV, Amsterdam, the Netherlands
| | - Elie I Tabet
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA
- Neuroscience Program, Harvard Medical School, Boston, MA, 02129, USA
| | - Tianhe Xiao
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA
- Neuroscience Program, Harvard Medical School, Boston, MA, 02129, USA
| | - Joelle El Hokayem
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA
- Neuroscience Program, Harvard Medical School, Boston, MA, 02129, USA
| | - Max Zinter
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA
- Neuroscience Program, Harvard Medical School, Boston, MA, 02129, USA
| | - Litia A Carvalho
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA
- Neuroscience Program, Harvard Medical School, Boston, MA, 02129, USA
| | - Koen Breyne
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA
- Neuroscience Program, Harvard Medical School, Boston, MA, 02129, USA
| | - David P Noske
- Department of Neurosurgery, Amsterdam , UMC Location Vrije Universiteit Amsterdam, 1081 HV, Amsterdam, the Netherlands
- Cancer Center Amsterdam, Brain Tumor Center and Liquid Biopsy Center, 1081 HV, Amsterdam, the Netherlands
| | | | - Bakhos A Tannous
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA.
- Neuroscience Program, Harvard Medical School, Boston, MA, 02129, USA.
- Present Address: Early Oncology R&D, ICC, AstraZeneca, Waltham, MA, 02451, USA.
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6
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Garg P, Singhal G, Pareek S, Kulkarni P, Horne D, Nath A, Salgia R, Singhal SS. Unveiling the potential of gene editing techniques in revolutionizing Cancer treatment: A comprehensive overview. Biochim Biophys Acta Rev Cancer 2025; 1880:189233. [PMID: 39638158 DOI: 10.1016/j.bbcan.2024.189233] [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: 06/20/2024] [Revised: 11/27/2024] [Accepted: 11/28/2024] [Indexed: 12/07/2024]
Abstract
Gene editing techniques have emerged as powerful tools in biomedical research, offering precise manipulation of genetic material with the potential to revolutionize cancer treatment strategies. This review provides a comprehensive overview of the current landscape of gene editing technologies, including CRISPR-Cas systems, base editing, prime editing, and synthetic gene circuits, highlighting their applications and potential in cancer therapy. It discusses the mechanisms, advantages, and limitations of each gene editing approach, emphasizing their transformative impact on targeting oncogenes, tumor suppressor genes, and drug resistance mechanisms in various cancer types. The review delves into population-level interventions and precision prevention strategies enabled by gene editing technologies, including gene drives, synthetic gene circuits, and precision prevention tools, for controlling cancer-causing genes, targeting pre-cancerous lesions, and implementing personalized preventive measures. Ethical considerations, regulatory challenges, and future directions in gene editing research for cancer treatment are also addressed. This review highlights how gene editing could revolutionize precision medicine by enhancing patient care and advancing cancer treatments with targeted, personalized methods. For these benefits to be fully realized, collaboration among researchers, doctors, regulators, and patient advocates is crucial in fighting cancer and meeting clinical needs.
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Affiliation(s)
- Pankaj Garg
- Department of Chemistry, GLA University, Mathura, Uttar Pradesh 281406, India
| | - Gargi Singhal
- Undergraduate Medical Sciences, S.N. Medical College Agra, Uttar Pradesh 282002, India
| | - Siddhika Pareek
- Department of Medical Oncology & Therapeutics Research, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Prakash Kulkarni
- Department of Medical Oncology & Therapeutics Research, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - David Horne
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Aritro Nath
- Department of Medical Oncology & Therapeutics Research, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Ravi Salgia
- Department of Medical Oncology & Therapeutics Research, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Sharad S Singhal
- Department of Medical Oncology & Therapeutics Research, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA.
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7
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Meena SS, Kosgei BK, Soko GF, Tingjun C, Chambuso R, Mwaiselage J, Han RPS. Developing anti-TDE vaccine for sensitizing cancer cells to treatment and metastasis control. NPJ Vaccines 2025; 10:18. [PMID: 39870669 PMCID: PMC11772600 DOI: 10.1038/s41541-024-01035-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 11/21/2024] [Indexed: 01/29/2025] Open
Abstract
Tumor-derived exosomes (TDEs) mediate oncogenic communication, which modifies target cells to reinforce a tumor-promoting microenvironment. TDEs support cancer progression by suppressing anti-tumor immune responses, promoting metastasis, and conferring drug resistance. Thus, targeting TDEs could improve the efficacy of anti-cancer treatments and control metastasis. Current strategies to inhibit TDE-mediated oncogenic communication including drug-based and genetic modification-based inhibition of TDE release and/or uptake, have proved to be inefficient. In this work, we propose TDE surface engineering to express foreign antigens that will trigger life-long anti-TDE immune responses. The possibility of combining the anti-TDE vaccines with other treatments such as chemotherapy, radiotherapy, targeted therapy, and surgery is also explored.
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Affiliation(s)
- Stephene S Meena
- Jiangzhong Cancer Research Center, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China.
- Jiangxi Engineering Research Center for Translational Cancer Technology, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China.
- Ocean Road Cancer Institute, Dar es Salaam, United Republic of Tanzania.
| | - Benson K Kosgei
- Jiangzhong Cancer Research Center, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
- Jiangxi Engineering Research Center for Translational Cancer Technology, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
| | - Geofrey F Soko
- Jiangzhong Cancer Research Center, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
- Ocean Road Cancer Institute, Dar es Salaam, United Republic of Tanzania
| | - Cheng Tingjun
- Jiangzhong Cancer Research Center, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
- Jiangxi Engineering Research Center for Translational Cancer Technology, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
| | - Ramadhani Chambuso
- Department of Global Health and Population, Harvard Chan School of Public Health, Harvard University, Cambridge, MA, USA
- Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Julius Mwaiselage
- Ocean Road Cancer Institute, Dar es Salaam, United Republic of Tanzania
| | - Ray P S Han
- Jiangzhong Cancer Research Center, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China.
- Jiangxi Engineering Research Center for Translational Cancer Technology, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China.
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8
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Pandey P, Nautiyal G, Purohit D, Lata S, Kumar V, Makhija M, Manchanda D, Minocha N, Kumar S, Kaushik D. Role of Nanoformulations in the Treatment of Lung Cancer. RECENT PATENTS ON NANOTECHNOLOGY 2025; 19:407-433. [PMID: 38321901 DOI: 10.2174/0118722105264531231205042817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 10/19/2023] [Accepted: 11/06/2023] [Indexed: 02/08/2024]
Abstract
Lung cancer is the second deadliest disease in the world. A major portion of deaths related to cancer are due to lung cancer in both males and females. Interestingly, unbelievable advances have occurred in recent years through the use of nanotechnology and development in both the diagnosis and treatment of lung cancer. Due to their in vivo stability, the nanotechnology-based pharmacological system gained huge attractiveness, solubility, absorption from the intestine, pharmacological effectiveness, etc. of various anticancer agents. However, this field needs to be utilized more to get maximum results in the treatment of lung cancer, along with wider context medicines. In the present review, authors have tried to concentrate their attention on lung cancer`s difficulties along with the current pharmacological and diagnostic situation, and current advancements in approaches based on nanotechnology for the treatment and diagnosis of lung cancer. While nanotechnology offers these promising avenues for lung cancer diagnosis and treatment, it is important to acknowledge the need for careful evaluation of safety, efficacy, and regulatory approval. With continued research and development, nanotechnology holds tremendous potential to revolutionize the management of lung cancer and improve patient outcomes. The review also highlights the involvement of endocrine systems, especially estrogen in lung cancer proliferation. Some of the recent clinical trials and patents on nanoparticle-based formulations that have applications in the treatment and diagnosis of lung cancer are also discussed.
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Affiliation(s)
- Parijat Pandey
- Department of Pharmaceutical Sciences, Gurugram University, Gurugram, 122018, Haryana, India
| | - Gunjan Nautiyal
- Department of Pharmaceutical Sciences, Gurugram University, Gurugram, 122018, Haryana, India
| | - Deepika Purohit
- Department of Pharmaceutical Sciences, Indira Gandhi University, Meerpur, Rewari, 123401, Haryana, India
| | - Sneh Lata
- Department of Pharmaceutical Sciences, Indira Gandhi University, Meerpur, Rewari, 123401, Haryana, India
| | - Virender Kumar
- College of Pharmacy, Pandit Bhagwat Dayal Sharma University of Health Sciences, Rohtak, 124001, Haryana, India
| | - Manish Makhija
- Department of Pharmaceutical Sciences, Indira Gandhi University, Meerpur, Rewari, 123401, Haryana, India
| | - Deeksha Manchanda
- Department of Pharmaceutical Sciences, Indira Gandhi University, Meerpur, Rewari, 123401, Haryana, India
| | - Neha Minocha
- Amity Institute of Pharmacy, Amity University, Gurugram, 122413, Haryana, India
- Chitkara University School of Pharmacy, Chitkara University, Himachal Pradesh, 174103, India
| | - Sunil Kumar
- Department of Pharmaceutical Sciences, Indira Gandhi University, Meerpur, Rewari, 123401, Haryana, India
| | - Deepak Kaushik
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, 124001, Haryana, India
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9
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Taeb S, Rostamzadeh D, Amini SM, Rahmati M, Golshekan M, Abedinzade M, Ahmadi E, Neha S, Najafi M. Revolutionizing Cancer Treatment: Harnessing the Power of Mesenchymal Stem Cells for Precise Targeted Therapy in the Tumor Microenvironment. Curr Top Med Chem 2025; 25:243-262. [PMID: 38797895 DOI: 10.2174/0115680266299112240514103048] [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: 12/17/2023] [Revised: 04/03/2024] [Accepted: 04/16/2024] [Indexed: 05/29/2024]
Abstract
In recent years, mesenchymal stem cells (MSCs) have emerged as promising anti-- cancer mediators with the potential to treat several cancers. MSCs have been modified to produce anti-proliferative, pro-apoptotic, and anti-angiogenic molecules that could be effective against a variety of malignancies. Additionally, customizing MSCs with cytokines that stimulate pro-tumorigenic immunity or using them as vehicles for traditional chemical molecules with anti-cancer characteristics. Even though the specific function of MSCs in tumors is still challenged, promising outcomes from preclinical investigations of MSC-based gene therapy for a variety of cancers inspire the beginning of clinical trials. In addition, the tumor microenvironment (TME) could have a substantial influence on normal tissue stem cells, which can affect the treatment outcomes. To overcome the complications of TME in cancer development, MSCs could provide some signs of hope for converting TME into unequivocal therapeutic tools. Hence, this review focuses on engineered MSCs (En-MSCs) as a promising approach to overcoming the complications of TME.
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Affiliation(s)
- Shahram Taeb
- Department of Radiology, School of Paramedical Sciences, Guilan University of Medical Sciences, Rasht, Iran
| | - Davoud Rostamzadeh
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, Connecticut, USA
| | - Seyed Mohammad Amini
- Radiation Biology Research center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Rahmati
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Mostafa Golshekan
- Guilan Road Trauma Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Mahmoud Abedinzade
- Department of Medical Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Elham Ahmadi
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, Connecticut, USA
| | - Singh Neha
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, Connecticut, USA
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
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10
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Srivatsa A, Schwartz R. Optimizing design of genomics studies for clonal evolution analysis. BIOINFORMATICS ADVANCES 2024; 4:vbae193. [PMID: 39678206 PMCID: PMC11645549 DOI: 10.1093/bioadv/vbae193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 11/06/2024] [Accepted: 11/29/2024] [Indexed: 12/17/2024]
Abstract
Motivation Genomic biotechnology has rapidly advanced, allowing for the inference and modification of genetic and epigenetic information at the single-cell level. While these tools hold enormous potential for basic and clinical research, they also raise difficult issues of how to design studies to deploy them most effectively. In designing a genomic study, a modern researcher might combine many sequencing modalities and sampling protocols, each with different utility, costs, and other tradeoffs. This is especially relevant for studies of somatic variation, which may involve highly heterogeneous cell populations whose differences can be probed via an extensive set of biotechnological tools. Efficiently deploying genomic technologies in this space will require principled ways to create study designs that recover desired genomic information while minimizing various measures of cost. Results The central problem this paper attempts to address is how one might create an optimal study design for a genomic analysis, with particular focus on studies involving somatic variation that occur most often with application to cancer genomics. We pose the study design problem as a stochastic constrained nonlinear optimization problem. We introduce a Bayesian optimization framework that iteratively optimizes for an objective function using surrogate modeling combined with pattern and gradient search. We demonstrate our procedure on several test cases to derive resource and study design allocations optimized for various goals and criteria, demonstrating its ability to optimize study designs efficiently across diverse scenarios. Availability and implementation https://github.com/CMUSchwartzLab/StudyDesignOptimization.
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Affiliation(s)
- Arjun Srivatsa
- Ray and Stephanie Lane Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, United States
| | - Russell Schwartz
- Ray and Stephanie Lane Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, United States
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, United States
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11
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Arjmand B, Alavi-Moghadam S, Khorsand G, Sarvari M, Arjmand R, Rezaei-Tavirani M, Rajaeinejad M, Mosaed R. Cell-Based Vaccines: Frontiers in Medical Technology for Cancer Treatment. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2024; 10:480-499. [DOI: 10.1007/s40883-024-00338-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 01/13/2024] [Accepted: 02/17/2024] [Indexed: 01/03/2025]
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12
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Shahzad A, Teng Z, Yameen M, Liu W, Cui K, Liu X, Sun Y, Duan Q, Xia J, Dong Y, Bai Z, Peng D, Zhang J, Xu Z, Pi J, Yang Z, Zhang Q. Innovative lipid nanoparticles: A cutting-edge approach for potential renal cell carcinoma therapeutics. Biomed Pharmacother 2024; 180:117465. [PMID: 39321512 DOI: 10.1016/j.biopha.2024.117465] [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: 07/19/2024] [Revised: 09/09/2024] [Accepted: 09/19/2024] [Indexed: 09/27/2024] Open
Abstract
The kidney plays a crucial role in regulating homeostasis within the human body. Renal cell carcinoma (RCC) is the most common form of kidney cancer, accounting for nearly 90 % of all renal malignancies. Despite the availability of various therapeutic strategies, RCC remains a challenging disease due to its resistance to conventional treatments. Nanotechnology has emerged as a promising field, offering new opportunities in cancer therapeutics. It presents several advantages over traditional methods, enabling diverse biomedical applications, including drug delivery, prevention, diagnosis, and treatment. Lipid nanoparticles (LNPs), approximately 100 nm in size, are derived from a range of lipids and other biochemical compounds. these particulates are designed to overcome biological barriers, allowing them to selectively accumulate at diseased target sites for effective therapeutic action. Many pharmaceutically important compounds face challenges such as poor solubility in aqueous solutions, chemical and physiological instability, or toxicity. LNP technology stands out as a promising drug delivery system for bioactive organic compounds. This article reviews the applications of LNPs in RCC treatment and explores their potential clinical translation, identifying the most viable LNPs for medical use. With ongoing advancement in LNP-based anticancer strategies, there is a growing potential to improve the management and treatment of renal cancer.
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Affiliation(s)
- Asif Shahzad
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Zhuoran Teng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Muhammad Yameen
- Department of Biochemistry, Government College University Faisalabad, Punjab 38000, Pakistan
| | - Wenjing Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Kun Cui
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Xiangjie Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Yijian Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Qiuxin Duan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - JiaoJiao Xia
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Yurong Dong
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Ziyuan Bai
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Dongmei Peng
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Jinshan Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Zhe Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Jiang Pi
- Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, The First Dongguan Affiliated Hospital, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China.
| | - Zhe Yang
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China.
| | - Qiao Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China.
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Lee M, Lee M, Song Y, Kim S, Park N. Recent Advances and Prospects of Nucleic Acid Therapeutics for Anti-Cancer Therapy. Molecules 2024; 29:4737. [PMID: 39407665 PMCID: PMC11477775 DOI: 10.3390/molecules29194737] [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: 09/13/2024] [Revised: 10/03/2024] [Accepted: 10/05/2024] [Indexed: 10/20/2024] Open
Abstract
Nucleic acid therapeutics are promising alternatives to conventional anti-cancer therapy, such as chemotherapy and radiation therapy. While conventional therapies have limitations, such as high side effects, low specificity, and drug resistance, nucleic acid therapeutics work at the gene level to eliminate the cause of the disease. Nucleic acid therapeutics treat diseases in various forms and using different mechanisms, including plasmid DNA (pDNA), small interfering RNA (siRNA), anti-microRNA (anti-miR), microRNA mimics (miRNA mimic), messenger RNA (mRNA), aptamer, catalytic nucleic acid (CNA), and CRISPR cas9 guide RNA (gRNA). In addition, nucleic acids have many advantages as nanomaterials, such as high biocompatibility, design flexibility, low immunogenicity, small size, relatively low price, and easy functionalization. Nucleic acid therapeutics can have a high therapeutic effect by being used in combination with various nucleic acid nanostructures, inorganic nanoparticles, lipid nanoparticles (LNPs), etc. to overcome low physiological stability and cell internalization efficiency. The field of nucleic acid therapeutics has advanced remarkably in recent decades, and as more and more nucleic acid therapeutics have been approved, they have already demonstrated their potential to treat diseases, including cancer. This review paper introduces the current status and recent advances in nucleic acid therapy for anti-cancer treatment and discusses the tasks and prospects ahead.
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Affiliation(s)
- Minhyuk Lee
- Department of Chemistry, Pohang University of Science and Technology, Pohang 37673, Republic of Korea
| | - Minjae Lee
- Department of Chemistry and the Natural Science Research Institute, Myongji University, 116 Myongji-ro, Yongin-si 17058, Republic of Korea
| | - Youngseo Song
- Department of Chemistry and the Natural Science Research Institute, Myongji University, 116 Myongji-ro, Yongin-si 17058, Republic of Korea
| | - Sungjee Kim
- Department of Chemistry, Pohang University of Science and Technology, Pohang 37673, Republic of Korea
| | - Nokyoung Park
- Department of Chemistry and the Natural Science Research Institute, Myongji University, 116 Myongji-ro, Yongin-si 17058, Republic of Korea
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14
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Ooi VY, Yeh TY. Recent Advances and Mechanisms of Phage-Based Therapies in Cancer Treatment. Int J Mol Sci 2024; 25:9938. [PMID: 39337427 PMCID: PMC11432602 DOI: 10.3390/ijms25189938] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/07/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
The increasing interest in bacteriophage technology has prompted its novel applications to treat different medical conditions, most interestingly cancer. Due to their high specificity, manipulability, nontoxicity, and nanosize nature, phages are promising carriers in targeted therapy and cancer immunotherapy. This approach is particularly timely, as current challenges in cancer research include damage to healthy cells, inefficiency in targeting, obstruction by biological barriers, and drug resistance. Some cancers are being kept at the forefront of phage research, such as colorectal cancer and HCC, while others like lymphoma, cervical cancer, and myeloma have not been retouched in a decade. Common mechanisms are immunogenic antigen display on phage coats and the use of phage as transporters to carry drugs, genes, and other molecules. To date, popular phage treatments being tested are gene therapy and phage-based vaccines using M13 and λ phage, with some vaccines having advanced to human clinical trials. The results from most of these studies have been promising, but limitations in phage-based therapies such as reticuloendothelial system clearance or diffusion inefficiency must be addressed. Before phage-based therapies for cancer can be successfully used in oncology practice, more in-depth research and support from local governments are required.
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Affiliation(s)
| | - Ting-Yu Yeh
- Agricultural Biotechnology Laboratory, Auxergen Inc., Riti Rossi Colwell Center, 701 E Pratt Street, Baltimore, MD 21202, USA
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15
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Shekho D, Mishra R, Kamal R, Bhatia R, Awasthi A. Breaking Barriers in Alzheimer's Disease: the Role of Advanced Drug Delivery Systems. AAPS PharmSciTech 2024; 25:207. [PMID: 39237748 DOI: 10.1208/s12249-024-02923-6] [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: 04/17/2024] [Accepted: 08/18/2024] [Indexed: 09/07/2024] Open
Abstract
Alzheimer's disease (AD), characterized by cognitive impairment, brain plaques, and tangles, is a global health concern affecting millions. It involves the build-up of amyloid-β (Aβ) and tau proteins, the formation of neuritic plaques and neurofibrillary tangles, cholinergic system dysfunction, genetic variations, and mitochondrial dysfunction. Various signaling pathways and metabolic processes are implicated in AD, along with numerous biomarkers used for diagnosis, risk assessment, and research. Despite these, there is no cure or effective treatment for AD. It is critically important to address this immediately to develop novel drug delivery systems (NDDS) capable of targeting the brain and delivering therapeutic agents to modulate the pathological processes of AD. This review summarizes AD, its pathogenesis, related signaling pathways, biomarkers, conventional treatments, the need for NDDS, and their application in AD treatment. It also covers preclinical, clinical, and ongoing trials, patents, and marketed AD formulations.
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Affiliation(s)
- Devank Shekho
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Ritika Mishra
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Raj Kamal
- Department of Quality Assurance, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Rohit Bhatia
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Ankit Awasthi
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, 142001, Punjab, India.
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India.
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16
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Enayati M, Liu W, Madry H, Neisiany RE, Cucchiarini M. Functionalized hydrogels as smart gene delivery systems to treat musculoskeletal disorders. Adv Colloid Interface Sci 2024; 331:103232. [PMID: 38889626 DOI: 10.1016/j.cis.2024.103232] [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: 01/15/2024] [Revised: 05/10/2024] [Accepted: 06/10/2024] [Indexed: 06/20/2024]
Abstract
Despite critical advances in regenerative medicine, the generation of definitive, reliable treatments for musculoskeletal diseases remains challenging. Gene therapy based on the delivery of therapeutic genetic sequences has strong value to offer effective, durable options to decisively manage such disorders. Furthermore, scaffold-mediated gene therapy provides powerful alternatives to overcome hurdles associated with classical gene therapy, allowing for the spatiotemporal delivery of candidate genes to sites of injury. Among the many scaffolds for musculoskeletal research, hydrogels raised increasing attention in addition to other potent systems (solid, hybrid scaffolds) due to their versatility and competence as drug and cell carriers in tissue engineering and wound dressing. Attractive functionalities of hydrogels for musculoskeletal therapy include their injectability, stimuli-responsiveness, self-healing, and nanocomposition that may further allow to upgrade of them as "intelligently" efficient and mechanically strong platforms, rather than as just inert vehicles. Such functionalized hydrogels may also be tuned to successfully transfer therapeutic genes in a minimally invasive manner in order to protect their cargos and allow for their long-term effects. In light of such features, this review focuses on functionalized hydrogels and demonstrates their competence for the treatment of musculoskeletal disorders using gene therapy procedures, from gene therapy principles to hydrogel functionalization methods and applications of hydrogel-mediated gene therapy for musculoskeletal disorders, while remaining challenges are being discussed in the perspective of translation in patients. STATEMENT OF SIGNIFICANCE: Despite advances in regenerative medicine, the generation of definitive, reliable treatments for musculoskeletal diseases remains challenging. Gene therapy has strong value in offering effective, durable options to decisively manage such disorders. Scaffold-mediated gene therapy provides powerful alternatives to overcome hurdles associated with classical gene therapy. Among many scaffolds for musculoskeletal research, hydrogels raised increasing attention. Functionalities including injectability, stimuli-responsiveness, and self-healing, tune them as "intelligently" efficient and mechanically strong platforms, rather than as just inert vehicles. This review introduces functionalized hydrogels for musculoskeletal disorder treatment using gene therapy procedures, from gene therapy principles to functionalized hydrogels and applications of hydrogel-mediated gene therapy for musculoskeletal disorders, while remaining challenges are discussed from the perspective of translation in patients.
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Affiliation(s)
- Mohammadsaeid Enayati
- Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, 66421 Homburg, Saar, Germany
| | - Wei Liu
- Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, 66421 Homburg, Saar, Germany
| | - Henning Madry
- Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, 66421 Homburg, Saar, Germany
| | - Rasoul Esmaeely Neisiany
- Biotechnology Centre, Silesian University of Technology, Krzywoustego 8, 44-100 Gliwice, Poland; Department of Polymer Engineering, Hakim Sabzevari University, Sabzevar 9617976487, Iran
| | - Magali Cucchiarini
- Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, 66421 Homburg, Saar, Germany.
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Song Z, Tao Y, Liu Y, Li J. Advances in delivery systems for CRISPR/Cas-mediated cancer treatment: a focus on viral vectors and extracellular vesicles. Front Immunol 2024; 15:1444437. [PMID: 39281673 PMCID: PMC11392784 DOI: 10.3389/fimmu.2024.1444437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 07/30/2024] [Indexed: 09/18/2024] Open
Abstract
The delivery of CRISPR/Cas systems holds immense potential for revolutionizing cancer treatment, with recent advancements focusing on extracellular vesicles (EVs) and viral vectors. EVs, particularly exosomes, offer promising opportunities for targeted therapy due to their natural cargo transport capabilities. Engineered EVs have shown efficacy in delivering CRISPR/Cas components to tumor cells, resulting in inhibited cancer cell proliferation and enhanced chemotherapy sensitivity. However, challenges such as off-target effects and immune responses remain significant hurdles. Viral vectors, including adeno-associated viruses (AAVs) and adenoviral vectors (AdVs), represent robust delivery platforms for CRISPR/Cas systems. AAVs, known for their safety profile, have already been employed in clinical trials for gene therapy, demonstrating their potential in cancer treatment. AdVs, capable of infecting both dividing and non-dividing cells, offer versatility in CRISPR/Cas delivery for disease modeling and drug discovery. Despite their efficacy, viral vectors present several challenges, including immune responses and off-target effects. Future directions entail refining delivery systems to enhance specificity and minimize adverse effects, heralding personalized and effective CRISPR/Cas-mediated cancer therapies. This article underscores the importance of optimized delivery mechanisms in realizing the full therapeutic potential of CRISPR/Cas technology in oncology. As the field progresses, addressing these challenges will be pivotal for translating CRISPR/Cas-mediated cancer treatments from bench to bedside.
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Affiliation(s)
- Zhidu Song
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China
| | - Ying Tao
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yue Liu
- Department of Emergency and Critical Care, The Second Hospital of Jilin University, Changchun, China
| | - Jian Li
- Department of Emergency and Critical Care, The Second Hospital of Jilin University, Changchun, China
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Moon TJ, Ta HM, Bhalotia A, Paulsen KE, Hutchinson DW, Arkema GM, Choi AS, Haynie MG, Ogunnaike L, Dever M, Wang LL, Karathanasis E. Nanoparticles targeting immune checkpoint protein VISTA induce potent antitumor immunity. J Immunother Cancer 2024; 12:e008977. [PMID: 39209454 PMCID: PMC11367342 DOI: 10.1136/jitc-2024-008977] [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] [Accepted: 08/12/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Immune checkpoint protein V-domain immunoglobulin suppressor of T cell activation (VISTA) controls antitumor immunity and is a valuable target for cancer immunotherapy. Previous mechanistic studies have indicated that VISTA impairs the toll-like receptor (TLR)-mediated activation of myeloid antigen-presenting cells, promoting the expansion of myeloid-derived suppressor cells, and suppressing tumor-reactive cytotoxic T cell function. METHODS The aim of this study was to develop a dual-action lipid nanoparticle (dual-LNP) coloaded with VISTA-specific siRNA and TLR9 agonist CpG oligonucleotide. We used three murine preclinical tumor models, melanoma YUMM1.7, melanoma B16F10, and colon carcinoma MC38 to assess the functional synergy of the two cargoes of the dual LNP and therapeutic efficacy. RESULTS The dual-LNP synergistically augmented antitumor immune responses and rejected large established tumors whereas LNPs containing VISTA siRNA or CpG alone were ineffective. In comparison with therapies using the soluble CpG and a VISTA-specific monoclonal antibody, the dual-LNP demonstrated superior therapeutic efficacy yet with reduced systemic inflammatory cytokine production. In three murine models, the dual-LNP treatment achieved a high cure rate. Tumor rejection was associated with influx of immune cells to tumor tissues, augmented dendritic cell activation, production of proinflammatory cytokines, and improved function of cytotoxic T cells. CONCLUSIONS Our studies show the dual-LNP ensured codelivery of its synergistic cargoes to tumor-infiltrating myeloid cells, leading to simultaneous silencing of VISTA and stimulation of TLR9. As a result, the dual-LNP drove a highly potent antitumor immune response that rejected large aggressive tumors, thus may be a promising therapeutic platform for treating immune-cold tumors.
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Affiliation(s)
- Taylor J Moon
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Hieu Minh Ta
- Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA
| | - Anubhuti Bhalotia
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Kai E Paulsen
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Diarmuid W Hutchinson
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Gabrielle M Arkema
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Andrew S Choi
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Michiko G Haynie
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Laolu Ogunnaike
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Margee Dever
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
| | - Li Lily Wang
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Efstathios Karathanasis
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA
- Case Comprehensive Cancer Center, Cleveland, Ohio, USA
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S S KD, Joga R, Srivastava S, Nagpal K, Dhamija I, Grover P, Kumar S. Regulatory landscape and challenges in CAR-T cell therapy development in the US, EU, Japan, and India. Eur J Pharm Biopharm 2024; 201:114361. [PMID: 38871092 DOI: 10.1016/j.ejpb.2024.114361] [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: 01/30/2024] [Revised: 06/02/2024] [Accepted: 06/10/2024] [Indexed: 06/15/2024]
Abstract
Chimeric Antigen Receptor-T cell (CAR-T) therapy has evolved as a revolutionary cancer treatment modality, offering remarkable clinical responses by harnessing the power of a patient's immune system to target and eliminate cancer cells. However, the development and commercialization of CAR-T cell therapies are accompanied by complex regulatory requirements and challenges. This therapy falls under the regulatory category of advanced therapy medicinal products. The regulatory framework and approval tools of regenerative medicine, especially CAR-T cell therapies, vary globally. The present work comprehensively analyses the regulatory landscape and challenges in CAR-T cell therapy development in four key regions: the United States, the European Union, Japan, and India. This work explores the unique requirements and considerations for preclinical studies, clinical trial design, manufacturing standards, safety evaluation, and post-marketing surveillance in each jurisdiction. Due to their complex nature, developers and manufacturers face several challenges. In India, despite advancements in treatment protocols and government-sponsorships, there are still several difficulties regarding access to treatment for the increasing number of cancer patients. However, India's first indigenously developed CAR-T cell therapy, NexCAR19, for B-cell lymphoma or leukemia, approved and available at a low cost compared to other available CAR-T therapies, raises great hope in the battle against cancer. Several strategies are proposed to address the identified hurdles from global and Indian perspectives. It discusses the benefits of aligning regulatory requirements across regions, eventually facilitating international development and enabling access to this transformative therapy.
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Affiliation(s)
- Kirthiga Devi S S
- Department of Regulatory Affairs, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana 500037, India
| | - Ramesh Joga
- Department of Regulatory Affairs, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana 500037, India
| | - Saurabh Srivastava
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500037, India
| | - Kalpana Nagpal
- Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh 201303, India
| | - Isha Dhamija
- Department of Pharmacology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500037, India
| | - Parul Grover
- KIET School of Pharmacy, KIET Group of Institutions, Delhi-NCR, Ghaziabad 201206, India
| | - Sandeep Kumar
- Department of Regulatory Affairs, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana 500037, India; Department of Pharmaceutics, NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, Rajasthan 303121, India.
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20
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Mohammadian Gol T, Zahedipour F, Trosien P, Ureña-Bailén G, Kim M, Antony JS, Mezger M. Gene therapy in pediatrics - Clinical studies and approved drugs (as of 2023). Life Sci 2024; 348:122685. [PMID: 38710276 DOI: 10.1016/j.lfs.2024.122685] [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: 01/19/2024] [Revised: 04/17/2024] [Accepted: 05/03/2024] [Indexed: 05/08/2024]
Abstract
Gene therapy in pediatrics represents a cutting-edge therapeutic strategy for treating a range of genetic disorders that manifest in childhood. Gene therapy involves the modification or correction of a mutated gene or the introduction of a functional gene into a patient's cells. In general, it is implemented through two main modalities namely ex vivo gene therapy and in vivo gene therapy. Currently, a noteworthy array of gene therapy products has received valid market authorization, with several others in various stages of the approval process. Additionally, a multitude of clinical trials are actively underway, underscoring the dynamic progress within this field. Pediatric genetic disorders in the fields of hematology, oncology, vision and hearing loss, immunodeficiencies, neurological, and metabolic disorders are areas for gene therapy interventions. This review provides a comprehensive overview of the evolution and current progress of gene therapy-based treatments in the clinic for pediatric patients. It navigates the historical milestones of gene therapies, currently approved gene therapy products by the U.S. Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) for children, and the promising future for genetic disorders. By providing a thorough compilation of approved gene therapy drugs and published results of completed or ongoing clinical trials, this review serves as a guide for pediatric clinicians to get a quick overview of the situation of clinical studies and approved gene therapy products as of 2023.
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Affiliation(s)
- Tahereh Mohammadian Gol
- University Children's Hospital, Department of Pediatrics I, Hematology and Oncology, University of Tübingen, Tübingen, Germany
| | - Fatemeh Zahedipour
- University Children's Hospital, Department of Pediatrics I, Hematology and Oncology, University of Tübingen, Tübingen, Germany; Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Paul Trosien
- University Children's Hospital, Department of Pediatrics I, Hematology and Oncology, University of Tübingen, Tübingen, Germany
| | - Guillermo Ureña-Bailén
- University Children's Hospital, Department of Pediatrics I, Hematology and Oncology, University of Tübingen, Tübingen, Germany
| | - Miso Kim
- University Children's Hospital, Department of Pediatrics I, Hematology and Oncology, University of Tübingen, Tübingen, Germany
| | - Justin S Antony
- University Children's Hospital, Department of Pediatrics I, Hematology and Oncology, University of Tübingen, Tübingen, Germany
| | - Markus Mezger
- University Children's Hospital, Department of Pediatrics I, Hematology and Oncology, University of Tübingen, Tübingen, Germany.
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Pan Y, Cheng J, Zhu Y, Zhang J, Fan W, Chen X. Immunological nanomaterials to combat cancer metastasis. Chem Soc Rev 2024; 53:6399-6444. [PMID: 38745455 DOI: 10.1039/d2cs00968d] [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: 05/16/2024]
Abstract
Metastasis causes greater than 90% of cancer-associated deaths, presenting huge challenges for detection and efficient treatment of cancer due to its high heterogeneity and widespread dissemination to various organs. Therefore, it is imperative to combat cancer metastasis, which is the key to achieving complete cancer eradication. Immunotherapy as a systemic approach has shown promising potential to combat metastasis. However, current clinical immunotherapies are not effective for all patients or all types of cancer metastases owing to insufficient immune responses. In recent years, immunological nanomaterials with intrinsic immunogenicity or immunomodulatory agents with efficient loading have been shown to enhance immune responses to eliminate metastasis. In this review, we would like to summarize various types of immunological nanomaterials against metastasis. Moreover, this review will summarize a series of immunological nanomaterial-mediated immunotherapy strategies to combat metastasis, including immunogenic cell death, regulation of chemokines and cytokines, improving the immunosuppressive tumour microenvironment, activation of the STING pathway, enhancing cytotoxic natural killer cell activity, enhancing antigen presentation of dendritic cells, and enhancing chimeric antigen receptor T cell therapy. Furthermore, the synergistic anti-metastasis strategies based on the combinational use of immunotherapy and other therapeutic modalities will also be introduced. In addition, the nanomaterial-mediated imaging techniques (e.g., optical imaging, magnetic resonance imaging, computed tomography, photoacoustic imaging, surface-enhanced Raman scattering, radionuclide imaging, etc.) for detecting metastasis and monitoring anti-metastasis efficacy are also summarized. Finally, the current challenges and future prospects of immunological nanomaterial-based anti-metastasis are also elucidated with the intention to accelerate its clinical translation.
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Affiliation(s)
- Yuanbo Pan
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310009, Zhejiang, China
- Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou, 310009, China
- Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore 119074, Singapore.
- Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Junjie Cheng
- Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, China
- Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore 119074, Singapore.
- Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Yang Zhu
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian, China.
- Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore 119074, Singapore.
- Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Jianmin Zhang
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310009, Zhejiang, China
- Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou, 310009, China
| | - Wenpei Fan
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, China.
| | - Xiaoyuan Chen
- Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore 119074, Singapore.
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
- Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
- Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, 11 Biopolis Way, Helios, Singapore 138667, Singapore
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Kim SS, Moghe M, Rait A, Donaldson K, Harford JB, Chang EH. SMARCB1 Gene Therapy Using a Novel Tumor-Targeted Nanomedicine Enhances Anti-Cancer Efficacy in a Mouse Model of Atypical Teratoid Rhabdoid Tumors. Int J Nanomedicine 2024; 19:5973-5993. [PMID: 38895149 PMCID: PMC11185260 DOI: 10.2147/ijn.s458323] [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: 01/06/2024] [Accepted: 06/11/2024] [Indexed: 06/21/2024] Open
Abstract
Purpose Atypical teratoid rhabdoid tumor (ATRT) is a deadly, fast-growing form of pediatric brain cancer with poor prognosis. Most ATRTs are associated with inactivation of SMARCB1, a subunit of the chromatin remodeling complex, which is involved in developmental processes. The recent identification of SMARCB1 as a tumor suppressor gene suggests that restoration of SMARCB1 could be an effective therapeutic approach. Methods We tested SMARCB1 gene therapy in SMARCB1-deficient rhabdoid tumor cells using a novel tumor-targeted nanomedicine (termed scL-SMARCB1) to deliver wild-type SMARCB1. Our nanomedicine is a systemically administered immuno-lipid nanoparticle that can actively cross the blood-brain barrier via transferrin receptor-mediated transcytosis and selectively target tumor cells via transferrin receptor-mediated endocytosis. We studied the antitumor activity of the scL-SMARCB1 nanocomplex either as a single agent or in combination with traditional treatment modalities in preclinical models of SMARCB1-deficient ATRT. Results Restoration of SMARCB1 expression by the scL-SMARCB1 nanocomplex blocked proliferation, and induced senescence and apoptosis in ATRT cells. Systemic administration of the scL-SMARCB1 nanocomplex demonstrated antitumor efficacy as monotherapy in mice bearing ATRT xenografts, where the expression of exogenous SMARCB1 modulates MYC-target genes. scL-SMARCB1 demonstrated even greater antitumor efficacy when combined with either cisplatin-based chemotherapy or radiation therapy, resulting in significantly improved survival of ATRT-bearing mice. Conclusion Collectively, our data suggest that restoring SMARCB1 function via the scL-SMARCB1 nanocomplex may lead to therapeutic benefits in ATRT patients when combined with traditional chemoradiation therapies.
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Affiliation(s)
- Sang-Soo Kim
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
- SynerGene Therapeutics, Inc, Potomac, MD, USA
| | - Manish Moghe
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Antonina Rait
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Kathryn Donaldson
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | | | - Esther H Chang
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
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23
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Teixeira ABDS, Ramalho MCC, de Souza I, de Andrade IAM, Osawa IYA, Guedes CB, de Oliveira BS, de Souza CHD, da Silva TL, Moreno NC, Latancia MT, Rocha CRR. The role of chaperone-mediated autophagy in drug resistance. Genet Mol Biol 2024; 47:e20230317. [PMID: 38829285 PMCID: PMC11145944 DOI: 10.1590/1678-4685-gmb-2023-0317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 04/19/2024] [Indexed: 06/05/2024] Open
Abstract
In the search for alternatives to overcome the challenge imposed by drug resistance development in cancer treatment, the modulation of autophagy has emerged as a promising alternative that has achieved good results in clinical trials. Nevertheless, most of these studies have overlooked a novel and selective type of autophagy: chaperone-mediated autophagy (CMA). Following its discovery, research into CMA's contribution to tumor progression has accelerated rapidly. Therefore, we now understand that stress conditions are the primary signal responsible for modulating CMA in cancer cells. In turn, the degradation of proteins by CMA can offer important advantages for tumorigenesis, since tumor suppressor proteins are CMA targets. Such mutual interaction between the tumor microenvironment and CMA also plays a crucial part in establishing therapy resistance, making this discussion the focus of the present review. Thus, we highlight how suppression of LAMP2A can enhance the sensitivity of cancer cells to several drugs, just as downregulation of CMA activity can lead to resistance in certain cases. Given this panorama, it is important to identify selective modulators of CMA to enhance the therapeutic response.
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Affiliation(s)
- Ana Beatriz da Silva Teixeira
- Universidade Federal de São Paulo (UNIFESP), Departamento de
Oncologia Clínica e Experimental, São Paulo, SP, Brazil
| | - Maria Carolina Clares Ramalho
- Universidade Federal de São Paulo (UNIFESP), Departamento de
Oncologia Clínica e Experimental, São Paulo, SP, Brazil
| | - Izadora de Souza
- Universidade Federal de São Paulo (UNIFESP), Departamento de
Oncologia Clínica e Experimental, São Paulo, SP, Brazil
| | | | - Isabeli Yumi Araújo Osawa
- Universidade Federal de São Paulo (UNIFESP), Departamento de
Oncologia Clínica e Experimental, São Paulo, SP, Brazil
| | - Camila Banca Guedes
- Universidade Federal de São Paulo (UNIFESP), Departamento de
Oncologia Clínica e Experimental, São Paulo, SP, Brazil
| | - Beatriz Silva de Oliveira
- Universidade Federal de São Paulo (UNIFESP), Departamento de
Oncologia Clínica e Experimental, São Paulo, SP, Brazil
| | | | - Tainá Lins da Silva
- Universidade Federal de São Paulo (UNIFESP), Departamento de
Oncologia Clínica e Experimental, São Paulo, SP, Brazil
| | - Natália Cestari Moreno
- National Institutes of Health, National Institute of Child Health
and Human Development, Laboratory of Genomic Integrity, Bethesda, MD, USA
| | - Marcela Teatin Latancia
- National Institutes of Health, National Institute of Child Health
and Human Development, Laboratory of Genomic Integrity, Bethesda, MD, USA
| | - Clarissa Ribeiro Reily Rocha
- Universidade Federal de São Paulo (UNIFESP), Departamento de
Oncologia Clínica e Experimental, São Paulo, SP, Brazil
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24
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Carrera-Pacheco SE, Mueller A, Puente-Pineda JA, Zúñiga-Miranda J, Guamán LP. Designing cytochrome P450 enzymes for use in cancer gene therapy. Front Bioeng Biotechnol 2024; 12:1405466. [PMID: 38860140 PMCID: PMC11164052 DOI: 10.3389/fbioe.2024.1405466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 04/30/2024] [Indexed: 06/12/2024] Open
Abstract
Cancer is a significant global socioeconomic burden, as millions of new cases and deaths occur annually. In 2020, almost 10 million cancer deaths were recorded worldwide. Advancements in cancer gene therapy have revolutionized the landscape of cancer treatment. An approach with promising potential for cancer gene therapy is introducing genes to cancer cells that encode for chemotherapy prodrug metabolizing enzymes, such as Cytochrome P450 (CYP) enzymes, which can contribute to the effective elimination of cancer cells. This can be achieved through gene-directed enzyme prodrug therapy (GDEPT). CYP enzymes can be genetically engineered to improve anticancer prodrug conversion to its active metabolites and to minimize chemotherapy side effects by reducing the prodrug dosage. Rational design, directed evolution, and phylogenetic methods are some approaches to developing tailored CYP enzymes for cancer therapy. Here, we provide a compilation of genetic modifications performed on CYP enzymes aiming to build highly efficient therapeutic genes capable of bio-activating different chemotherapeutic prodrugs. Additionally, this review summarizes promising preclinical and clinical trials highlighting engineered CYP enzymes' potential in GDEPT. Finally, the challenges, limitations, and future directions of using CYP enzymes for GDEPT in cancer gene therapy are discussed.
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Affiliation(s)
- Saskya E. Carrera-Pacheco
- Centro de Investigación Biomédica (CENBIO), Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
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25
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Moaveni AK, Amiri M, Shademan B, Farhadi A, Behroozi J, Nourazarian A. Advances and challenges in gene therapy strategies for pediatric cancer: a comprehensive update. Front Mol Biosci 2024; 11:1382190. [PMID: 38836106 PMCID: PMC11149429 DOI: 10.3389/fmolb.2024.1382190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 03/27/2024] [Indexed: 06/06/2024] Open
Abstract
Pediatric cancers represent a tragic but also promising area for gene therapy. Although conventional treatments have improved survival rates, there is still a need for targeted and less toxic interventions. This article critically analyzes recent advances in gene therapy for pediatric malignancies and discusses the challenges that remain. We explore the innovative vectors and delivery systems that have emerged, such as adeno-associated viruses and non-viral platforms, which show promise in addressing the unique pathophysiology of pediatric tumors. Specifically, we examine the field of chimeric antigen receptor (CAR) T-cell therapies and their adaptation for solid tumors, which historically have been more challenging to treat than hematologic malignancies. We also discuss the genetic and epigenetic complexities inherent to pediatric cancers, such as tumor heterogeneity and the dynamic tumor microenvironment, which pose significant hurdles for gene therapy. Ethical considerations specific to pediatric populations, including consent and long-term follow-up, are also analyzed. Additionally, we scrutinize the translation of research from preclinical models that often fail to mimic pediatric cancer biology to the regulatory landscapes that can either support or hinder innovation. In summary, this article provides an up-to-date overview of gene therapy in pediatric oncology, highlighting both the rapid scientific progress and the substantial obstacles that need to be addressed. Through this lens, we propose a roadmap for future research that prioritizes the safety, efficacy, and complex ethical considerations involved in treating pediatric patients. Our ultimate goal is to move from incremental advancements to transformative therapies.
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Affiliation(s)
- Amir Kian Moaveni
- Pediatric Urology and Regenerative Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Amiri
- Pediatric Urology and Regenerative Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Behrouz Shademan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arezoo Farhadi
- Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Javad Behroozi
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Alireza Nourazarian
- Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran
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26
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Yoon AR, Jiao A, Hong J, Kim B, Yun CO. Tumor microenvironment-modulating oncolytic adenovirus combined with GSK-3β inhibitor enhances antitumor immune response against bladder cancer. Front Immunol 2024; 15:1360436. [PMID: 38812516 PMCID: PMC11133599 DOI: 10.3389/fimmu.2024.1360436] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 04/29/2024] [Indexed: 05/31/2024] Open
Abstract
Bladder cancer is a common type of cancer around the world, and the majority of patients are diagnosed with non-muscle-invasive bladder cancer (NMIBC). Although low-risk NMIBC has a good prognosis, the disease recurrence rate and development of treatment-refractory disease remain high in intermediate- to high-risk NMIBC patients. To address these challenges for the treatment of NMIBC, a novel combination therapy composed of an oncolytic adenovirus (oAd) co-expressing interleukin (IL)-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), and relaxin (RLX; HY-oAd) and a clinical-stage glycogen synthase kinase (GSK)-3β inhibitor (9-ING-41; elraglusib) was investigated in the present report. Our findings demonstrate that HY-oAd and 9-ING-41 combination therapy (HY-oAd+9-ING-41) exerted superior inhibition of tumor growth compared with respective monotherapy in a syngeneic NMIBC tumor model. HY-oAd+9-ING-41 induced high-level tumor extracellular matrix (ECM) degradation and a more potent antitumor immune response than the respective monotherapy. In detail, HY-oAd+9-ING-41 induced superior accumulation of intratumoral T cells, prevention of immune cell exhaustion, and induction of tumor-specific adaptive immune response compared to either monotherapy. Collectively, these results demonstrate that the combination of HY-oAd and 9-ING-41 may be a promising approach to elicit a potent antitumor immune response against bladder cancer.
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Affiliation(s)
- A-Rum Yoon
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea
- Institute of Nano Science and Technology (INST), Hanyang University, Seoul, Republic of Korea
- Hanyang Institute of Bioscience and Biotechnology (HY-IBB), Hanyang University, Seoul, Republic of Korea
| | - Ao Jiao
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea
| | - JinWoo Hong
- GeneMedicine Co., Ltd., Seoul, Republic of Korea
| | - Bomi Kim
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea
| | - Chae-Ok Yun
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea
- Institute of Nano Science and Technology (INST), Hanyang University, Seoul, Republic of Korea
- Hanyang Institute of Bioscience and Biotechnology (HY-IBB), Hanyang University, Seoul, Republic of Korea
- GeneMedicine Co., Ltd., Seoul, Republic of Korea
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27
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Kumar A, Goyal A. Emerging molecules, tools, technology, and future of surgical knife in gastroenterology. World J Gastrointest Surg 2024; 16:988-998. [PMID: 38690056 PMCID: PMC11056674 DOI: 10.4240/wjgs.v16.i4.988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/18/2024] [Accepted: 04/03/2024] [Indexed: 04/22/2024] Open
Abstract
The 21st century has started with several innovations in the medical sciences, with wide applications in health care management. This development has taken in the field of medicines (newer drugs/molecules), various tools and technology which has completely changed the patient management including abdominal surgery. Surgery for abdominal diseases has moved from maximally invasive to minimally invasive (laparoscopic and robotic) surgery. Some of the newer medicines have its impact on need for surgical intervention. This article focuses on the development of these emerging molecules, tools, and technology and their impact on present surgical form and its future effects on the surgical intervention in gastroenterological diseases.
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Affiliation(s)
- Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Anirudh Goyal
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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28
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Patra R, Halder S, Saha R, Jana K, Sarkar K. Highly Efficient Photoswitchable Smart Polymeric Nanovehicle for Gene and Anticancer Drug Delivery in Triple-Negative Breast Cancer. ACS Biomater Sci Eng 2024; 10:2299-2323. [PMID: 38551335 DOI: 10.1021/acsbiomaterials.4c00115] [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: 04/09/2024]
Abstract
Over the past few decades, there has been significant interest in smart drug delivery systems capable of carrying multiple drugs efficiently, particularly for treating genetic diseases such as cancer. Despite the development of various drug delivery systems, a safe and effective method for delivering both anticancer drugs and therapeutic genes for cancer therapy remains elusive. In this study, we describe the synthesis of a photoswitchable smart polymeric vehicle comprising a photoswitchable spiropyran moiety and an amino-acid-based cationic monomer-based block copolymer using reversible addition-fragmentation chain transfer (RAFT) polymerization. This system aims at diagnosing triple-negative breast cancer and subsequently delivering genes and anticancer agents. Triple-negative breast cancer patients have elevated concentrations of Cu2+ ions, making them excellent targets for diagnosis. The polymer can detect Cu2+ ions with a low limit of detection value of 9.06 nM. In vitro studies on doxorubicin drug release demonstrated sustained delivery at acidic pH level similar to the tumor environment. Furthermore, the polymer exhibited excellent blood compatibility even at the concentration as high as 500 μg/mL. Additionally, it displayed a high transfection efficiency of approximately 82 ± 5% in MDA-MB-231 triple-negative breast cancer cells at an N/P ratio of 50:1. It is observed that mitochondrial membrane depolarization and intracellular reactive oxygen species generation are responsible for apoptosis and the higher number of apoptotic cells, which occurred through the arrest of the G2/M phase of the cell cycle were observed. Therefore, the synthesized light-responsive cationic polymer may be an effective system for diagnosis, with an efficient anticancer drug and gene carrier for the treatment of triple-negative breast cancer in the future.
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Affiliation(s)
- Rishik Patra
- Gene Therapy and Tissue Engineering Lab, Department of Polymer Science and Technology, University of Calcutta, 92, A.P.C. Road, Kolkata 700009, India
| | - Satyajit Halder
- Division of Molecular Medicine, Centenary Campus, Bose Institute, P-1/12 C.I.T. Scheme VII-M, Kolkata 700054, India
| | - Rima Saha
- Gene Therapy and Tissue Engineering Lab, Department of Polymer Science and Technology, University of Calcutta, 92, A.P.C. Road, Kolkata 700009, India
| | - Kuladip Jana
- Division of Molecular Medicine, Centenary Campus, Bose Institute, P-1/12 C.I.T. Scheme VII-M, Kolkata 700054, India
| | - Kishor Sarkar
- Gene Therapy and Tissue Engineering Lab, Department of Polymer Science and Technology, University of Calcutta, 92, A.P.C. Road, Kolkata 700009, India
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29
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Saghapour E, Yue Z, Sharma R, Kumar S, Sembay Z, Willey CD, Chen JY. Explorative Discovery of Gene Signatures and Clinotypes in Glioblastoma Cancer Through GeneTerrain Knowledge Map Representation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.01.587278. [PMID: 38617348 PMCID: PMC11014492 DOI: 10.1101/2024.04.01.587278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
This study introduces the GeneTerrain Knowledge Map Representation (GTKM), a novel method for visualizing gene expression data in cancer research. GTKM leverages protein-protein interactions to graphically display differentially expressed genes (DEGs) on a 2-dimensional contour plot, offering a more nuanced understanding of gene interactions and expression patterns compared to traditional heatmap methods. The research demonstrates GTKM's utility through four case studies on glioblastoma (GBM) datasets, focusing on survival analysis, subtype identification, IDH1 mutation analysis, and drug sensitivities of different tumor cell lines. Additionally, a prototype website has been developed to showcase these findings, indicating the method's adaptability for various cancer types. The study reveals that GTKM effectively identifies gene patterns associated with different clinical outcomes in GBM, and its profiles enable the identification of sub-gene signature patterns crucial for predicting survival. The methodology promises significant advancements in precision medicine, providing a powerful tool for understanding complex gene interactions and identifying potential therapeutic targets in cancer treatment.
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Affiliation(s)
- Ehsan Saghapour
- Department of Biomedical Informatics and Data Science, University of Alabama at Birmingham, Birmingham, AL, US
| | - Zongliang Yue
- Health Outcome Research and Policy Department, Harrison College of Pharmacy, Auburn University, AL, US
| | - Rahul Sharma
- Department of Biomedical Informatics and Data Science, University of Alabama at Birmingham, Birmingham, AL, US
| | - Sidharth Kumar
- Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL, US
| | - Zhandos Sembay
- Department of Biomedical Informatics and Data Science, University of Alabama at Birmingham, Birmingham, AL, US
| | - Christopher D Willey
- Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL, US
| | - Jake Y Chen
- Department of Biomedical Informatics and Data Science, University of Alabama at Birmingham, Birmingham, AL, US
- Systems Pharmacology AI Research Center, University of Alabama at Birmingham, AL, US
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30
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Srivatsa A, Schwartz R. Optimizing Design of Genomics Studies for Clonal Evolution Analysis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.14.585055. [PMID: 38559253 PMCID: PMC10980045 DOI: 10.1101/2024.03.14.585055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Genomic biotechnologies have seen rapid development over the past two decades, allowing for both the inference and modification of genetic and epigenetic information at the single cell level. While these tools present enormous potential for basic research, diagnostics, and treatment, they also raise difficult issues of how to design research studies to deploy these tools most effectively. In designing a study at the population or individual level, a researcher might combine several different sequencing modalities and sampling protocols, each with different utility, costs, and other tradeoffs. The central problem this paper attempts to address is then how one might create an optimal study design for a genomic analysis, with particular focus on studies involving somatic variation, typically for applications in cancer genomics. We pose the study design problem as a stochastic constrained nonlinear optimization problem and introduce a simulation-centered optimization procedure that iteratively optimizes the objective function using surrogate modeling combined with pattern and gradient search. Finally, we demonstrate the use of our procedure on diverse test cases to derive resource and study design allocations optimized for various objectives for the study of somatic cell populations.
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Affiliation(s)
- Arjun Srivatsa
- Ray and Stephanie Lane Computational Biology Department, Carnegie Mellon University, Pittsburgh PA 15213, USA
| | - Russell Schwartz
- Ray and Stephanie Lane Computational Biology Department, Carnegie Mellon University, Pittsburgh PA 15213, USA
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh PA 15213, USA
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31
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Sun M, Zhang H, Liu J, Chen J, Cui Y, Wang S, Zhang X, Yang Z. Extracellular Vesicles: A New Star for Gene Drug Delivery. Int J Nanomedicine 2024; 19:2241-2264. [PMID: 38465204 PMCID: PMC10924919 DOI: 10.2147/ijn.s446224] [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: 10/24/2023] [Accepted: 02/20/2024] [Indexed: 03/12/2024] Open
Abstract
Recently, gene therapy has become a subject of considerable research and has been widely evaluated in various disease models. Though it is considered as a stand-alone agent for COVID-19 vaccination, gene therapy is still suffering from the following drawbacks during its translation from the bench to the bedside: the high sensitivity of exogenous nucleic acids to enzymatic degradation; the severe side effects induced either by exogenous nucleic acids or components in the formulation; and the difficulty to cross the barriers before reaching the therapeutic target. Therefore, for the successful application of gene therapy, a safe and reliable transport vector is urgently needed. Extracellular vesicles (EVs) are the ideal candidate for the delivery of gene drugs owing to their low immunogenicity, good biocompatibility and low toxicity. To better understand the properties of EVs and their advantages as gene drug delivery vehicles, this review covers from the origin of EVs to the methods of EVs generation, as well as the common methods of isolation and purification in research, with their pros and cons discussed. Meanwhile, the engineering of EVs for gene drugs is also highlighted. In addition, this paper also presents the progress in the EVs-mediated delivery of microRNAs, small interfering RNAs, messenger RNAs, plasmids, and antisense oligonucleotides. We believe this review will provide a theoretical basis for the development of gene drugs.
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Affiliation(s)
- Man Sun
- School of Life Sciences, Jilin University, Changchun, 130012, People’s Republic of China
| | - Huan Zhang
- School of Life Sciences, Jilin University, Changchun, 130012, People’s Republic of China
| | - Jiayi Liu
- School of Life Sciences, Jilin University, Changchun, 130012, People’s Republic of China
| | - Jiayi Chen
- School of Life Sciences, Jilin University, Changchun, 130012, People’s Republic of China
| | - Yaxin Cui
- School of Life Sciences, Jilin University, Changchun, 130012, People’s Republic of China
| | - Simiao Wang
- School of Life Sciences, Jilin University, Changchun, 130012, People’s Republic of China
| | - Xiangyu Zhang
- Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, 310020, People’s Republic of China
| | - Zhaogang Yang
- School of Life Sciences, Jilin University, Changchun, 130012, People’s Republic of China
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Islam P, Schaly S, Abosalha AK, Boyajian J, Thareja R, Ahmad W, Shum-Tim D, Prakash S. Nanotechnology in development of next generation of stent and related medical devices: Current and future aspects. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2024; 16:e1941. [PMID: 38528392 DOI: 10.1002/wnan.1941] [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: 07/28/2023] [Revised: 12/08/2023] [Accepted: 01/03/2024] [Indexed: 03/27/2024]
Abstract
Coronary stents have saved millions of lives in the last three decades by treating atherosclerosis especially, by preventing plaque protrusion and subsequent aneurysms. They attenuate the vascular SMC proliferation and promote reconstruction of the endothelial bed to ensure superior revascularization. With the evolution of modern stent types, nanotechnology has become an integral part of stent technology. Nanocoating and nanosurface fabrication on metallic and polymeric stents have improved their drug loading capacity as well as other mechanical, physico-chemical, and biological properties. Nanofeatures can mimic the natural nanofeatures of vascular tissue and control drug-delivery. This review will highlight the role of nanotechnology in addressing the challenges of coronary stents and the recent advancements in the field of related medical devices. Different generations of stents carrying nanoparticle-based formulations like liposomes, lipid-polymer hybrid NPs, polymeric micelles, and dendrimers are discussed highlighting their roles in local drug delivery and anti-restenotic properties. Drug nanoparticles like Paclitaxel embedded in metal stents are discussed as a feature of first-generation drug-eluting stents. Customized precision stents ensure safe delivery of nanoparticle-mediated genes or concerted transfer of gene, drug, and/or bioactive molecules like antibodies, gene mimics via nanofabricated stents. Nanotechnology can aid such therapies for drug delivery successfully due to its easy scale-up possibilities. However, limitations of this technology such as their potential cytotoxic effects associated with nanoparticle delivery that can trigger hypersensitivity reactions have also been discussed in this review. This article is categorized under: Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.
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Affiliation(s)
- Paromita Islam
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
| | - Sabrina Schaly
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
| | - Ahmed Kh Abosalha
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, 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 and Health Sciences, McGill University, Montreal, Quebec, Canada
| | - Rahul Thareja
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
| | - Waqar Ahmad
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
| | - Dominique Shum-Tim
- Division of Cardiac Surgery, Royal Victoria Hospital, McGill University Health Centre, McGill University, Faculty of Medicine and Health Sciences, Montreal, Quebec, Canada
| | - Satya Prakash
- Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
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Singh RR, Mondal I, Janjua T, Popat A, Kulshreshtha R. Engineered smart materials for RNA based molecular therapy to treat Glioblastoma. Bioact Mater 2024; 33:396-423. [PMID: 38059120 PMCID: PMC10696434 DOI: 10.1016/j.bioactmat.2023.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 10/19/2023] [Accepted: 11/14/2023] [Indexed: 12/08/2023] Open
Abstract
Glioblastoma (GBM) is an aggressive malignancy of the central nervous system (CNS) that remains incurable despite the multitude of improvements in cancer therapeutics. The conventional chemo and radiotherapy post-surgery have only been able to improve the prognosis slightly; however, the development of resistance and/or tumor recurrence is almost inevitable. There is a pressing need for adjuvant molecular therapies that can successfully and efficiently block tumor progression. During the last few decades, non-coding RNAs (ncRNAs) have emerged as key players in regulating various hallmarks of cancer including that of GBM. The levels of many ncRNAs are dysregulated in cancer, and ectopic modulation of their levels by delivering antagonists or overexpression constructs could serve as an attractive option for cancer therapy. The therapeutic potential of several types of ncRNAs, including miRNAs, lncRNAs, and circRNAs, has been validated in both in vitro and in vivo models of GBM. However, the delivery of these RNA-based therapeutics is highly challenging, especially to the tumors of the brain as the blood-brain barrier (BBB) poses as a major obstacle, among others. Also, since RNA is extremely fragile in nature, careful considerations must be met while designing a delivery agent. In this review we have shed light on how ncRNA therapy can overcome the limitations of its predecessor conventional therapy with an emphasis on smart nanomaterials that can aide in the safe and targeted delivery of nucleic acids to treat GBM. Additionally, critical gaps that currently exist for successful transition from viral to non-viral vector delivery systems have been identified. Finally, we have provided a perspective on the future directions, potential pathways, and target areas for achieving rapid clinical translation of, RNA-based macromolecular therapy to advance the effective treatment of GBM and other related diseases.
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Affiliation(s)
- Ravi Raj Singh
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia
- University of Queensland –IIT Delhi Academy of Research (UQIDAR)
| | - Indranil Mondal
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
| | - Taskeen Janjua
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Amirali Popat
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia
- Department of Functional Materials and Catalysis, Faculty of Chemistry, University of Vienna, Währinger Straße 42, 1090 Vienna, Austria
| | - Ritu Kulshreshtha
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology Delhi, New Delhi, India
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Chu Z, Li Z, Yong H, Che D, Li B, Yan C, Zhou T, Wang X, Feng Y, Guo K, Geng S. Enhanced gene transfection and induction of apoptosis in melanoma cells by branched poly(β-amino ester)s with uniformly distributed branching units. J Control Release 2024; 367:197-208. [PMID: 38246205 DOI: 10.1016/j.jconrel.2024.01.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 01/05/2024] [Accepted: 01/13/2024] [Indexed: 01/23/2024]
Abstract
Melanoma, one of the most devastating forms of skin cancer, currently lacks effective clinical treatments. Delivery of functional genes to modulate specific protein expression to induce melanoma cell apoptosis could be a promising therapeutic approach. However, transfecting melanoma cells using non-viral methods, particularly with cationic polymers, presents significant challenges. In this study, we synthesized three branched poly(β-amino ester)s (HPAEs) with evenly distributed branching units but varying space lengths through a two-step "oligomer combination" strategy. The unique topological structure enables HPAEs to condense DNA to form nano-sized polyplexes with favorable physiochemical properties. Notably, HPAEs, especially HPAE-2 with intermediate branching unit space length, demonstrated significantly higher gene transfection efficiency than the leading commercial gene transfection reagent, jetPRIME, in human melanoma cells. Furthermore, HPAE-2 efficiently delivered the Bax-encoding plasmid into melanoma cells, leading to a pronounced pro-apoptotic effect without causing noticeable cytotoxicity. This study establishes a potent non-viral platform for gene transfection of melanoma cells by harnessing the distribution of branching units, paving the way for potential clinical applications of gene therapy in melanoma treatment.
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Affiliation(s)
- Zhaowei Chu
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Zhili Li
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
| | - Haiyang Yong
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Delu Che
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Bingjie Li
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Cong Yan
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Tong Zhou
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Xi Wang
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Yuqing Feng
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Kun Guo
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Songmei Geng
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
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Xiu-Ying H, Yue-Xiang Z, Hui-Si Y, Hong-Zhou Y, Qing-Jie X, Ting-Hua W. PDGFBB facilitates tumorigenesis and malignancy of lung adenocarcinoma associated with PI3K-AKT/MAPK signaling. Sci Rep 2024; 14:4191. [PMID: 38378786 PMCID: PMC10879171 DOI: 10.1038/s41598-024-54801-7] [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: 09/17/2023] [Accepted: 02/16/2024] [Indexed: 02/22/2024] Open
Abstract
Lung adenocarcinoma (LUAD) remains one of the most aggressive tumors and the efficacy of conventional treatment has been bleak. Nowadays, gene-targeted therapy has become a new favorite in tumor therapy. Herein, we investigated the effect of platelet derived growth factor BB (PDGFBB) on LUAD. Firstly, PDGFBB was upregulated in LUAD patients and closely linked with poor survival. Furthermore, the expression of PDGFBB and PDGFRα/β in LUAD cells was higher than that in normal lung cells. By loss-of-function with herpes simplex virus (HSV)-PDGFi-shRNA, we found that PDGFBB knockdown caused a significant decrease in proliferation and migration, but evoked apoptosis of LUAD cells in vitro. Conversely, exogenous PDGFBB held adverse effect. Additionally, A549 cells with PDGFBB knockdown had a low probability of tumorigenesis in vivo. Moreover, PDGFBB knockdown restrained the growth of xenografts derived from normal A549 cells. Mechanistically, PDGFBB knockdown suppressed PI3K/AKT and Ras/MAPK signaling, while PDGFBB was the opposite. Therefore, we concluded that PDGFBB might facilitate the tumorigenesis and malignancy of LUAD through its functional downstream nodes-PI3K/AKT and Ras/MAPK signaling, which supported that PDGFBB could serve as a rational therapeutic target for LUAD.
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Affiliation(s)
- He Xiu-Ying
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
- Institute of Neurological Disease, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Zheng Yue-Xiang
- School of Integrated Traditional Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Yang Hui-Si
- School of Integrated Traditional Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Yu Hong-Zhou
- Institute of Neurological Disease, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xia Qing-Jie
- Institute of Neurological Disease, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Wang Ting-Hua
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.
- Institute of Neurological Disease, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
- Laboratory Zoology Department, Institute of Neuroscience, Kunming Medical University, Kunming, China.
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Lian S, Lamprou D, Zhao M. Electrospinning technologies for the delivery of Biopharmaceuticals: Current status and future trends. Int J Pharm 2024; 651:123641. [PMID: 38029864 DOI: 10.1016/j.ijpharm.2023.123641] [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: 08/11/2023] [Revised: 11/15/2023] [Accepted: 11/26/2023] [Indexed: 12/01/2023]
Abstract
This review provides an in-depth exploration of electrospinning techniques employed to produce micro- or nanofibres of biopharmaceuticals using polymeric solutions or melts with high-voltage electricity. Distinct from prior reviews, the current work narrows its focus on the recent developments and advanced applications in biopharmaceutical formulations. It begins with an overview of electrospinning principles, covering both solution and melt modes. Various methods for incorporating biopharmaceuticals into electrospun fibres, such as surface adsorption, blending, emulsion, co-axial, and high-throughput electrospinning, are elaborated. The review also surveys a wide array of biopharmaceuticals formulated through electrospinning, thereby identifying both opportunities and challenges in this emerging field. Moreover, it outlines the analytical techniques for characterizing electrospun fibres and discusses the legal and regulatory requirements for their production. This work aims to offer valuable insights into the evolving realm of electrospun biopharmaceutical delivery systems.
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Affiliation(s)
- Shangjie Lian
- School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK
| | | | - Min Zhao
- School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK; China Medical University- Queen's University Belfast Joint College (CQC), China Medical University, Shenyang 110000, China
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Firdaus Z, Li X. Unraveling the Genetic Landscape of Neurological Disorders: Insights into Pathogenesis, Techniques for Variant Identification, and Therapeutic Approaches. Int J Mol Sci 2024; 25:2320. [PMID: 38396996 PMCID: PMC10889342 DOI: 10.3390/ijms25042320] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 02/09/2024] [Accepted: 02/13/2024] [Indexed: 02/25/2024] Open
Abstract
Genetic abnormalities play a crucial role in the development of neurodegenerative disorders (NDDs). Genetic exploration has indeed contributed to unraveling the molecular complexities responsible for the etiology and progression of various NDDs. The intricate nature of rare and common variants in NDDs contributes to a limited understanding of the genetic risk factors associated with them. Advancements in next-generation sequencing have made whole-genome sequencing and whole-exome sequencing possible, allowing the identification of rare variants with substantial effects, and improving the understanding of both Mendelian and complex neurological conditions. The resurgence of gene therapy holds the promise of targeting the etiology of diseases and ensuring a sustained correction. This approach is particularly enticing for neurodegenerative diseases, where traditional pharmacological methods have fallen short. In the context of our exploration of the genetic epidemiology of the three most prevalent NDDs-amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease, our primary goal is to underscore the progress made in the development of next-generation sequencing. This progress aims to enhance our understanding of the disease mechanisms and explore gene-based therapies for NDDs. Throughout this review, we focus on genetic variations, methodologies for their identification, the associated pathophysiology, and the promising potential of gene therapy. Ultimately, our objective is to provide a comprehensive and forward-looking perspective on the emerging research arena of NDDs.
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Affiliation(s)
- Zeba Firdaus
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA;
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Xiaogang Li
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA;
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
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Tavares V, Marques IS, Melo IGD, Assis J, Pereira D, Medeiros R. Paradigm Shift: A Comprehensive Review of Ovarian Cancer Management in an Era of Advancements. Int J Mol Sci 2024; 25:1845. [PMID: 38339123 PMCID: PMC10856127 DOI: 10.3390/ijms25031845] [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: 12/31/2023] [Revised: 01/30/2024] [Accepted: 02/02/2024] [Indexed: 02/12/2024] Open
Abstract
Ovarian cancer (OC) is the female genital malignancy with the highest lethality. Patients present a poor prognosis mainly due to the late clinical presentation allied with the common acquisition of chemoresistance and a high rate of tumour recurrence. Effective screening, accurate diagnosis, and personalised multidisciplinary treatments are crucial for improving patients' survival and quality of life. This comprehensive narrative review aims to describe the current knowledge on the aetiology, prevention, diagnosis, and treatment of OC, highlighting the latest significant advancements and future directions. Traditionally, OC treatment involves the combination of cytoreductive surgery and platinum-based chemotherapy. Although more therapeutical approaches have been developed, the lack of established predictive biomarkers to guide disease management has led to only marginal improvements in progression-free survival (PFS) while patients face an increasing level of toxicity. Fortunately, because of a better overall understanding of ovarian tumourigenesis and advancements in the disease's (epi)genetic and molecular profiling, a paradigm shift has emerged with the identification of new disease biomarkers and the proposal of targeted therapeutic approaches to postpone disease recurrence and decrease side effects, while increasing patients' survival. Despite this progress, several challenges in disease management, including disease heterogeneity and drug resistance, still need to be overcome.
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Affiliation(s)
- Valéria Tavares
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP), Pathology and Laboratory Medicine Department, Clinical Pathology SV/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto), Porto Comprehensive Cancer Centre (Porto.CCC), 4200-072 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-072 Porto, Portugal
- ICBAS-Instituto de Ciências Biomédicas Abel Salazar, University of Porto, 4050-313 Porto, Portugal
| | - Inês Soares Marques
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP), Pathology and Laboratory Medicine Department, Clinical Pathology SV/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto), Porto Comprehensive Cancer Centre (Porto.CCC), 4200-072 Porto, Portugal
- Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
| | - Inês Guerra de Melo
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP), Pathology and Laboratory Medicine Department, Clinical Pathology SV/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto), Porto Comprehensive Cancer Centre (Porto.CCC), 4200-072 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-072 Porto, Portugal
| | - Joana Assis
- Clinical Research Unit, Research Center of IPO Porto (CI-IPOP), RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto), Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal
| | - Deolinda Pereira
- Oncology Department, Portuguese Institute of Oncology of Porto (IPOP), 4200-072 Porto, Portugal
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP), Pathology and Laboratory Medicine Department, Clinical Pathology SV/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto), Porto Comprehensive Cancer Centre (Porto.CCC), 4200-072 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-072 Porto, Portugal
- ICBAS-Instituto de Ciências Biomédicas Abel Salazar, University of Porto, 4050-313 Porto, Portugal
- Faculty of Health Sciences, Fernando Pessoa University, 4200-150 Porto, Portugal
- Research Department, Portuguese League Against Cancer (NRNorte), 4200-172 Porto, Portugal
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Tang F, Ding A, Xu Y, Ye Y, Li L, Xie R, Huang W. Gene and Photothermal Combination Therapy: Principle, Materials, and Amplified Anticancer Intervention. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2307078. [PMID: 37775950 DOI: 10.1002/smll.202307078] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/19/2023] [Indexed: 10/01/2023]
Abstract
Gene therapy (GT) and photothermal therapy (PTT) have emerged as promising alternatives to chemotherapy and radiotherapy for cancer treatment, offering noninvasiveness and reduced side effects. However, their efficacy as standalone treatments is limited. GT exhibits slow response rates, while PTT is confined to local tumor ablation. The convergence of GT and PTT, known as GT-PTT, facilitated by photothermal gene nanocarriers, has attracted considerable attention across various disciplines. In this integrated approach, GT reciprocates PTT by sensitizing cellular response to heat, while PTT benefits GT by improving gene translocation, unpacking, and expression. Consequently, this integration presents a unique opportunity for cancer therapy with rapid response and improved effectiveness. Extensive efforts over the past few years have been dedicated to the development of GT-PTT, resulting in notable achievements and rapid progress from the laboratory to potential clinical applications. This comprehensive review outlines recent advances in GT-PTT, including synergistic mechanisms, material systems, imaging-guided therapy, and anticancer applications. It also explores the challenges and future prospects in this nascent field. By presenting innovative ideas and insights into the implementation of GT-PTT for enhanced cancer therapy, this review aims to inspire further progress in this promising area of research.
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Affiliation(s)
- Fang Tang
- The Institute of Flexible Electronics (IFE, Future Technologies), Xiamen University, Xiamen, 361005, China
- Future Display Institute in Xiamen, Xiamen, 361005, China
| | - Aixiang Ding
- The Institute of Flexible Electronics (IFE, Future Technologies), Xiamen University, Xiamen, 361005, China
| | - Yao Xu
- The Institute of Flexible Electronics (IFE, Future Technologies), Xiamen University, Xiamen, 361005, China
| | - Yingsong Ye
- The Institute of Flexible Electronics (IFE, Future Technologies), Xiamen University, Xiamen, 361005, China
| | - Lin Li
- The Institute of Flexible Electronics (IFE, Future Technologies), Xiamen University, Xiamen, 361005, China
- Future Display Institute in Xiamen, Xiamen, 361005, China
- Frontiers Science Center for Flexible Electronics (IFE), Northwestern Polytechnical University, Xi'an, 710072, China
| | - Rongjun Xie
- Fujian Key Laboratory of Materials Genome, College of Materials, Xiamen University, Xiamen, 361005, China
| | - Wei Huang
- The Institute of Flexible Electronics (IFE, Future Technologies), Xiamen University, Xiamen, 361005, China
- Future Display Institute in Xiamen, Xiamen, 361005, China
- Frontiers Science Center for Flexible Electronics (IFE), Northwestern Polytechnical University, Xi'an, 710072, China
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Adhikari S, Nath P, Das A, Datta A, Baildya N, Duttaroy AK, Pathak S. A review on metal complexes and its anti-cancer activities: Recent updates from in vivo studies. Biomed Pharmacother 2024; 171:116211. [PMID: 38290253 DOI: 10.1016/j.biopha.2024.116211] [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: 10/21/2023] [Revised: 12/22/2023] [Accepted: 01/22/2024] [Indexed: 02/01/2024] Open
Abstract
Research into cancer therapeutics has uncovered various potential medications based on metal-containing scaffolds after the discovery and clinical applications of cisplatin as an anti-cancer agent. This has resulted in many metallodrugs that can be put into medical applications. These metallodrugs have a wider variety of functions and mechanisms of action than pure organic molecules. Although platinum-based medicines are very efficient anti-cancer agents, they are often accompanied by significant side effects and toxicity and are limited by resistance. Some of the most studied and developed alternatives to platinum-based anti-cancer medications include metallodrugs based on ruthenium, gold, copper, iridium, and osmium, which showed effectiveness against many cancer cell lines. These metal-based medicines represent an exciting new category of potential cancer treatments and sparked a renewed interest in the search for effective anti-cancer therapies. Despite the widespread development of metal complexes touted as powerful and promising in vitro anti-cancer therapeutics, only a small percentage of these compounds have shown their worth in vivo models. Metallodrugs, which are more effective and less toxic than platinum-based drugs and can treat drug-resistant cancer cells, are the focus of this review. Here, we highlighted some of the most recently developed Pt, Ru, Au, Cu, Ir, and Os complexes that have shown significant in vivo antitumor properties between 2017 and 2023.
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Affiliation(s)
- Suman Adhikari
- Department of Chemistry, Govt. Degree Collage, Dharmanagar, Tripura (N) 799253, India.
| | - Priyatosh Nath
- Department of Human Physiology, Tripura University, Suryamaninagar, West Tripura 799022, India
| | - Alakesh Das
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai 603103, India
| | - Abhijit Datta
- Department of Botany, Ambedkar College, Fatikroy, Unakoti 799290, Tripura, India
| | - Nabajyoti Baildya
- Department of Chemistry, Milki High School, Milki, Malda 732209, India
| | - Asim K Duttaroy
- Department of Nutrition, Institute of Medical Sciences, Faculty of Medicine, University of Oslo, Norway.
| | - Surajit Pathak
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai 603103, India
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Batool A, Rashid W, Fatima K, Khan SU. Mechanisms of Cancer Resistance to Various Therapies. DRUG RESISTANCE IN CANCER: MECHANISMS AND STRATEGIES 2024:31-75. [DOI: 10.1007/978-981-97-1666-1_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Singh M, Brooks A, Toofan P, McLuckie K. Selection of appropriate non-clinical animal models to ensure translatability of novel AAV-gene therapies to the clinic. Gene Ther 2024; 31:56-63. [PMID: 37612361 DOI: 10.1038/s41434-023-00417-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 07/19/2023] [Accepted: 08/04/2023] [Indexed: 08/25/2023]
Abstract
Gene Therapy Medicinal Products consist of a recombinant nucleic acid intended for the modulation or manipulation of a genetic sequence. A single administration of a novel gene therapy has the potential to be curative, with a durable long-term benefit to patients. Adeno-associated viral vectors have become the viral vector of choice for in vivo delivery of therapeutic transgenes as they are mildly immunogenic, can effectively transduce a variety of human tissues and cells, and have low levels of genomic integration. Central to the effective translation of data generated in discovery studies to the clinic is the selection of appropriate animal species for pivotal non-clinical studies. This review aims to support the selection of appropriate animal models for non-clinical studies to advance the development of novel adeno-associated virus gene therapies.
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Affiliation(s)
- Mark Singh
- Cell and Gene Therapy Catapult, 12th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London, UK.
| | - Andrew Brooks
- Cell and Gene Therapy Catapult, 12th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London, UK
| | - Parto Toofan
- Cell and Gene Therapy Catapult, 12th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London, UK
| | - Keith McLuckie
- Cell and Gene Therapy Catapult, 12th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London, UK
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Shams M, Abdallah S, Alsadoun L, Hamid YH, Gasim R, Hassan A. Oncological Horizons: The Synergy of Medical and Surgical Innovations in Cancer Treatment. Cureus 2023; 15:e49249. [PMID: 38143618 PMCID: PMC10743204 DOI: 10.7759/cureus.49249] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/21/2023] [Indexed: 12/26/2023] Open
Abstract
The landscape of cancer treatment has witnessed a remarkable transformation in recent years, marked by the convergence of medical and surgical innovations. Historically, cancer therapy faced challenges, including limited efficacy and severe side effects. This narrative review explores the historical progression of cancer treatments, shedding light on significant breakthroughs in both medical and surgical oncology. It comprehensively addresses the medical domain, covering chemotherapy, targeted therapies, immunotherapy, hormonal treatments, and radiological procedures. Simultaneously, it delves into the surgical realm, discussing the evolution of surgical techniques, minimally invasive procedures, and the role of surgery across various stages of cancer. The article emphasizes the fusion of medical and surgical approaches, highlighting neoadjuvant and adjuvant therapies and the significance of multidisciplinary tumor boards. It also addresses innovations, challenges, and the pivotal role of patient-centered care. Furthermore, it offers insights into the future directions and forecasts in the constantly evolving field of integrated oncological care. This review provides a comprehensive understanding of the dynamic and transformative nature of cancer treatment, reflecting the unwavering commitment of the medical and surgical communities in the ongoing fight against cancer.
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Affiliation(s)
| | | | - Lara Alsadoun
- Trauma and Orthopaedics, Chelsea and Westminster Hospital, London, GBR
| | - Yusra H Hamid
- Community Medicine, Faculty of Medicine, University of Khartoum, Khartoum, SDN
| | - Rayan Gasim
- Internal Medicine, University of Khartoum, Khartoum, SDN
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Srivastava N, Chudasama B, Baranwal M. Advancement in magnetic hyperthermia-based targeted therapy for cancer treatment. Biointerphases 2023; 18:060801. [PMID: 38078795 DOI: 10.1116/6.0003079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 11/14/2023] [Indexed: 12/18/2023] Open
Abstract
Magnetic hyperthermia utilizing magnetic nanoparticles (MNPs) and an alternating magnetic field (AMF) represents a promising approach in the field of cancer treatment. Active targeting has emerged as a valuable strategy to enhance the effectiveness and specificity of drug delivery. Active targeting utilizes specific biomarkers that are predominantly found in abundance on cancer cells while being minimally expressed on healthy cells. Current comprehensive review provides an overview of several cancer-specific biomarkers, including human epidermal growth factor, transferrin, folate, luteinizing hormone-releasing hormone, integrin, cluster of differentiation (CD) receptors such as CD90, CD95, CD133, CD20, and CD44 also CXCR4 and vascular endothelial growth factor, these biomarkers bind to ligands present on the surface of MNPs, enabling precise targeting. Additionally, this review touches various combination therapies employed to combat cancer. Magnetic hyperthermia synergistically enhances the efficacy of conventional cancer treatments such as targeted chemotherapy, radiation therapy, gene therapy, and immunotherapy.
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Affiliation(s)
- Neha Srivastava
- Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala 147004, India
| | - Bhupendra Chudasama
- School of Physics and Materials Science, Thapar Institute of Engineering and Technology, Patiala 147004, India
| | - Manoj Baranwal
- Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala 147004, India
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Dave BP, Shah YB, Maheshwari KG, Mansuri KA, Prajapati BS, Postwala HI, Chorawala MR. Pathophysiological Aspects and Therapeutic Armamentarium of Alzheimer's Disease: Recent Trends and Future Development. Cell Mol Neurobiol 2023; 43:3847-3884. [PMID: 37725199 PMCID: PMC11407742 DOI: 10.1007/s10571-023-01408-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 08/31/2023] [Indexed: 09/21/2023]
Abstract
Alzheimer's disease (AD) is the primary cause of dementia and is characterized by the death of brain cells due to the accumulation of insoluble amyloid plaques, hyperphosphorylation of tau protein, and the formation of neurofibrillary tangles within the cells. AD is also associated with other pathologies such as neuroinflammation, dysfunction of synaptic connections and circuits, disorders in mitochondrial function and energy production, epigenetic changes, and abnormalities in the vascular system. Despite extensive research conducted over the last hundred years, little is established about what causes AD or how to effectively treat it. Given the severity of the disease and the increasing number of affected individuals, there is a critical need to discover effective medications for AD. The US Food and Drug Administration (FDA) has approved several new drug molecules for AD management since 2003, but these drugs only provide temporary relief of symptoms and do not address the underlying causes of the disease. Currently, available medications focus on correcting the neurotransmitter disruption observed in AD, including cholinesterase inhibitors and an antagonist of the N-methyl-D-aspartate (NMDA) receptor, which temporarily alleviates the signs of dementia but does not prevent or reverse the course of AD. Research towards disease-modifying AD treatments is currently underway, including gene therapy, lipid nanoparticles, and dendrimer-based therapy. These innovative approaches aim to target the underlying pathological processes of AD rather than just managing the symptoms. This review discusses the novel aspects of pathogenesis involved in the causation of AD of AD and in recent developments in the therapeutic armamentarium for the treatment of AD such as gene therapy, lipid nanoparticles, and dendrimer-based therapy, and many more.
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Affiliation(s)
- Bhavarth P Dave
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, Gujarat, 380009, India
| | - Yesha B Shah
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, Gujarat, 380009, India
| | - Kunal G Maheshwari
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, Gujarat, 380009, India
| | - Kaif A Mansuri
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, Gujarat, 380009, India
| | - Bhadrawati S Prajapati
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, Gujarat, 380009, India
| | - Humzah I Postwala
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, Gujarat, 380009, India
| | - Mehul R Chorawala
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, Gujarat, 380009, India.
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Komel T, Bosnjak M, Sersa G, Cemazar M. Expression of GFP and DsRed fluorescent proteins after gene electrotransfer of tumour cells in vitro. Bioelectrochemistry 2023; 153:108490. [PMID: 37356264 DOI: 10.1016/j.bioelechem.2023.108490] [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: 02/22/2023] [Revised: 06/15/2023] [Accepted: 06/17/2023] [Indexed: 06/27/2023]
Abstract
Fluorescent reporter genes are widely used to study the transfection of various types of primary cells and cell lines. The aim of our research was to investigate the expression dynamics of GFP and DsRed reporter genes individually and combined after gene electrotransfer of plasmids with two different electroporation protocols in B16F10 and CT26 cells in vitro. The cytotoxicity after gene electrotransfer of both plasmids was first determined. Second, the intensity of fluorescence and the percentage of cells transfected with both plasmids individually and in combination were monitored in real time. The results show that the percentage of viability after gene electrotransfer of plasmids using the EP2 pulses was significantly higher compared to the EP1 pulses. In contrast, the percentage of transfected cells and fluorescence intensity were higher after gene electrotransfer with the EP1 pulse protocol. Moreover, the percentage of transfected cells was higher and started earlier in the B16F10 cell line than in the CT26 cell line. However, fluorescence intensity was higher in CT26 cells. Co-expression of fluorescent proteins was achieved only in a small number of cells. In conclusion, this study elucidated some of the dynamics of reporter gene expression in cancer cell lines after gene electrotransfer.
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Affiliation(s)
- Tilen Komel
- Institute of Oncology Ljubljana, Department of Experimental Oncology, Zaloska 2, SI-1000 Ljubljana, Slovenia; University of Ljubljana, Faculty of Medicine, Vrazov trg 2, SI-1000 Ljubljana, Slovenia
| | - Masa Bosnjak
- Institute of Oncology Ljubljana, Department of Experimental Oncology, Zaloska 2, SI-1000 Ljubljana, Slovenia
| | - Gregor Sersa
- Institute of Oncology Ljubljana, Department of Experimental Oncology, Zaloska 2, SI-1000 Ljubljana, Slovenia; University of Ljubljana, Faculty of Health Sciences, Zdravstvena pot 5, SI - 1000 Ljubljana, Slovenia
| | - Maja Cemazar
- Institute of Oncology Ljubljana, Department of Experimental Oncology, Zaloska 2, SI-1000 Ljubljana, Slovenia; University of Primorska, Faculty of Health Sciences, Polje 42, SI - 6310 Izola, Slovenia.
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Khan MS, Gowda BHJ, Nasir N, Wahab S, Pichika MR, Sahebkar A, Kesharwani P. Advancements in dextran-based nanocarriers for treatment and imaging of breast cancer. Int J Pharm 2023; 643:123276. [PMID: 37516217 DOI: 10.1016/j.ijpharm.2023.123276] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 07/12/2023] [Accepted: 07/26/2023] [Indexed: 07/31/2023]
Abstract
Breast cancer is the most prevalent type of cancer worldwide,particularly among women, with substantial side effects after therapy. Despite the availability of numerous therapeutic approaches, particularly chemotherapy, the survival rates for breast cancer have declined over time. The therapies currently utilized for breast cancer treatment do not specifically target cancerous cells, resulting in significant adverse effects and potential harm to healthy cells alongside the cancer cells. As a result, nanoparticle-based drug delivery systems have emerged. Among various types of nanoparticles, natural polysaccharide-based nanoparticles have gained significant attention due to their ability to precisely control the drug release and achieve targeted drug delivery. Moreover, polysaccharides are biocompatible, biodegradable, easily modifiable, and renewable, which makes them a unique material for nanoformulation. In recent years, dextran and its derivatives have gained much interest in the field of breast cancer therapy. Dextran is a hydrophilic polysaccharide composed of a main chain formed by α-1,6 linked glucopyranoside residues and a side chain composed of residues linked in α-1,2/3/4 positions. Different dextran-antitumor medication conjugates enhancethe efficacy of anticancer agents. With this context, the present review provides brief insights into dextran and its modification. Further, it meticulously discusses the role of dextran-based nanoparticles in breast cancer therapy and imaging, followed by snippets on their toxicity. Lastly, it presents clinical trials and future perspectives of dextran-based nanoparticles in breast cancer treatment.
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Affiliation(s)
- Mohammad Sameer Khan
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - B H Jaswanth Gowda
- Department of Pharmaceutics, Yenepoya Pharmacy College & Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, Karnataka, India
| | - Nazim Nasir
- Department of Basic Medical Sciences, College of Applied Medical Sciences, Khamis Mushait, Saudi Arabia
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia
| | - Mallikarjuna Rao Pichika
- Pharmaceutical Chemistry, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India; Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
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Chu W, Shastry S, Barbieri E, Prodromou R, Greback-Clarke P, Smith W, Moore B, Kilgore R, Cummings C, Pancorbo J, Gilleskie G, Daniele MA, Menegatti S. Peptide ligands for the affinity purification of adeno-associated viruses from HEK 293 cell lysates. Biotechnol Bioeng 2023; 120:2283-2300. [PMID: 37435968 PMCID: PMC10440015 DOI: 10.1002/bit.28495] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 06/15/2023] [Accepted: 06/30/2023] [Indexed: 07/13/2023]
Abstract
Adeno-associated viruses (AAVs) are the vector of choice for delivering gene therapies that can cure inherited and acquired diseases. Clinical research on various AAV serotypes significantly increased in recent years alongside regulatory approvals of AAV-based therapies. The current AAV purification platform hinges on the capture step, for which several affinity resins are commercially available. These adsorbents rely on protein ligands-typically camelid antibodies-that provide high binding capacity and selectivity, but suffer from low biochemical stability and high cost, and impose harsh elution conditions (pH < 3) that can harm the transduction activity of recovered AAVs. Addressing these challenges, this study introduces peptide ligands that selectively capture AAVs and release them under mild conditions (pH = 6.0). The peptide sequences were identified by screening a focused library and modeled in silico against AAV serotypes 2 and 9 (AAV2 and AAV9) to select candidate ligands that target homologous sites at the interface of the VP1-VP2 and VP2-VP3 virion proteins with mild binding strength (KD ~ 10-5 -10- 6 M). Selected peptides were conjugated to Toyopearl resin and evaluated via binding studies against AAV2 and AAV9, demonstrating the ability to target both serotypes with values of dynamic binding capacity (DBC10% > 1013 vp/mL of resin) and product yields (~50%-80%) on par with commercial adsorbents. The peptide-based adsorbents were finally utilized to purify AAV2 from a HEK 293 cell lysate, affording high recovery (50%-80%), 80- to 400-fold reduction of host cell proteins (HCPs), and high transduction activity (up to 80%) of the purified viruses.
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Affiliation(s)
- Wenning Chu
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, USA
| | - Shriarjun Shastry
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, USA
- Biomanufacturing Training and Education Center (BTEC), North Carolina State University, Raleigh, North Carolina, USA
| | - Eduardo Barbieri
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, USA
| | - Raphael Prodromou
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, USA
| | - Paul Greback-Clarke
- Biomanufacturing Training and Education Center (BTEC), North Carolina State University, Raleigh, North Carolina, USA
| | - Will Smith
- Biomanufacturing Training and Education Center (BTEC), North Carolina State University, Raleigh, North Carolina, USA
| | - Brandyn Moore
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, USA
| | - Ryan Kilgore
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, USA
| | - Christopher Cummings
- Biomanufacturing Training and Education Center (BTEC), North Carolina State University, Raleigh, North Carolina, USA
| | - Jennifer Pancorbo
- Biomanufacturing Training and Education Center (BTEC), North Carolina State University, Raleigh, North Carolina, USA
| | - Gary Gilleskie
- Biomanufacturing Training and Education Center (BTEC), North Carolina State University, Raleigh, North Carolina, USA
| | - Michael A Daniele
- North Carolina Viral Vector Initiative in Research and Learning (NC-VVIRAL), North Carolina State University, Raleigh, North Carolina, USA
- Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina at Chapel Hill, Raleigh, North Carolina, USA
| | - Stefano Menegatti
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina, USA
- Biomanufacturing Training and Education Center (BTEC), North Carolina State University, Raleigh, North Carolina, USA
- North Carolina Viral Vector Initiative in Research and Learning (NC-VVIRAL), North Carolina State University, Raleigh, North Carolina, USA
- LigaTrap Technologies LLC, Raleigh, North Carolina, USA
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Nair B, Kuriakose A, Baby B, Nath L. Tumor-Specific Growth Factor (TSGF): A Futuristic Tumor Biomarker in Early Diagnosis of Cancer. Adv Pharm Bull 2023; 13:483-488. [PMID: 37646066 PMCID: PMC10460812 DOI: 10.34172/apb.2023.051] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 02/04/2022] [Accepted: 04/29/2022] [Indexed: 09/01/2023] Open
Abstract
Despite the significant improvement in the treatment modalities, cancer is one of the fastest-growing chronic disease conditions all over the world. Genetic and Epigenetic alterations in the normal physiology of the cell are the key factor for tumor development. These changes can trigger the production of abnormal protein expressions through stimulation of different signaling pathways and can deeply affect normal cell growth and proliferation. Any altered protein expression, genetic variation, micro-RNA or post-translational protein modifications that indicate tumorigenesis can act as an early signal termed as biomarker. Cancer, being a multistep process with accumulating genetic and epigenetic alterations, could be detected early with suitable biomarkers. There are several proteins such as AFP, CA-125, PSA, troponin, CEA, osteopontin, CA 19-9 that act as biomarkers which help in early detection, prognosis, and monitoring of disease progression, a hunt for newer biomarkers with higher specificity and sensitivity is still ongoing. Tumor-specific growth factor (TSGF) is one such budding and prevailing tumor biomarker used for the early-stage detection of several types of carcinomas. TSGF is a gene that helps in tumor angiogenesis and gets released during the preliminary stages from cancer cells that ensure the vascular proliferation of the same. In this review, the clinical investigations of TSGF in different kinds of malignancy is discussed in detail and suggests the possibility of using TSGF as a biomarker in early diagnosis of cancer.
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Affiliation(s)
- Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita VishwaVidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala 682041, India
| | - Anisha Kuriakose
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita VishwaVidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala 682041, India
| | | | - Lekshmi.R. Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita VishwaVidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala 682041, India
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Makgoo L, Mosebi S, Mbita Z. The Role of Death-Associated Protein Kinase-1 in Cell Homeostasis-Related Processes. Genes (Basel) 2023; 14:1274. [PMID: 37372454 DOI: 10.3390/genes14061274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/10/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Tremendous amount of financial resources and manpower have been invested to understand the function of numerous genes that are deregulated during the carcinogenesis process, which can be targeted for anticancer therapeutic interventions. Death-associated protein kinase 1 (DAPK-1) is one of the genes that have shown potential as biomarkers for cancer treatment. It is a member of the kinase family, which also includes Death-associated protein kinase 2 (DAPK-2), Death-associated protein kinase 3 (DAPK-3), Death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK-1) and Death-associated protein kinase-related apoptosis-inducing kinase 2 (DRAK-2). DAPK-1 is a tumour-suppressor gene that is hypermethylated in most human cancers. Additionally, DAPK-1 regulates a number of cellular processes, including apoptosis, autophagy and the cell cycle. The molecular basis by which DAPK-1 induces these cell homeostasis-related processes for cancer prevention is less understood; hence, they need to be investigated. The purpose of this review is to discuss the current understanding of the mechanisms of DAPK-1 in cell homeostasis-related processes, especially apoptosis, autophagy and the cell cycle. It also explores how the expression of DAPK-1 affects carcinogenesis. Since deregulation of DAPK-1 is implicated in the pathogenesis of cancer, altering DAPK-1 expression or activity may be a promising therapeutic strategy against cancer.
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Affiliation(s)
- Lilian Makgoo
- Department of Biochemistry, Microbiology and Biotechnology, University of Limpopo, Private Bag X1106, Pietersburg 0727, Sovenga, South Africa
| | - Salerwe Mosebi
- Department of Life and Consumer Sciences, University of South Africa, Private Bag X6, Johanessburg 1710, Florida, South Africa
| | - Zukile Mbita
- Department of Biochemistry, Microbiology and Biotechnology, University of Limpopo, Private Bag X1106, Pietersburg 0727, Sovenga, South Africa
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