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Gui Y, Hou R, Huang Y, Zhou Y, Liu S, Meng L, Li Y, Sang Lam F, Ding R, Cao Y, Li G, Lu X, Li X. Discovering Cell-Targeting Ligands and Cell-Surface Receptors by Selection of DNA-Encoded Chemical Libraries against Cancer Cells without Predefined Targets. Angew Chem Int Ed Engl 2025; 64:e202421172. [PMID: 39794292 DOI: 10.1002/anie.202421172] [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: 10/31/2024] [Revised: 12/26/2024] [Accepted: 01/10/2025] [Indexed: 01/13/2025]
Abstract
Small molecules that can bind to specific cells have broad application in cancer diagnosis and treatment. Screening large chemical libraries against live cells is an effective strategy for discovering cell-targeting ligands. The DNA-encoded chemical library (DEL or DECL) technology has emerged as a robust tool in drug discovery and has been successfully utilized in identifying ligands for biological targets. However, nearly all DEL selections have predefined targets, while target-agnostic DEL selections interrogating the entire cell surface remain underexplored. Herein, we systematically optimized a cell-based DEL selection method against cancer cells without predefined targets. A 104.96-million-member DEL was selected against MDA-MB-231 and MCF-7 breast cancer cells, representing high and low metastatic properties, respectively, which led to the identification of cell-specific small molecules. We further demonstrated cell-targeting applications of these ligands in cancer photodynamic therapy and targeted drug delivery. Finally, leveraging the DNA tag of DEL compounds, we identified α-enolase (ENO1) as the cell surface receptor of one of the ligands targeting the more aggressive MDA-MB-231 cells. Overall, this work offers an efficient approach for discovering cell-targeting small molecule ligands by using DELs and demonstrates that DELs can be a useful tool to identify specific surface receptors on cancer cells.
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Grants
- 2023A1515010711 Basic and Applied Basic Research Foundation of Guangdong Province
- AoE/P-705/16, 17301118, 17111319, 17303220, 17300321, 17300423, C7005-20G, C7016-22G, C7035-23G, N_HKU702/23, and T12-705-24-R Research Grants Council, University Grants Committee
- SZBL2020090501008 Shenzhen Bay Laboratory
- 91953203, 22377139 National Natural Science Foundation of China
- Major Project Science and Technology Commission of Shanghai Municipality
- Laboratory for Synthetic Chemistry and Chemical Biology Innovation and Technology Commission
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Affiliation(s)
- Yuhan Gui
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China
- Laboratory for Synthetic Chemistry and Chemical Biology Limited, Health@InnoHK, Innovation and Technology Commission, Units, 1503-1511, 15/F., Building 17 W, Hong Kong SAR, China
| | - Rui Hou
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China
- Laboratory for Synthetic Chemistry and Chemical Biology Limited, Health@InnoHK, Innovation and Technology Commission, Units, 1503-1511, 15/F., Building 17 W, Hong Kong SAR, China
| | - Yuchen Huang
- Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen, China
| | - Yu Zhou
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China
- Laboratory for Synthetic Chemistry and Chemical Biology Limited, Health@InnoHK, Innovation and Technology Commission, Units, 1503-1511, 15/F., Building 17 W, Hong Kong SAR, China
- Present address: Institute of Translational Medicine & School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China, 211198
| | - Shihao Liu
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China
| | - Ling Meng
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China
- Laboratory for Synthetic Chemistry and Chemical Biology Limited, Health@InnoHK, Innovation and Technology Commission, Units, 1503-1511, 15/F., Building 17 W, Hong Kong SAR, China
| | - Ying Li
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China
| | - Fong Sang Lam
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China
- Laboratory for Synthetic Chemistry and Chemical Biology Limited, Health@InnoHK, Innovation and Technology Commission, Units, 1503-1511, 15/F., Building 17 W, Hong Kong SAR, China
| | - Ruoyun Ding
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China
| | - Yan Cao
- School of Pharmacy, Naval Medical University, Shanghai, 200433, China
| | - Gang Li
- Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen, China
| | - Xiaojie Lu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Zhang Jiang Hi-Tech Park, Pudong, Shanghai, 201203, P. R. China
| | - Xiaoyu Li
- Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China
- Laboratory for Synthetic Chemistry and Chemical Biology Limited, Health@InnoHK, Innovation and Technology Commission, Units, 1503-1511, 15/F., Building 17 W, Hong Kong SAR, China
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Soto MR, Lewis MM, Leal J, Pan Y, Mohanty RP, Veyssi A, Maier EY, Heiser BJ, Ghosh D. Discovery of peptides for ligand-mediated delivery of mRNA lipid nanoparticles to cystic fibrosis lung epithelia. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102375. [PMID: 39640013 PMCID: PMC11617931 DOI: 10.1016/j.omtn.2024.102375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 10/25/2024] [Indexed: 12/07/2024]
Abstract
For cystic fibrosis patients, a lung-targeted gene therapy would significantly alleviate pulmonary complications associated with morbidity and mortality. However, mucus in the airways and cell entry pose huge delivery barriers for local gene therapy. Here, we used phage display technology to select for and identify mucus- and cell-penetrating peptides against primary human bronchial epithelial cells from cystic fibrosis patients cultured at the air-liquid interface. At the air-liquid interface, primary human bronchial epithelial cells produce mucus and reflect cystic fibrosis disease pathology, making it a clinically relevant model. Using this model, we discovered a lead candidate peptide and incorporated it into lipid nanoparticles to deliver mRNA to primary human bronchial epithelia in vitro and mouse lungs in vivo. Compared to lipid nanoparticles without our peptide, peptide-lipid nanoparticles demonstrated up to 7.8-fold and 3.4-fold higher reporter luciferase bioactivity in vitro and in vivo, respectively. Importantly, these peptides facilitated higher specific uptake of nanoparticles into lung epithelia relative to other cell types. Since gene delivery to primary human bronchial epithelia is a significant challenge, we are encouraged by these results and anticipate that our peptide could be used to successfully deliver cystic fibrosis gene therapies in future work.
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Affiliation(s)
- Melissa R. Soto
- Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, Austin, TX 78712, USA
| | - Mae M. Lewis
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton St., Austin, TX 78712, USA
| | - Jasmim Leal
- Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, Austin, TX 78712, USA
| | - Yuting Pan
- Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, Austin, TX 78712, USA
| | - Rashmi P. Mohanty
- Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, Austin, TX 78712, USA
| | - Arian Veyssi
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton St., Austin, TX 78712, USA
| | - Esther Y. Maier
- College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, Austin, TX 78712, USA
| | - Brittany J. Heiser
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton St., Austin, TX 78712, USA
| | - Debadyuti Ghosh
- Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, Austin, TX 78712, USA
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Muravyeva A, Smirnikhina S. Strategies for Modifying Adenoviral Vectors for Gene Therapy. Int J Mol Sci 2024; 25:12461. [PMID: 39596526 PMCID: PMC11595218 DOI: 10.3390/ijms252212461] [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: 10/21/2024] [Revised: 11/13/2024] [Accepted: 11/18/2024] [Indexed: 11/28/2024] Open
Abstract
Adenoviral vectors (AdVs) are effective vectors for gene therapy due to their broad tropism, large capacity, and high transduction efficiency, making them widely used as oncolytic vectors and for creating vector-based vaccines. This review also considers the application of adenoviral vectors in oncolytic virotherapy and gene therapy for inherited diseases, analyzing strategies to enhance their efficacy and specificity. However, despite significant progress in this field, the use of adenoviral vectors is limited by their high immunogenicity, low specificity to certain cell types, and limited duration of transgene expression. Various strategies and technologies aimed at improving the characteristics of adenoviral vectors are being developed to overcome these limitations. Significant attention is being paid to the creation of tissue-specific promoters, which allow for the controlled expression of transgenes, as well as capsid modifications that enhance tropism to target cells, which also play a key role in reducing immunogenicity and increasing the efficiency of gene delivery. This review focuses on modern approaches to adenoviral vector modifications made to enhance their effectiveness in gene therapy, analyzing the current achievements, challenges, and prospects for applying these technologies in clinical practice, as well as identifying future research directions necessary for successful clinical implementation.
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Affiliation(s)
| | - Svetlana Smirnikhina
- Laboratory of Genome Editing, Research Centre for Medical Genetics, Moskvorechye, 1, 115522 Moscow, Russia
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Fan M, Zhang X, Liu H, Li L, Wang F, Luo L, Zhou X, Liang XJ, Zhang J, Li Z. Reversing Immune Checkpoint Inhibitor-Associated Cardiotoxicity via Bioorthogonal Metabolic Engineering-Driven Extracellular Vesicle Redirecting. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2412340. [PMID: 39308257 DOI: 10.1002/adma.202412340] [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: 08/20/2024] [Revised: 09/12/2024] [Indexed: 11/08/2024]
Abstract
The cardiotoxicity induced by immune checkpoint inhibitors (ICIs) is associated with high mortality rates. T cells play an important role in ICI-induced cardiac injury. The inhibition of local T-cell activity is considered an effective strategy for alleviating ICI-related cardiotoxicity. Tumor-derived extracellular vesicles (EVs) contribute to immunosuppression via PD-L1 overexpression. In this study, a bioorthogonal metabolic engineering-driven EV redirecting (Biomeder) strategy for in situ engineered EVs with myocardial-targeting peptides is developed. Accumulated tumor-derived EV (TuEVs) reverses the immune environment in the heart by increasing PD-L1 levels in cardiomyocytes and/or by directly inhibiting T-cell activity. More importantly, it is found that the redirection of TuEVs further disrupts immunosuppression in tumors, which facilitates anti-tumor activity. Thus, redirecting TuEVs to the heart simultaneously enhances the antitumor efficacy and safety of ICI-based therapy. Furthermore, the Biomeder strategy is successfully expanded to prevent ICI-induced type 1 diabetes. This Biomeder technique is a universal method for the treatment of various ICI-related adverse events.
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Affiliation(s)
- Miao Fan
- The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, 523059, China
- College of Chemistry & Materials Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, State Key Laboratory of New Pharmaceutical Preparations and Excipients, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding, 071002, China
- College of Pharmacy, Hebei Medical University, Shijiazhuang, 050017, China
| | - Xing Zhang
- College of Chemistry & Materials Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, State Key Laboratory of New Pharmaceutical Preparations and Excipients, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding, 071002, China
| | - Huifang Liu
- College of Pharmaceutical Science, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, 071002, China
| | - Lanya Li
- The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, 523059, China
- CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, 100190, China
| | - Fei Wang
- The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, 523059, China
- CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, 100190, China
| | - Li Luo
- The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, 523059, China
- CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, 100190, China
| | - Xiaohan Zhou
- The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, 523059, China
- CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, 100190, China
| | - Xing-Jie Liang
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Southern Medical University, Guangdong, 510515, China
| | - Jinchao Zhang
- College of Chemistry & Materials Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, State Key Laboratory of New Pharmaceutical Preparations and Excipients, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding, 071002, China
| | - Zhenhua Li
- The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, 523059, China
- CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, 100190, China
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5
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Singh D. Beyond the membrane: Exploring non-viral methods for mitochondrial gene delivery. Mitochondrion 2024; 78:101922. [PMID: 38897397 DOI: 10.1016/j.mito.2024.101922] [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: 04/10/2024] [Revised: 05/22/2024] [Accepted: 06/15/2024] [Indexed: 06/21/2024]
Abstract
Mitochondrial disorders, stemming from mutations in mitochondrial DNA (mtDNA), present a significant therapeutic challenge due to their complex pathophysiology and broad spectrum of clinical manifestations. Traditional gene therapy approaches, primarily reliant on viral vectors, face obstacles such as potential immunogenicity, insertional mutagenesis, and the specificity of targeting mtDNA. This review delves into non-viral methods for mitochondrial gene delivery, emerging as a promising alternative to overcome these limitations. Focusing on lipid-based nanoparticles, polymer-based vectors, and mitochondrial-targeted peptides, the mechanisms of action, advantages, and current applications in treating mitochondrial diseases was well elucidated. Non-viral vectors offer several benefits, including reduced immunogenicity, enhanced safety profiles, and the flexibility to carry a wide range of genetic material. We examine case studies where these methods have been applied, highlighting their potential in correcting pathogenic mtDNA mutations and mitigating disease phenotypes. Despite their promise, challenges such as delivery efficiency, specificity, and long-term expression stability persist. The review underscores the need for ongoing research to refine these delivery systems carry a wide range of genetic material. We examine case studies where these methods settings. As we advance our understanding of mitochondrial biology and gene delivery technologies, non-viral methods hold the potential to revolutionize the treatment of mitochondrial disorders, offering hope for therapies that can precisely target and correct the underlying genetic defects.
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Affiliation(s)
- Dilpreet Singh
- University Institute of Pharma Sciences, Chandigarh University, Gharuan, Mohali 140413, India; University Centre for Research and Development, Chandigarh University, Gharuan, Mohali 140413, India.
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6
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Keller AP, Huemer M, Chang CC, Mairpady Shambat S, Bjurnemark C, Oberortner N, Santschi MV, Zinsli LV, Röhrig C, Sobieraj AM, Shen Y, Eichenseher F, Zinkernagel AS, Loessner MJ, Schmelcher M. Systemic application of bone-targeting peptidoglycan hydrolases as a novel treatment approach for staphylococcal bone infection. mBio 2023; 14:e0183023. [PMID: 37768041 PMCID: PMC10653945 DOI: 10.1128/mbio.01830-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 08/08/2023] [Indexed: 09/29/2023] Open
Abstract
IMPORTANCE The rising prevalence of antimicrobial resistance in S. aureus has rendered treatment of staphylococcal infections increasingly difficult, making the discovery of alternative treatment options a high priority. Peptidoglycan hydrolases, a diverse group of bacteriolytic enzymes, show high promise as such alternatives due to their rapid and specific lysis of bacterial cells, independent of antibiotic resistance profiles. However, using these enzymes for the systemic treatment of local infections, such as osteomyelitis foci, needs improvement, as the therapeutic distributes throughout the whole host, resulting in low concentrations at the actual infection site. In addition, the occurrence of intracellularly persisting bacteria can lead to relapsing infections. Here, we describe an approach using tissue-targeting to increase the local concentration of therapeutic enzymes in the infected bone. The enzymes were modified with a short targeting moiety that mediated accumulation of the therapeutic in osteoblasts and additionally enables targeting of intracellularly surviving bacteria.
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Affiliation(s)
- Anja P. Keller
- Institute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland
| | - Markus Huemer
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Chun-Chi Chang
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Srikanth Mairpady Shambat
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | | | - Nicole Oberortner
- Institute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland
| | | | - Léa V. Zinsli
- Institute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland
| | - Christian Röhrig
- Institute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland
| | - Anna M. Sobieraj
- Institute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland
| | - Yang Shen
- Institute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland
| | - Fritz Eichenseher
- Institute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland
| | - Annelies S. Zinkernagel
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Martin J. Loessner
- Institute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland
| | - Mathias Schmelcher
- Institute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland
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Ragothaman M, Yoo SY. Engineered Phage-Based Cancer Vaccines: Current Advances and Future Directions. Vaccines (Basel) 2023; 11:vaccines11050919. [PMID: 37243023 DOI: 10.3390/vaccines11050919] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/22/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
Bacteriophages have emerged as versatile tools in the field of bioengineering, with enormous potential in tissue engineering, vaccine development, and immunotherapy. The genetic makeup of phages can be harnessed for the development of novel DNA vaccines and antigen display systems, as they can provide a highly organized and repetitive presentation of antigens to immune cells. Bacteriophages have opened new possibilities for the targeting of specific molecular determinants of cancer cells. Phages can be used as anticancer agents and carriers of imaging molecules and therapeutics. In this review, we explored the role of bacteriophages and bacteriophage engineering in targeted cancer therapy. The question of how the engineered bacteriophages can interact with the biological and immunological systems is emphasized to comprehend the underlying mechanism of phage use in cancer immunotherapy. The effectiveness of phage display technology in identifying high-affinity ligands for substrates, such as cancer cells and tumor-associated molecules, and the emerging field of phage engineering and its potential in the development of effective cancer treatments are discussed. We also highlight phage usage in clinical trials as well as the related patents. This review provides a new insight into engineered phage-based cancer vaccines.
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Affiliation(s)
- Murali Ragothaman
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 46241, Republic of Korea
| | - So Young Yoo
- BIO-IT Foundry Technology Institute, Pusan National University, Busan 46241, Republic of Korea
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Lin P, Xue Y, Mu X, Shao Y, Lu Q, Jin X, Yinwang E, Zhang Z, Zhou H, Teng W, Sun H, Chen W, Shi W, Shi C, Zhou X, Jiang X, Yu X, Ye Z. Tumor Customized 2D Supramolecular Nanodiscs for Ultralong Tumor Retention and Precise Photothermal Therapy of Highly Heterogeneous Cancers. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2200179. [PMID: 35396783 DOI: 10.1002/smll.202200179] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/18/2022] [Indexed: 06/14/2023]
Abstract
Target therapy for highly heterogeneous cancers represents a major clinical challenge due to the lack of recurrent therapeutic targets identified in these tumors. Herein, the authors report a tumor-customized targeting photothermal therapy (PTT) strategy for highly heterogeneous cancers, by which 2D supramolecular self-assembled nanodiscs are modified with tumor-specific binding peptides identified by phage display techniques. Taking osteosarcoma (OS) as a model heterogeneous cancer, an OS targeting peptide (OTP) is first selected after biopanning and is demonstrated to successfully bind to this heterogeneous cancer cells/tissues. Successful conjugation of OTP to heptamethine cyanine (Cy7)-based 2D nanodiscs Cy7-TCF (2-dicyanomethylene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran,TCF) enables the 2D nanodiscs to specifically target the heterogeneous tumor. Notably, a single dose injection of this targeted nanodisc (T-ND) not only effectively induces enhanced photothermal tumor ablation under near-infrared light, but also exhibits sevenfold increase of tumor retention time (more than 24 days) compared to generic nanomedicine. Thus, the authors' findings suggest that the combination of phage display-based affinity peptides selection and 2D supramolecular nanodiscs leads to the development of a platform technology for highly heterogeneous cancers precise therapy, offering specific tumor targeting, ultralong tumor retention, and precise PTT.
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Affiliation(s)
- Peng Lin
- Orthopedics Research Institute of Zhejiang University, Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, 310000, P. R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310000, P. R. China
| | - Yucheng Xue
- Orthopedics Research Institute of Zhejiang University, Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, 310000, P. R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310000, P. R. China
| | - Xueluer Mu
- Key Lab of Biobased Polymer Materials of Shandong Provincial, Education Department, College of Polymer Science and Engineering, Qingdao University of Science and Technology, Qingdao, Shandong, 266042, P. R. China
| | - Youyou Shao
- Department of Nephrology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, P. R. China
| | - Qian Lu
- Department of Orthopedics, Huzhou Hospital, Zhejiang University, Huzhou Central Hospital, Huzhou, Zhejiang, 313000, China
| | - Xiangang Jin
- Orthopedics Research Institute of Zhejiang University, Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, 310000, P. R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310000, P. R. China
| | - Eloy Yinwang
- Orthopedics Research Institute of Zhejiang University, Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, 310000, P. R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310000, P. R. China
| | - Zengjie Zhang
- Orthopedics Research Institute of Zhejiang University, Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, 310000, P. R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310000, P. R. China
| | - Hao Zhou
- Orthopedics Research Institute of Zhejiang University, Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, 310000, P. R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310000, P. R. China
| | - Wangsiyuan Teng
- Orthopedics Research Institute of Zhejiang University, Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, 310000, P. R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310000, P. R. China
| | - Hangxiang Sun
- Orthopedics Research Institute of Zhejiang University, Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, 310000, P. R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310000, P. R. China
| | - Weida Chen
- Orthopedics Research Institute of Zhejiang University, Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, 310000, P. R. China
| | - Wei Shi
- Orthopedics Research Institute of Zhejiang University, Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, 310000, P. R. China
| | - Cangyi Shi
- Orthopedics Research Institute of Zhejiang University, Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, 310000, P. R. China
| | - Xianfeng Zhou
- Key Lab of Biobased Polymer Materials of Shandong Provincial, Education Department, College of Polymer Science and Engineering, Qingdao University of Science and Technology, Qingdao, Shandong, 266042, P. R. China
| | - Xuesheng Jiang
- Department of Orthopedics, Huzhou Hospital, Zhejiang University, Huzhou Central Hospital, Huzhou, Zhejiang, 313000, China
| | - Xiaohua Yu
- Orthopedics Research Institute of Zhejiang University, Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, 310000, P. R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310000, P. R. China
| | - Zhaoming Ye
- Orthopedics Research Institute of Zhejiang University, Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, 310000, P. R. China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, 310000, P. R. China
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9
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Yue H, Li Y, Yang M, Mao C. T7 Phage as an Emerging Nanobiomaterial with Genetically Tunable Target Specificity. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2103645. [PMID: 34914854 PMCID: PMC8811829 DOI: 10.1002/advs.202103645] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 10/27/2021] [Indexed: 05/05/2023]
Abstract
Bacteriophages, also known as phages, are specific antagonists against bacteria. T7 phage has drawn massive attention in precision medicine owing to its distinctive advantages, such as short replication cycle, ease in displaying peptides and proteins, high stability and cloning efficiency, facile manipulation, and convenient storage. By introducing foreign gene into phage DNA, T7 phage can present foreign peptides or proteins site-specifically on its capsid, enabling it to become a nanoparticle that can be genetically engineered to screen and display a peptide or protein capable of recognizing a specific target with high affinity. This review critically introduces the biomedical use of T7 phage, ranging from the detection of serological biomarkers and bacterial pathogens, recognition of cells or tissues with high affinity, design of gene vectors or vaccines, to targeted therapy of different challenging diseases (e.g., bacterial infection, cancer, neurodegenerative disease, inflammatory disease, and foot-mouth disease). It also discusses perspectives and challenges in exploring T7 phage, including the understanding of its interactions with human body, assembly into scaffolds for tissue regeneration, integration with genome editing, and theranostic use in clinics. As a genetically modifiable biological nanoparticle, T7 phage holds promise as biomedical imaging probes, therapeutic agents, drug and gene carriers, and detection tools.
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Affiliation(s)
- Hui Yue
- School of Materials Science and EngineeringZhejiang UniversityHangzhouZhejiang310027P. R. China
| | - Yan Li
- Institute of Applied Bioresource ResearchCollege of Animal ScienceZhejiang UniversityYuhangtang Road 866HangzhouZhejiang310058P. R. China
| | - Mingying Yang
- Institute of Applied Bioresource ResearchCollege of Animal ScienceZhejiang UniversityYuhangtang Road 866HangzhouZhejiang310058P. R. China
| | - Chuanbin Mao
- School of Materials Science and EngineeringZhejiang UniversityHangzhouZhejiang310027P. R. China
- Department of Chemistry and BiochemistryStephenson Life Science Research CenterInstitute for Biomedical Engineering, Science and TechnologyUniversity of Oklahoma101 Stephenson ParkwayNormanOklahoma73019‐5251USA
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10
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Liu X, Zhang L, Jiang W, Yang Z, Gan Z, Yu C, Tao R, Chen H. In vitro and in vivo evaluation of liposomes modified with polypeptides and red cell membrane as a novel drug delivery system for myocardium targeting. Drug Deliv 2021; 27:599-606. [PMID: 32308051 PMCID: PMC7191910 DOI: 10.1080/10717544.2020.1754525] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Ischemic cardiac disease (ICD) is a cardiovascular disease with high morbidity and mortality. In this study, a novel myocardial targeted drug delivery system was developed represented by co-modified liposomes consisting of red cell membrane (RCM), and the peptides TAT and PCM. Liposomes were prepared using a membrane dispersion-ultrasonic method; the prepared 1% TAT and 3% PCM micelles were mixed with liposomes and under overnight stirring to form polypeptid-modified liposomes. RCM was isolated from mice blood, and the mechanical force facilitated RCM adhesion to the lipid bilayer. The characteristics of liposomes such as the morphology, particle size, zeta-potential, and RCM-conjugation to lipsomes were evaluated. Uptake efficiency and cellular toxicity of liposomes were evaluated in vitro on myocardial cells (MCs). As regard the experiments in vivo, liposomes were intravenously injected into mice, and the blood and organs were collectedat different times to analyze the pharmacokinetics profile of liposomes. The cellular uptake and intracellular distribution of liposomes of different composition into MCs demonstrated that RCM-modified liposomes had the best delivery capability. The pharmacokinetics study further demonstrated that RCM-modified liposomes had prolonged mean residence time (MRT) and more accumulation in the heart. This study indicated that RCM can be used to modify liposomes in combination with polypeptides, because such modification increases the myocardial targeting of liposomes. Therefore, this system constructed in this study might be a potentially effective myocardial drug delivery system.
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Affiliation(s)
- Xueyan Liu
- College of Pharmacy, Chongqing Medical University, Chongqing, China.,Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing, China
| | - Liangke Zhang
- College of Pharmacy, Chongqing Medical University, Chongqing, China.,Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing, China
| | - Wengao Jiang
- College of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Zhangyou Yang
- College of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Zongjie Gan
- College of Pharmacy, Chongqing Medical University, Chongqing, China.,Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing, China.,Research Center for Innovative Pharmaceutical and Excipient Analysis Technology, Chongqing Medical University, Chongqing, China
| | - Chao Yu
- College of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Ran Tao
- College of Pharmacy, Chongqing Medical University, Chongqing, China.,Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing, China
| | - Huali Chen
- College of Pharmacy, Chongqing Medical University, Chongqing, China.,Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing, China.,Research Center for Innovative Pharmaceutical and Excipient Analysis Technology, Chongqing Medical University, Chongqing, China
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11
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Abstract
Mutations in approximately 80 genes have been implicated as the cause of various genetic kidney diseases. However, gene delivery to kidney cells from the blood is inefficient because of the natural filtering functions of the glomerulus, and research into and development of gene therapy directed toward kidney disease has lagged behind as compared with hepatic, neuromuscular, and ocular gene therapy. This lack of progress is in spite of numerous genetic mouse models of human disease available to the research community and many vectors in existence that can theoretically deliver genes to kidney cells with high efficiency. In the past decade, several groups have begun to develop novel injection techniques in mice, such as retrograde ureter, renal vein, and direct subcapsular injections to help resolve the issue of gene delivery to the kidney through the blood. In addition, the ability to retarget vectors specifically toward kidney cells has been underutilized but shows promise. This review discusses how recent advances in gene delivery to the kidney and the field of gene therapy can leverage the wealth of knowledge of kidney genetics to work toward developing gene therapy products for patients with kidney disease.
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Affiliation(s)
- Jeffrey D Rubin
- Virology and Gene Therapy Graduate Program, Mayo Clinic, Rochester, MN, USA
| | - Michael A Barry
- Division of Infectious Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
- Department of Immunology, Mayo Clinic, Rochester, MN, USA.
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
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12
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Barry MA, Rubin JD, Lu SC. Retargeting adenoviruses for therapeutic applications and vaccines. FEBS Lett 2020; 594:1918-1946. [PMID: 31944286 PMCID: PMC7311308 DOI: 10.1002/1873-3468.13731] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 12/02/2019] [Accepted: 12/03/2019] [Indexed: 12/29/2022]
Abstract
Adenoviruses (Ads) are robust vectors for therapeutic applications and vaccines, but their use can be limited by differences in their in vitro and in vivo pharmacologies. This review emphasizes that there is not just one Ad, but a whole virome of diverse viruses that can be used as therapeutics. It discusses that true vector targeting involves not only retargeting viruses, but importantly also detargeting the viruses from off-target cells.
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Affiliation(s)
- Michael A Barry
- Department of Medicine, Division of Infectious Diseases, Department of Immunology, Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Jeffrey D Rubin
- Virology and Gene Therapy Graduate Program, Mayo Graduate School, Mayo Clinic, Rochester, MN, USA
| | - Shao-Chia Lu
- Virology and Gene Therapy Graduate Program, Mayo Graduate School, Mayo Clinic, Rochester, MN, USA
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13
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Xu H, Cao B, Li Y, Mao C. Phage nanofibers in nanomedicine: Biopanning for early diagnosis, targeted therapy, and proteomics analysis. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2020; 12:e1623. [PMID: 32147974 DOI: 10.1002/wnan.1623] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 01/02/2020] [Accepted: 02/04/2020] [Indexed: 12/16/2022]
Abstract
Display of a peptide or protein of interest on the filamentous phage (also known as bacteriophage), a biological nanofiber, has opened a new route for disease diagnosis and therapy as well as proteomics. Earlier phage display was widely used in protein-protein or antigen-antibody studies. In recent years, its application in nanomedicine is becoming increasingly popular and encouraging. We aim to review the current status in this research direction. For better understanding, we start with a brief introduction of basic biology and structure of the filamentous phage. We present the principle of phage display and library construction method on the basis of the filamentous phage. We summarize the use of the phage displayed peptide library for selecting peptides with high affinity against cells or tissues. We then review the recent applications of the selected cell or tissue targeting peptides in developing new targeting probes and therapeutics to advance the early diagnosis and targeted therapy of different diseases in nanomedicine. We also discuss the integration of antibody phage display and modern proteomics in discovering new biomarkers or target proteins for disease diagnosis and therapy. Finally, we propose an outlook for further advancing the potential impact of phage display on future nanomedicine. This article is categorized under: Biology-Inspired Nanomaterials > Protein and Virus-Based Structures.
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Affiliation(s)
- Hong Xu
- Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, Oklahoma, USA
| | - Binrui Cao
- Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, Oklahoma, USA
| | - Yan Li
- Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, Oklahoma, USA
| | - Chuanbin Mao
- Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, Oklahoma, USA
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14
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Methods for generating and screening libraries of genetically encoded cyclic peptides in drug discovery. Nat Rev Chem 2020; 4:90-101. [PMID: 37128052 DOI: 10.1038/s41570-019-0159-2] [Citation(s) in RCA: 136] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/16/2019] [Indexed: 12/14/2022]
Abstract
Drug discovery has traditionally focused on using libraries of small molecules to identify therapeutic drugs, but new modalities, especially libraries of genetically encoded cyclic peptides, are increasingly used for this purpose. Several technologies now exist for the production of libraries of cyclic peptides, including phage display, mRNA display and split-intein circular ligation of peptides and proteins. These different approaches are each compatible with particular methods of screening libraries, such as functional or affinity-based screening, and screening in vitro or in cells. These techniques allow the rapid preparation of libraries of hundreds of millions of molecules without the need for chemical synthesis, and have therefore lowered the entry barrier to generating and screening for inhibitors of a given target. This ease of use combined with the inherent advantages of the cyclic-peptide scaffold has yielded inhibitors of targets that have proved difficult to drug with small molecules. Multiple reports demonstrate that cyclic peptides act as privileged scaffolds in drug discovery, particularly against 'undruggable' targets such as protein-protein interactions. Although substantial challenges remain in the clinical translation of hits from screens of cyclic-peptide libraries, progress continues to be made in this area, with an increasing number of cyclic peptides entering clinical trials. Here, we detail the various platforms for producing and screening libraries of genetically encoded cyclic peptides and discuss and evaluate the advantages and disadvantages of each approach when deployed for drug discovery.
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15
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Mohanty RP, Liu X, Kim JY, Peng X, Bhandari S, Leal J, Arasappan D, Wylie DC, Dong T, Ghosh D. Identification of peptide coatings that enhance diffusive transport of nanoparticles through the tumor microenvironment. NANOSCALE 2019; 11:17664-17681. [PMID: 31536061 PMCID: PMC7209769 DOI: 10.1039/c9nr05783h] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
In solid tumors, increasing drug penetration promotes their regression and improves the therapeutic index of compounds. However, the heterogeneous extracellular matrix (ECM) acts as a steric and interaction barrier that hinders effective transport of therapeutics, including nanomedicines. Specifically, the interactions between the ECM and surface physicochemical properties of nanomedicines (e.g. charge, hydrophobicity) affect their diffusion and penetration. To address the challenges using existing surface chemistries, we used peptide-presenting phage libraries as a high-throughput approach to screen and identify peptides as coatings with desired physicochemical properties that improve diffusive transport through the tumor microenvironment. Through iterative screening against the ECM and identification by next-generation DNA sequencing and analysis, we selected individual clones and quantify their transport by diffusion assays. Here, we identified a net-neutral charge, hydrophilic peptide P4 that facilitates significantly higher diffusive transport of phage than negative control through in vitro tumor ECM. Through alanine mutagenesis, we confirmed that the hydrophilicity, charge, and spatial ordering impact diffusive transport. The P4 phage clone exhibited almost 200-fold improved uptake in ex vivo pancreatic tumor xenografts compared to the negative control. Nanoparticles coated with P4 exhibited ∼40-fold improvement in diffusivity in pancreatic tumor tissues, and P4-coated particles demonstrated less hindered diffusivity through the ECM compared to functionalized control particles. By leveraging the power of molecular diversity using phage display, we can greatly expand the chemical space of surface chemistries that can improve the transport of nanomedicines through the complex tumor microenvironment to ultimately improve their efficacy.
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Affiliation(s)
- Rashmi P Mohanty
- Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, USA.
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16
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Bordelon T, Bobay B, Murphy A, Reese H, Shanahan C, Odeh F, Broussard A, Kormos C, Menegatti S. Translating antibody-binding peptides into peptoid ligands with improved affinity and stability. J Chromatogr A 2019; 1602:284-299. [DOI: 10.1016/j.chroma.2019.05.047] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 05/03/2019] [Accepted: 05/24/2019] [Indexed: 12/18/2022]
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17
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Jończyk-Matysiak E, Łodej N, Kula D, Owczarek B, Orwat F, Międzybrodzki R, Neuberg J, Bagińska N, Weber-Dąbrowska B, Górski A. Factors determining phage stability/activity: challenges in practical phage application. Expert Rev Anti Infect Ther 2019; 17:583-606. [PMID: 31322022 DOI: 10.1080/14787210.2019.1646126] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Introduction: Phages consist of nucleic acids and proteins that may lose their activity under different physico-chemical conditions. The production process of phage formulations may decrease phage infectivity. Ingredients present in the preparation may influence phage particles, although preparation and storage conditions may also cause variations in phage titer. Significant factors are the manner of phage application, the patient's immune system status, the type of medication being taken, and diet. Areas covered: We discuss factors determining phage activity and stability, which is relevant for the preparation and application of phage formulations with the highest therapeutic efficacy. Our article should be helpful for more insightful implementation of clinical trials, which could pave the way for successful phage therapy. Expert opinion: The number of naturally occurring phages is practically unlimited and phages vary in their susceptibility to external factors. Modern methods offer engineering techniques which should lead to enhanced precision in phage delivery and anti-bacterial activity. Recent data suggesting that phages may also be used in treating nonbacterial infections as well as anti-inflammatory and immunomodulatory agents add further weight to such studies. It may be anticipated that different phage activities could have varying susceptibility to factors determining their actions.
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Affiliation(s)
- Ewa Jończyk-Matysiak
- a Bacteriophage Laboratory, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences , Wroclaw , Poland
| | - Norbert Łodej
- a Bacteriophage Laboratory, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences , Wroclaw , Poland
| | - Dominika Kula
- a Bacteriophage Laboratory, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences , Wroclaw , Poland
| | - Barbara Owczarek
- a Bacteriophage Laboratory, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences , Wroclaw , Poland
| | - Filip Orwat
- a Bacteriophage Laboratory, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences , Wroclaw , Poland
| | - Ryszard Międzybrodzki
- a Bacteriophage Laboratory, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences , Wroclaw , Poland.,b Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw , Warsaw , Poland.,c Phage Therapy Unit, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences , Wroclaw , Poland
| | - Joanna Neuberg
- a Bacteriophage Laboratory, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences , Wroclaw , Poland
| | - Natalia Bagińska
- a Bacteriophage Laboratory, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences , Wroclaw , Poland
| | - Beata Weber-Dąbrowska
- a Bacteriophage Laboratory, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences , Wroclaw , Poland.,c Phage Therapy Unit, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences , Wroclaw , Poland
| | - Andrzej Górski
- a Bacteriophage Laboratory, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences , Wroclaw , Poland.,b Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw , Warsaw , Poland.,c Phage Therapy Unit, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences , Wroclaw , Poland
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18
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Wang Y, Gao S, Lv J, Lin Y, Zhou L, Han L. Phage Display Technology and its Applications in Cancer Immunotherapy. Anticancer Agents Med Chem 2019; 19:229-235. [PMID: 30370861 DOI: 10.2174/1871520618666181029140814] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2017] [Revised: 06/01/2018] [Accepted: 06/20/2018] [Indexed: 02/06/2023]
Abstract
Background:Phage display is an effective technology for generation and selection targeting protein for a variety of purpose, which is based on a direct linkage between the displayed protein and the DNA sequence encoding it and utilized in selecting peptides, improving peptides affinity and indicating protein-protein interactions. Phage particles displaying peptide have the potential to apply in the identification of cell-specific targeting molecules, identification of cancer cell surface biomarkers, identification anti-cancer peptide, and the design of peptide-based anticancer therapy.Method/Results:Literature searches, reviews and assessments about Phage were performed in this review from PubMed and Medline databases.Conclusion:The phage display technology is an inexpensive method for expressing exogenous peptides, generating unique peptides that bind any given target and investigating protein-protein interactions. Due to the powerful ability to insert exogenous gene and display exogenous peptides on the surface, phages may represent a powerful peptide delivery system that can be utilized to develop rapid, efficient, safe and inexpensive cancer therapy methods.
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Affiliation(s)
- Yicun Wang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, Second Hospital of Jilin University, Changchun, China
| | - Shuohui Gao
- Third Hospital of Jilin University, Changchun, China
| | - Jiayin Lv
- Third Hospital of Jilin University, Changchun, China
| | - Yang Lin
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, Second Hospital of Jilin University, Changchun, China
| | - Li Zhou
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, Second Hospital of Jilin University, Changchun, China
| | - Liying Han
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, Second Hospital of Jilin University, Changchun, China
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19
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Mucus-penetrating phage-displayed peptides for improved transport across a mucus-like model. Int J Pharm 2018; 553:57-64. [PMID: 30268850 DOI: 10.1016/j.ijpharm.2018.09.055] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 09/21/2018] [Accepted: 09/21/2018] [Indexed: 01/19/2023]
Abstract
The objective of this work is to use phage display libraries as a screening tool to identify peptides that facilitate transport across the mucus barrier. Mucus is a complex selective barrier to particles and molecules, limiting penetration to the epithelial surface of mucosal tissues. In mucus-associated diseases such as cystic fibrosis (CF), mucus has increased viscoelasticity and a higher concentration of covalent and non-covalent physical entanglements compared to healthy tissues, which greatly hinders permeability and transport of drugs and particles across the mucosae for therapeutic delivery. Treatment of CF lung diseases and associated infections must overcome this abnormal mucosal barrier. Critical bottlenecks hindering effective drug penetration remain and while recent studies have shown hydrophilic, net-neutral charge polymers can improve the transport of nanoparticles and minimize interactions with mucus, there is a dearth of alternative carriers available. We hypothesized that the screening of a phage peptide library against a CF mucus model would lead to the identification of phage-displayed peptide sequences able to improve transport in mucus. These combinatorial libraries possess a large diversity of peptide-based formulations (108-109) to achieve unprecedented screening for potential mucus-penetrating peptides. Here, phage clones displaying discovered peptides were shown to have up to 2.6-fold enhanced diffusivity in the CF mucus model. In addition, we demonstrate reduced binding affinities to mucin compared to wild-type control. These findings suggest that phage display libraries can be used as a strategy to improve transmucosal delivery.
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20
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Peng X, Nguyen A, Ghosh D. Quantification of M13 and T7 bacteriophages by TaqMan and SYBR green qPCR. J Virol Methods 2017; 252:100-107. [PMID: 29196210 DOI: 10.1016/j.jviromet.2017.11.012] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 10/23/2017] [Accepted: 11/27/2017] [Indexed: 12/17/2022]
Abstract
TaqMan and SYBR Green quantitative PCR (qPCR) methods were developed as DNA-based approaches to reproducibly enumerate M13 and T7 phages from phage display selection experiments individually and simultaneously. The genome copies of M13 and T7 phages were quantified by TaqMan or SYBR Green qPCR referenced against M13 and T7 DNA standard curves of known concentrations. TaqMan qPCR was capable of quantifying M13 and T7 phage DNA simultaneously with a detection range of 2.75*101-2.75*108genome copies(gc)/μL and 2.66*101-2.66*108 genome copies(gc)/μL respectively. TaqMan qPCR demonstrated an efficient amplification efficiency (Es) of 0.97 and 0.90 for M13 and T7 phage DNA, respectively. SYBR Green qPCR was ten-fold more sensitive than TaqMan qPCR, able to quantify 2.75-2.75*107gc/μL and 2.66*101-2.66*107gc/μL of M13 and T7 phage DNA, with an amplification efficiency Es of 1.06 and 0.78, respectively. Due to its superior sensitivity, SYBR Green qPCR was used to enumerate M13 and T7 phage display clones selected against a cell line, and quantified titers demonstrated accuracy comparable to titers from traditional double-layer plaque assay. Compared to enzyme linked immunosorbent assay, both qPCR methods exhibited increased detection sensitivity and reproducibility. These qPCR methods are reproducible, sensitive, and time-saving to determine their titers and to quantify a large number of phage samples individually or simultaneously, thus avoiding the need for time-intensive double-layer plaque assay. These findings highlight the attractiveness of qPCR for phage enumeration for applications ranging from selection to next-generation sequencing (NGS).
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Affiliation(s)
- Xiujuan Peng
- Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy
| | - Alex Nguyen
- College of Natural Science, University of Texas, Austin, United States
| | - Debadyuti Ghosh
- Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy.
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21
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Nguyen TV, Anguiano-Zarate SS, Matchett WE, Barry ME, Barry MA. Retargeted and detargeted adenovirus for gene delivery to the muscle. Virology 2017; 514:118-123. [PMID: 29172089 DOI: 10.1016/j.virol.2017.10.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 09/29/2017] [Accepted: 10/03/2017] [Indexed: 01/09/2023]
Abstract
We previously selected muscle binding peptides 12.51 and 12.52 from "context-specific" phage display libraries for introduction into adenovirus (Ad) vectors. In this work, these peptides were inserted into the hypervariable region (HVR) 5 loop of the Ad5 hexon protein to display 720 peptides per virions. HVR-12.51 and 12.52 increased transduction of C2C12 cells up to 20-fold when compared to unmodified Ad5. 12.51 increased in vivo muscle transduction 2 to 7-fold over unmodified Ad after intramuscular injection in mice and hamsters. 12.52 did not increase muscle transduction. Notably, insertion of 12.51 into the hexon reduced liver transduction 80-fold when compared to unmodified Ad5 after intravenous injection. Increased muscle transduction in mice translated into increased immune responses after gene-based vaccination. These data suggest there are merits to retargeting and detargeting benefits to modifying the hexons of Ads with peptide ligands.
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Affiliation(s)
- Tien V Nguyen
- Department of Internal Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, MN, United States; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, United States
| | | | - William E Matchett
- Virology and Gene Therapy Graduate Program, Mayo Clinic, Rochester, MN, United States
| | - Mary E Barry
- Department of Internal Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, MN, United States; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, United States
| | - Michael A Barry
- Department of Internal Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, MN, United States; Department of Immunology, Mayo Clinic, Rochester, MN, United States; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, United States.
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22
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ten Brummelhuis N, Wilke P, Börner HG. Identification of Functional Peptide Sequences to Lead the Design of Precision Polymers. Macromol Rapid Commun 2017; 38. [DOI: 10.1002/marc.201700632] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 09/26/2017] [Indexed: 12/16/2022]
Affiliation(s)
- Niels ten Brummelhuis
- Laboratory for Organic Synthesis of Functional Systems; Department of Chemistry; Humboldt-Universität zu Berlin; Brook-Taylor-Str. 2 D-12489 Berlin Germany
| | - Patrick Wilke
- Laboratory for Organic Synthesis of Functional Systems; Department of Chemistry; Humboldt-Universität zu Berlin; Brook-Taylor-Str. 2 D-12489 Berlin Germany
| | - Hans G. Börner
- Laboratory for Organic Synthesis of Functional Systems; Department of Chemistry; Humboldt-Universität zu Berlin; Brook-Taylor-Str. 2 D-12489 Berlin Germany
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23
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Wang X, Huang H, Zhang L, Bai Y, Chen H. PCM and TAT co-modified liposome with improved myocardium delivery: in vitro and in vivo evaluations. Drug Deliv 2017; 24:339-345. [PMID: 28165817 PMCID: PMC8241121 DOI: 10.1080/10717544.2016.1253121] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 10/20/2016] [Accepted: 10/23/2016] [Indexed: 10/25/2022] Open
Abstract
In this study, PCM and TAT co-modified liposome was developed as a novel drug carrier for myocardium delivery with evaluation of its in vitro and in vivo properties. Liposomes containing fluorescent probe coumarin-6 were prepared by thin-film hydration. The PCM ligands specifically bind to the PCM receptors in the extracellular connective tissue of primary myocardium cells (MCs), while the TAT ligands functioned as a classical cell penetrating peptide to make liposomes internalized by MCs. The unmodified liposome (L), PCM-modified liposome (PL), TAT-modified liposome (TL) and PCM and TAT co-modified liposome (PTL) were prepared and characterized. The cellular uptake and intracellular distribution of various liposomes by MCs demonstrated that PTL had the best delivery capability. Peptide inhibition assay indicated that the uptake of PL could be inhibited by PCM. However, TAT could almost not suppress the uptake of TL. In addition, the CCK-8 experiments showed that liposomes had low cytotoxicity. In vivo fluorescent images of frozen sections and HPLC-fluorescence analysis further demonstrated that PTL had highest myocardium distribution. The results of this study demonstrated that PCM and TAT co-modifying could improve the myocardial targeting ability of liposome.
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Affiliation(s)
- Xin Wang
- Department of pharmaceutics, School of Pharmacy, Chongqing Medical University, Chongqing, P. R. China and
- Chongqing Research Center for Pharmaceutical Engineering, Chongqing, P. R. China
| | - Hua Huang
- Department of pharmaceutics, School of Pharmacy, Chongqing Medical University, Chongqing, P. R. China and
- Chongqing Research Center for Pharmaceutical Engineering, Chongqing, P. R. China
| | - Liangke Zhang
- Department of pharmaceutics, School of Pharmacy, Chongqing Medical University, Chongqing, P. R. China and
- Chongqing Research Center for Pharmaceutical Engineering, Chongqing, P. R. China
| | - Yan Bai
- Department of pharmaceutics, School of Pharmacy, Chongqing Medical University, Chongqing, P. R. China and
- Chongqing Research Center for Pharmaceutical Engineering, Chongqing, P. R. China
| | - Huali Chen
- Department of pharmaceutics, School of Pharmacy, Chongqing Medical University, Chongqing, P. R. China and
- Chongqing Research Center for Pharmaceutical Engineering, Chongqing, P. R. China
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David A. Peptide ligand-modified nanomedicines for targeting cells at the tumor microenvironment. Adv Drug Deliv Rev 2017; 119:120-142. [PMID: 28506743 DOI: 10.1016/j.addr.2017.05.006] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 03/17/2017] [Accepted: 05/09/2017] [Indexed: 02/06/2023]
Abstract
Since their initial discovery more than 30years ago, tumor-homing peptides have become an increasingly useful tool for targeted delivery of therapeutic and diagnostic agents into tumors. Today, it is well accepted that cells at the tumor microenvironment (TME) contribute in many ways to cancer development and progression. Tumor-homing peptide-decorated nanomedicines can interact specifically with surface receptors expressed on cells in the TME, improve cellular uptake of nanomedicines by target cells, and impair tumor growth and progression. Moreover, peptide ligand-modified nanomedicines can potentially accumulate in the target tissue at higher concentrations than would small conjugates, thus increasing overall target tissue exposure to the therapeutic agent, enhance therapeutic efficacy and reduce side effects. This review describes the most studied peptide ligands aimed at targeting cells in the TME, discusses major obstacles and principles in the design of ligands for drug targeting and provides an overview of homing peptides in ligand-targeted nanomedicines that are currently in development for cancer therapy and diagnosis.
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Affiliation(s)
- Ayelet David
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, and the Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.
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25
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Molecular tumor targeting of gelonin by fusion with F3 peptide. Acta Pharmacol Sin 2017; 38:897-906. [PMID: 28414205 DOI: 10.1038/aps.2017.20] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Accepted: 01/20/2017] [Indexed: 12/11/2022]
Abstract
Therapeutically potent macromolecular drugs have shown great promise for overcoming the limitations of small-molecule anti-cancer drugs. But tumor cell-selective intracellular delivery of the macromolecules remains a major hurdle for their successful clinical application. To overcome this challenge, we engineered a novel genetic fusion protein (F3-Gel) that composed of F3 peptide, a tumor-homing peptide, and gelonin, a plant-derived ribosome-inactivating protein (RIP), and then evaluated its anti-cancer activity in vitro and in vivo. The F3-Gel-encoding gene was synthesized by genetic recombination, and F3-Gel was successfully expressed in E coli. The anti-cancer activity of the produced F3-Gel was evaluated by various in vitro assays, which revealed that F3-Gel maintained equipotent protein synthesis inhibition activity (IC50=11 pmol/L) as unmodified gelonin (IC50=10 pmol/L). Furthermore, F3-Gel displayed enhanced cellular uptake into cancer cells (U87 MG, HeLa, LnCaP and 9L) than noncancerous cells (293 HEK and SVGp12). Compared with gelonin, F3-Gel exerted significantly higher cytotoxicity against these cancer cells. F3-Gel displayed significantly greater inhibition of protein translation in U87 MG cells: F3-Gel (0.5 μmol/L) was able to reduce the protein level to less than 50%, while gelonin (1 μmol/L) did not affect the intracellular protein level. In a U87 MG xenograft tumor-bearing mouse model, F3-Gel was accumulated in the tumor site at much higher levels and maintained for a prolonged time compared with gelonin. Administration of F3-Gel (0.5, 0.75 mol/kg, iv) caused 36% and 66%, respectively, inhibition of tumor growth in U87 MG xenograft mice, suggesting that it is a promising candidate drug for cancer treatment. Furthermore, this study demonstrates that fusion of F3 peptide to a potent macromolecule could provides an effective method for targeting tumors and eventually could improve their druggability.
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26
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Petrenko V, Gillespie J. Paradigm shift in bacteriophage-mediated delivery of anticancer drugs: from targeted 'magic bullets' to self-navigated 'magic missiles'. Expert Opin Drug Deliv 2017; 14:373-384. [PMID: 27466706 PMCID: PMC5544533 DOI: 10.1080/17425247.2016.1218463] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
INTRODUCTION New phage-directed nanomedicines have emerged recently as a result of the in-depth study of the genetics and structure of filamentous phage and evolution of phage display and phage nanobiotechnology. This review focuses on the progress made in the development of the cancer-targeted nanomaterials and discusses the trends in using phage as a bioselectable molecular navigation system. Areas covered: The merging of phage display technologies with nanotechnology in recent years has proved promising in different areas of medicine and technology, such as medical diagnostics, molecular imaging, vaccine development and targeted drug/gene delivery, which is the focus of this review. The authors used data obtained from their research group and sourced using Science Citation Index (Web of Science) and NCBI PubMed search resources. Expert opinion: First attempts of adapting traditional concepts of direct targeting of tumor using phage-targeted nanomedicines has shown minimal improvements. With discovery and study of biological and technical barriers that prevent anti-tumor drug delivery, a paradigm shift from traditional drug targeting to nanomedicine navigation systems is required. The advanced bacteriophage-driven self-navigation systems are thought to overcome those barriers using more precise, localized phage selection methods, multi-targeting 'promiscuous' ligands and advanced multifunctional nanomedicine platforms.
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Affiliation(s)
- V.A. Petrenko
- Department of Pathobiology, Auburn University, AL 36849, USA
| | - J.W. Gillespie
- Department of Pathobiology, Auburn University, AL 36849, USA
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27
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Dissanayake S, Denny WA, Gamage S, Sarojini V. Recent developments in anticancer drug delivery using cell penetrating and tumor targeting peptides. J Control Release 2017; 250:62-76. [DOI: 10.1016/j.jconrel.2017.02.006] [Citation(s) in RCA: 198] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Revised: 02/02/2017] [Accepted: 02/02/2017] [Indexed: 12/13/2022]
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28
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Sunderland KS, Yang M, Mao C. Phage-Enabled Nanomedicine: From Probes to Therapeutics in Precision Medicine. Angew Chem Int Ed Engl 2017; 56:1964-1992. [PMID: 27491926 PMCID: PMC5311110 DOI: 10.1002/anie.201606181] [Citation(s) in RCA: 122] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2016] [Indexed: 01/08/2023]
Abstract
Both lytic and temperate bacteriophages (phages) can be applied in nanomedicine, in particular, as nanoprobes for precise disease diagnosis and nanotherapeutics for targeted disease treatment. Since phages are bacteria-specific viruses, they do not naturally infect eukaryotic cells and are not toxic to them. They can be genetically engineered to target nanoparticles, cells, tissues, and organs, and can also be modified with functional abiotic nanomaterials for disease diagnosis and treatment. This Review will summarize the current use of phage structures in many aspects of precision nanomedicine, including ultrasensitive biomarker detection, enhanced bioimaging for disease diagnosis, targeted drug and gene delivery, directed stem cell differentiation, accelerated tissue formation, effective vaccination, and nanotherapeutics for targeted disease treatment. We will also propose future directions in the area of phage-based nanomedicines, and discuss the state of phage-based clinical trials.
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Affiliation(s)
- Kegan S Sunderland
- Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, Oklahoma, 73019, USA
| | - Mingying Yang
- Institute of Applied Bioresource Research, College of Animal Science, Zhejiang University, Yuhangtang Road 866, Hangzhou, Zhejiang, 310058, China
| | - Chuanbin Mao
- Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, Oklahoma, 73019, USA
- School of Materials Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, China
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29
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Li Y, Lee RJ, Huang X, Li Y, Lv B, Wang T, Qi Y, Hao F, Lu J, Meng Q, Teng L, Zhou Y, Xie J, Teng L. Single-step microfluidic synthesis of transferrin-conjugated lipid nanoparticles for siRNA delivery. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2017; 13:371-381. [DOI: 10.1016/j.nano.2016.09.014] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 09/10/2016] [Accepted: 09/24/2016] [Indexed: 11/26/2022]
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30
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Sun X, Li Y, Liu T, Li Z, Zhang X, Chen X. Peptide-based imaging agents for cancer detection. Adv Drug Deliv Rev 2017; 110-111:38-51. [PMID: 27327937 PMCID: PMC5235994 DOI: 10.1016/j.addr.2016.06.007] [Citation(s) in RCA: 170] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 06/10/2016] [Accepted: 06/11/2016] [Indexed: 12/31/2022]
Abstract
Selective receptor-targeting peptide based agents have attracted considerable attention in molecular imaging of tumor cells that overexpress corresponding peptide receptors due to their unique properties such as rapid clearance from circulation as well as high affinities and specificities for their targets. The rapid growth of chemistry modification techniques has enabled the design and development of various peptide-based imaging agents with enhanced metabolic stability, favorable pharmacokinetics, improved binding affinity and selectivity, better imaging ability as well as biosafety. Among them, many radiolabeled peptides have already been translated into the clinic with impressive diagnostic accuracy and sensitivity. This review summarizes the current status in the development of peptide-based imaging agents with an emphasis on the consideration of probe design including the identification of suitable peptides, the chemical modification of probes and the criteria for clinical translation. Specific examples in clinical trials have been provided as well with respect to their diagnostic capability compared with other FDA approved imaging agents.
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Affiliation(s)
- Xiaolian Sun
- Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China.
| | - Yesen Li
- Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Ting Liu
- Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Zijing Li
- Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Xianzhong Zhang
- Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China.
| | - Xiaoyuan Chen
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health, Bethesda, MD 20892, United States.
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31
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Sunderland KS, Yang M, Mao C. Nanomedizin auf Phagenbasis: von Sonden zu Therapeutika für eine Präzisionsmedizin. Angew Chem Int Ed Engl 2017. [DOI: 10.1002/ange.201606181] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Kegan S. Sunderland
- Department of Chemistry and Biochemistry Stephenson Life Sciences Research Center University of Oklahoma 101 Stephenson Parkway Norman Oklahoma 73019 USA
| | - Mingying Yang
- Institute of Applied Bioresource Research College of Animal Science Zhejiang University Yuhangtang Road 866 Hangzhou Zhejiang 310058 China
| | - Chuanbin Mao
- Department of Chemistry and Biochemistry Stephenson Life Sciences Research Center University of Oklahoma 101 Stephenson Parkway Norman Oklahoma 73019 USA
- School of Materials Science and Engineering Zhejiang University Hangzhou Zhejiang 310027 China
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32
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Martins IM, Reis RL, Azevedo HS. Phage Display Technology in Biomaterials Engineering: Progress and Opportunities for Applications in Regenerative Medicine. ACS Chem Biol 2016; 11:2962-2980. [PMID: 27661443 DOI: 10.1021/acschembio.5b00717] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The field of regenerative medicine has been gaining momentum steadily over the past few years. The emphasis in regenerative medicine is to use various in vitro and in vivo approaches that leverage the intrinsic healing mechanisms of the body to treat patients with disabling injuries and chronic diseases such as diabetes, osteoarthritis, and degenerative disorders of the cardiovascular and central nervous system. Phage display has been successfully employed to identify peptide ligands for a wide variety of targets, ranging from relatively small molecules (enzymes, cell receptors) to inorganic, organic, and biological (tissues) materials. Over the past two decades, phage display technology has advanced tremendously and has become a powerful tool in the most varied fields of research, including biotechnology, materials science, cell biology, pharmacology, and diagnostics. The growing interest in and success of phage display libraries is largely due to its incredible versatility and practical use. This review discusses the potential of phage display technology in biomaterials engineering for applications in regenerative medicine.
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Affiliation(s)
- Ivone M. Martins
- 3B’s Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of
the European Institute of Excellence on Tissue Engineering and Regenerative
Medicine, AvePark, 4805-717 Barco, Guimarães, Portugal
- ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
- CEB − Centre of Biological Engineering, University of Minho, 4710-057, Braga, Portugal
| | - Rui L. Reis
- 3B’s Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of
the European Institute of Excellence on Tissue Engineering and Regenerative
Medicine, AvePark, 4805-717 Barco, Guimarães, Portugal
- ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Helena S. Azevedo
- 3B’s Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of
the European Institute of Excellence on Tissue Engineering and Regenerative
Medicine, AvePark, 4805-717 Barco, Guimarães, Portugal
- ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
- School of Engineering & Materials Science, Queen Mary University of London, London E1 4NS, United Kingdom
- Institute
of Bioengineering, Queen Mary University of London, London E1 4NS, United Kingdom
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33
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Karimi M, Mirshekari H, Moosavi Basri SM, Bahrami S, Moghoofei M, Hamblin MR. Bacteriophages and phage-inspired nanocarriers for targeted delivery of therapeutic cargos. Adv Drug Deliv Rev 2016; 106:45-62. [PMID: 26994592 PMCID: PMC5026880 DOI: 10.1016/j.addr.2016.03.003] [Citation(s) in RCA: 133] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 03/04/2016] [Accepted: 03/08/2016] [Indexed: 02/08/2023]
Abstract
The main goal of drug delivery systems is to target therapeutic cargoes to desired cells and to ensure their efficient uptake. Recently a number of studies have focused on designing bio-inspired nanocarriers, such as bacteriophages, and synthetic carriers based on the bacteriophage structure. Bacteriophages are viruses that specifically recognize their bacterial hosts. They can replicate only inside their host cell and can act as natural gene carriers. Each type of phage has a particular shape, a different capacity for loading cargo, a specific production time, and their own mechanisms of supramolecular assembly, that have enabled them to act as tunable carriers. New phage-based technologies have led to the construction of different peptide libraries, and recognition abilities provided by novel targeting ligands. Phage hybridization with non-organic compounds introduces new properties to phages and could be a suitable strategy for construction of bio-inorganic carriers. In this review we try to cover the major phage species that have been used in drug and gene delivery systems, and the biological application of phages as novel targeting ligands and targeted therapeutics.
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Affiliation(s)
- Mahdi Karimi
- Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirshekari
- Advanced Nanobiotechnology & Nanomedicine Research Group [ANNRG], Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Masoud Moosavi Basri
- Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran; Civil & Environmental Engineering Department, Shahid Beheshti University, Tehran, Iran
| | - Sajad Bahrami
- Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran; Student Research Committee, Iran University of Medical Sciences, Tehran, IR, Iran
| | - Mohsen Moghoofei
- Student Research Committee, Iran University of Medical Sciences, Tehran, IR, Iran; Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
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34
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Sharma S, Chatterjee S, Datta S, Prasad R, Dubey D, Prasad RK, Vairale MG. Bacteriophages and its applications: an overview. Folia Microbiol (Praha) 2016; 62:17-55. [PMID: 27718043 DOI: 10.1007/s12223-016-0471-x] [Citation(s) in RCA: 123] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 09/12/2016] [Indexed: 01/21/2023]
Abstract
Bacteriophages (or phages), the most abundant viral entity of the planet, are omni-present in all the ecosystems. On the basis of their unique characteristics and anti-bacterial property, phages are being freshly evaluated taxonomically. Phages replicate inside the host either by lytic or lysogenic mode after infecting and using the cellular machinery of a bacterium. Since their discovery by Twort and d'Herelle in the early 1900s, phage became an important agent for combating pathogenic bacteria in clinical treatments and its related research gained momentum. However, due to recent emergence of bacterial resistance on antibiotics, applications of phage (phage therapy) become an inevitable option of research. Phage particles become popular as a biotechnological tool and treatment of pathogenic bacteria in a range of applied areas. However, there are few concerns over the application of phage-based solutions. This review deals with the updated phage taxonomy (ICTV 2015 Release and subsequent revision) and phage biology and the recent development of its application in the areas of biotechnology, biosensor, therapeutic medicine, food preservation, aquaculture diseases, pollution remediation, and wastewater treatment and issues related with limitations of phage-based remedy.
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Affiliation(s)
- Sonika Sharma
- Defence Research Laboratory, DRDO, Tezpur, Assam, 784001, India
| | | | | | - Rishika Prasad
- Defence Research Laboratory, DRDO, Tezpur, Assam, 784001, India
- School of Biomedical Engineering, Cornell University, Ithaca, NY, 14850, USA
| | | | | | - Mohan G Vairale
- Defence Research Laboratory, DRDO, Tezpur, Assam, 784001, India
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35
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Aghebati-Maleki L, Bakhshinejad B, Baradaran B, Motallebnezhad M, Aghebati-Maleki A, Nickho H, Yousefi M, Majidi J. Phage display as a promising approach for vaccine development. J Biomed Sci 2016; 23:66. [PMID: 27680328 PMCID: PMC5041315 DOI: 10.1186/s12929-016-0285-9] [Citation(s) in RCA: 146] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 09/13/2016] [Indexed: 12/31/2022] Open
Abstract
Bacteriophages are specific antagonists to bacterial hosts. These viral entities have attracted growing interest as optimal vaccine delivery vehicles. Phages are well-matched for vaccine design due to being highly stable under harsh environmental conditions, simple and inexpensive large scale production, and potent adjuvant capacities. Phage vaccines have efficient immunostimulatory effects and present a high safety profile because these viruses have made a constant relationship with the mammalian body during a long-standing evolutionary period. The birth of phage display technology has been a turning point in the development of phage-based vaccines. Phage display vaccines are made by expressing multiple copies of an antigen on the surface of immunogenic phage particles, thereby eliciting a powerful and effective immune response. Also, the ability to produce combinatorial peptide libraries with a highly diverse pool of randomized ligands has transformed phage display into a straightforward, versatile and high throughput screening methodology for the identification of potential vaccine candidates against different diseases in particular microbial infections. These libraries can be conveniently screened through an affinity selection-based strategy called biopanning against a wide variety of targets for the selection of mimotopes with high antigenicity and immunogenicity. Also, they can be panned against the antiserum of convalescent individuals to recognize novel peptidomimetics of pathogen-related epitopes. Phage display has represented enormous promise for finding new strategies of vaccine discovery and production and current breakthroughs promise a brilliant future for the development of different phage-based vaccine platforms.
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Affiliation(s)
- Leili Aghebati-Maleki
- Immunology Research Center, Tabriz University of Medical sciences, Tabriz, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Babak Bakhshinejad
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Ali Aghebati-Maleki
- Immunology Research Center, Tabriz University of Medical sciences, Tabriz, Iran
| | - Hamid Nickho
- Immunology Research Center, Tabriz University of Medical sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Jafar Majidi
- Immunology Research Center, Tabriz University of Medical sciences, Tabriz, Iran. .,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Wen AM, Steinmetz NF. Design of virus-based nanomaterials for medicine, biotechnology, and energy. Chem Soc Rev 2016; 45:4074-126. [PMID: 27152673 PMCID: PMC5068136 DOI: 10.1039/c5cs00287g] [Citation(s) in RCA: 257] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This review provides an overview of recent developments in "chemical virology." Viruses, as materials, provide unique nanoscale scaffolds that have relevance in chemical biology and nanotechnology, with diverse areas of applications. Some fundamental advantages of viruses, compared to synthetically programmed materials, include the highly precise spatial arrangement of their subunits into a diverse array of shapes and sizes and many available avenues for easy and reproducible modification. Here, we will first survey the broad distribution of viruses and various methods for producing virus-based nanoparticles, as well as engineering principles used to impart new functionalities. We will then examine the broad range of applications and implications of virus-based materials, focusing on the medical, biotechnology, and energy sectors. We anticipate that this field will continue to evolve and grow, with exciting new possibilities stemming from advancements in the rational design of virus-based nanomaterials.
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Affiliation(s)
- Amy M Wen
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA.
| | - Nicole F Steinmetz
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA. and Department of Radiology, Case Western Reserve University, Cleveland, OH 44106, USA and Department of Materials Science and Engineering, Case Western Reserve University, Cleveland, OH 44106, USA and Department of Macromolecular Science and Engineering, Case Western Reserve University, Cleveland, OH 44106, USA and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
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37
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Stern LA, Schrack IA, Johnson SM, Deshpande A, Bennett NR, Harasymiw LA, Gardner MK, Hackel BJ. Geometry and expression enhance enrichment of functional yeast-displayed ligands via cell panning. Biotechnol Bioeng 2016; 113:2328-41. [PMID: 27144954 DOI: 10.1002/bit.26001] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Revised: 03/23/2016] [Accepted: 04/25/2016] [Indexed: 01/10/2023]
Abstract
Yeast surface display has proven to be an effective tool in the discovery and evolution of ligands with new or improved binding activity. Selections for binding activity are generally carried out using immobilized or fluorescently labeled soluble domains of target molecules such as recombinant ectodomain fragments. While this method typically provides ligands with high affinity and specificity for the soluble molecular target, translation to binding true membrane-bound cellular target is commonly problematic. Direct selections against mammalian cell surfaces can be carried out either exclusively or in combination with soluble target-based selections to further direct towards ligands for genuine cellular target. Using a series of fibronectin domain, affibody, and Gp2 ligands and human cell lines expressing a range of their targets, epidermal growth factor receptor and carcinoembryonic antigen, this study quantitatively identifies the elements that dictate ligand enrichment and yield. Most notably, extended flexible linkers between ligand and yeast enhance enrichment ratios from 1.4 ± 0.8 to 62 ± 57 for a low-affinity (>600 nM) binder on cells with high target expression and from 14 ± 13 to 74 ± 25 for a high-affinity binder (2 nM) on cells with medium valency. Inversion of the yeast display fusion from C-terminal display to N-terminal display still enables enrichment albeit with 40-97% reduced efficacy. Collectively, this study further enlightens the conditions-while highlighting new approaches-that yield successful enrichment of yeast-displayed binding ligands via panning on mammalian cells. Biotechnol. Bioeng. 2016;113: 2328-2341. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Lawrence A Stern
- Department of Chemical Engineering and Materials Science, University of Minnesota-Twin Cities, Minneapolis, Minnesota, 55455
| | - Ian A Schrack
- Department of Chemical Engineering and Materials Science, University of Minnesota-Twin Cities, Minneapolis, Minnesota, 55455
| | - Sadie M Johnson
- Department of Chemical Engineering and Materials Science, University of Minnesota-Twin Cities, Minneapolis, Minnesota, 55455
| | - Aakash Deshpande
- Department of Chemical Engineering and Materials Science, University of Minnesota-Twin Cities, Minneapolis, Minnesota, 55455
| | - Nathaniel R Bennett
- Department of Chemical Engineering and Materials Science, University of Minnesota-Twin Cities, Minneapolis, Minnesota, 55455
| | - Lauren A Harasymiw
- Department of Genetics, Cell Biology, and Development, University of Minnesota-Twin Cities, Minneapolis, Minnesota
| | - Melissa K Gardner
- Department of Genetics, Cell Biology, and Development, University of Minnesota-Twin Cities, Minneapolis, Minnesota
| | - Benjamin J Hackel
- Department of Chemical Engineering and Materials Science, University of Minnesota-Twin Cities, Minneapolis, Minnesota, 55455.
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38
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Chung J, Shim H, Kim K, Lee D, Kim WJ, Kang DH, Kang SW, Jo H, Kwon K. Discovery of novel peptides targeting pro-atherogenic endothelium in disturbed flow regions -Targeted siRNA delivery to pro-atherogenic endothelium in vivo. Sci Rep 2016; 6:25636. [PMID: 27173134 PMCID: PMC4901192 DOI: 10.1038/srep25636] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 04/20/2016] [Indexed: 01/27/2023] Open
Abstract
Atherosclerosis occurs preferentially in arterial regions exposed to disturbed blood flow. Targeting these pro-atherogenic regions is a potential anti-atherogenic therapeutic approach, but it has been extremely challenging. Here, using in vivo phage display approach and the partial carotid ligation model of flow-induced atherosclerosis in mouse, we identified novel peptides that specifically bind to endothelial cells (ECs) exposed to disturbed flow condition in pro-atherogenic regions. Two peptides, CLIRRTSIC and CPRRSHPIC, selectively bound to arterial ECs exposed to disturbed flow not only in the partially ligated carotids but also in the lesser curvature and branching point of the aortic arch in mice as well as human pulmonary artery branches. Peptides were conjugated to branched polyethylenimine-polyethylene glycol polymer to generate polyplexes carrying siRNA targeting intercellular adhesion molecule-1 (siICAM-1). In mouse model, CLIRRTSIC polyplexes carrying si-ICAM-1 specifically bound to endothelium in disturbed flow regions, reducing endothelial ICAM-1 expression. Mass spectrometry analysis revealed that non-muscle myosin heavy chain II A (NMHC IIA) is a protein targeted by CLIRRTSIC peptide. Further studies showed that shear stress regulates NMHC IIA expression and localization in ECs. The CLIRRTSIC is a novel peptide that could be used for targeted delivery of therapeutics such as siRNAs to pro-atherogenic endothelium.
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Affiliation(s)
- Jihwa Chung
- Medical Research Institute, School of Medicine, Ewha Womans University, Seoul,158-710, Republic of Korea
| | - Hyunbo Shim
- Departments of Bioinspired Science and Life Science, Ewha Womans University, 11-1 Daehyun-dong, Seodaemoon-gu, Seoul, 120-750, Republic of Korea
| | - Kwanchang Kim
- Department of Thoracic surgery, School of Medicine, Ewha Womans University, Seoul, 158-710, Republic of Korea
| | - Duhwan Lee
- Center for Self-assembly and Complexity, Institute for Basic Science (IBS), and Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea
| | - Won Jong Kim
- Center for Self-assembly and Complexity, Institute for Basic Science (IBS), and Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea
| | - Dong Hoon Kang
- Department of Life Science, College of Natural Science, Ewha Womans University, 11-1 Daehyun-dong, Seodaemoon-gu, Seoul, 120-750, Republic of Korea
| | - Sang Won Kang
- Department of Life Science, College of Natural Science, Ewha Womans University, 11-1 Daehyun-dong, Seodaemoon-gu, Seoul, 120-750, Republic of Korea
| | - Hanjoong Jo
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA
| | - Kihwan Kwon
- Medical Research Institute, School of Medicine, Ewha Womans University, Seoul,158-710, Republic of Korea.,Department of Internal Medicine, Cardiology Division, School of Medicine, Ewha Womans University, Seoul, 158-710, Republic of Korea
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Domingo-Calap P, Georgel P, Bahram S. Back to the future: bacteriophages as promising therapeutic tools. HLA 2016; 87:133-40. [PMID: 26891965 DOI: 10.1111/tan.12742] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 01/18/2016] [Indexed: 01/21/2023]
Abstract
Bacteriophages (phages), natural predators of bacteria, are becoming increasingly attractive in medical and pharmaceutical applications. After their discovery almost a century ago, they have been particularly instrumental in the comprehension of basic molecular biology and genetics processes. The more recent emergence of multi-drug-resistant bacteria requires novel therapeutic strategies, and phages are being (re)considered as promising potential antibacterial tools. Furthermore, phages are also used for other purposes, e.g. vaccine production, gene/drug carriers, bacterial detection and typing. These new alternative approaches using phages are of major interest and have allowed unexpected developments, from the decipherment of fundamental biological processes to potential clinical applications.
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Affiliation(s)
- P Domingo-Calap
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, LabEx Transplantex, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.,Fédération Hospitalo-Universitaire OMICARE, Centre de Recherche d'Immunologie et d'Hématologie, Strasbourg, France
| | - P Georgel
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, LabEx Transplantex, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.,Fédération Hospitalo-Universitaire OMICARE, Centre de Recherche d'Immunologie et d'Hématologie, Strasbourg, France
| | - S Bahram
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, LabEx Transplantex, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.,Fédération Hospitalo-Universitaire OMICARE, Centre de Recherche d'Immunologie et d'Hématologie, Strasbourg, France
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40
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Wu CH, Liu IJ, Lu RM, Wu HC. Advancement and applications of peptide phage display technology in biomedical science. J Biomed Sci 2016; 23:8. [PMID: 26786672 PMCID: PMC4717660 DOI: 10.1186/s12929-016-0223-x] [Citation(s) in RCA: 228] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Accepted: 01/11/2016] [Indexed: 12/25/2022] Open
Abstract
Combinatorial phage library is a powerful research tool for high-throughput screening of protein interactions. Of all available molecular display techniques, phage display has proven to be the most popular approach. Screening phage-displayed random peptide libraries is an effective means of identifying peptides that can bind target molecules and regulate their function. Phage-displayed peptide libraries can be used for (i) B-cell and T-cell epitope mapping, (ii) selection of bioactive peptides bound to receptors or proteins, disease-specific antigen mimics, peptides bound to non-protein targets, cell-specific peptides, or organ-specific peptides, and (iii) development of peptide-mediated drug delivery systems and other applications. Targeting peptides identified using phage display technology may be useful for basic research and translational medicine. In this review article, we summarize the latest technological advancements in the application of phage-displayed peptide libraries to applied biomedical sciences.
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Affiliation(s)
- Chien-Hsun Wu
- Institute of Cellular and Organismic Biology, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei, 11529, Taiwan
| | - I-Ju Liu
- Institute of Cellular and Organismic Biology, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei, 11529, Taiwan
| | - Ruei-Min Lu
- Institute of Cellular and Organismic Biology, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei, 11529, Taiwan
| | - Han-Chung Wu
- Institute of Cellular and Organismic Biology, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei, 11529, Taiwan.
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41
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Nance ME, Duan D. Perspective on Adeno-Associated Virus Capsid Modification for Duchenne Muscular Dystrophy Gene Therapy. Hum Gene Ther 2015; 26:786-800. [PMID: 26414293 PMCID: PMC4692109 DOI: 10.1089/hum.2015.107] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 09/01/2015] [Indexed: 12/19/2022] Open
Abstract
Duchenne muscular dystrophy (DMD) is a X-linked, progressive childhood myopathy caused by mutations in the dystrophin gene, one of the largest genes in the genome. It is characterized by skeletal and cardiac muscle degeneration and dysfunction leading to cardiac and/or respiratory failure. Adeno-associated virus (AAV) is a highly promising gene therapy vector. AAV gene therapy has resulted in unprecedented clinical success for treating several inherited diseases. However, AAV gene therapy for DMD remains a significant challenge. Hurdles for AAV-mediated DMD gene therapy include the difficulty to package the full-length dystrophin coding sequence in an AAV vector, the necessity for whole-body gene delivery, the immune response to dystrophin and AAV capsid, and the species-specific barriers to translate from animal models to human patients. Capsid engineering aims at improving viral vector properties by rational design and/or forced evolution. In this review, we discuss how to use the state-of-the-art AAV capsid engineering technologies to overcome hurdles in AAV-based DMD gene therapy.
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MESH Headings
- Animals
- Capsid/chemistry
- Capsid/metabolism
- Capsid Proteins/genetics
- Capsid Proteins/metabolism
- Dependovirus/genetics
- Dependovirus/metabolism
- Dystrophin/deficiency
- Dystrophin/genetics
- Gene Expression
- Genetic Therapy/methods
- Genetic Vectors/chemistry
- Genetic Vectors/metabolism
- Humans
- Muscle, Skeletal/metabolism
- Muscle, Skeletal/pathology
- Muscular Dystrophy, Animal/genetics
- Muscular Dystrophy, Animal/metabolism
- Muscular Dystrophy, Animal/pathology
- Muscular Dystrophy, Animal/therapy
- Muscular Dystrophy, Duchenne/genetics
- Muscular Dystrophy, Duchenne/metabolism
- Muscular Dystrophy, Duchenne/pathology
- Muscular Dystrophy, Duchenne/therapy
- Mutation
- Protein Engineering
- Species Specificity
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Affiliation(s)
- Michael E. Nance
- Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, Missouri
| | - Dongsheng Duan
- Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, Missouri
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Nwabor OF, Dickson ID, Ajibo QC. Epidemiology of <i>Salmonella</i> and <i>Salmonellosis</i>. INTERNATIONAL LETTERS OF NATURAL SCIENCES 2015. [DOI: 10.56431/p-w7t10s] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The prevalence of enteritis and its accompanying diarrheal and other health challenges linked to infections with Salmonella has continuously plagued sub Saharan Africa. In Nigeria, typhoid fever is among the major widespread diseases affecting both young and old as a result of many interrelated factors such as inadequate sanitaion, indiscriminate use of antibiotics and fecal contamination of water sources. Morbidity associated with illness due to Salmonella continues to increase with untold fatal consequences, often resulting in death. An accurate figure of cases is difficult to arrive at because only large outbreaks are mostly investigated whereas sporadic cases are under-reported. A vast majority of rural dwellers in Africa often resort to self-medication or seek no treatment at all, hence serving as carries of this disease. Non typhoidal cases of salmonellosis account for about 1.3 billion cases with 3 million deaths annually. Given the magnitude of the economic losses incurred by African nations in the battle against salmonella and salmonellosis, this article takes a critical look at the genus Salmonella, its morphology, isolation, physiological and biochemical characteristics, typing methods, methods of detection, virulence factor, epidemiology and methods of spread within the environment.
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43
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Quinn CM, Lu M, Suiter CL, Hou G, Zhang H, Polenova T. Magic angle spinning NMR of viruses. PROGRESS IN NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY 2015; 86-87:21-40. [PMID: 25919197 PMCID: PMC4413014 DOI: 10.1016/j.pnmrs.2015.02.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Revised: 01/27/2015] [Accepted: 02/08/2015] [Indexed: 05/02/2023]
Abstract
Viruses, relatively simple pathogens, are able to replicate in many living organisms and to adapt to various environments. Conventional atomic-resolution structural biology techniques, X-ray crystallography and solution NMR spectroscopy provided abundant information on the structures of individual proteins and nucleic acids comprising viruses; however, viral assemblies are not amenable to analysis by these techniques because of their large size, insolubility, and inherent lack of long-range order. In this article, we review the recent advances in magic angle spinning NMR spectroscopy that enabled atomic-resolution analysis of structure and dynamics of large viral systems and give examples of several exciting case studies.
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Affiliation(s)
- Caitlin M Quinn
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, United States; Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, 1051 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA 15261, United States.
| | - Manman Lu
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, United States; Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, 1051 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA 15261, United States.
| | - Christopher L Suiter
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, United States; Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, 1051 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA 15261, United States.
| | - Guangjin Hou
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, United States; Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, 1051 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA 15261, United States.
| | - Huilan Zhang
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, United States.
| | - Tatyana Polenova
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, United States; Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, 1051 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA 15261, United States.
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Li J, Feng L, Jiang X. In vivo phage display screen for peptide sequences that cross the blood-cerebrospinal-fluid barrier. Amino Acids 2014; 47:401-5. [PMID: 25408466 DOI: 10.1007/s00726-014-1874-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2014] [Accepted: 11/10/2014] [Indexed: 11/26/2022]
Abstract
There is lack of a barrier between CSF and brain, thus peptide that can cross the blood-cerebrospinal-fluid barrier (BCSFB) will have a greater chance of providing access to the brain. In this study, we screened for a novel peptide sequence that can cross the BCSFB from the systemic circulation using phage display. We applied a 12-mer phage display peptide library (Ph.D.-12) intravenously in rats and recovered phage from the cerebrospinal fluid. A longer circulation time was used according to the biodistributive CSF/blood ratio of the phage particles. Following sequential rounds of isolation, several phages were sequenced, and a peptide sequence (TPSYDTYAAELR, referred to as the TPS peptide) was identified. Clone 12-1, which encoded the TPS peptide, was enriched approximately 53 times greater than the random library phage. After labeling with FITC, the TPS peptide demonstrated significantly greater brain accumulation efficiency. This study demonstrates the feasibility of using in vivo phage display to screen for peptides that can cross the BCSFB from the systemic circulation. In conclusion, the TPS peptide represents a previously unreported promising motif that can be used to design a drug delivery system that can cross the BCSFB.
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Affiliation(s)
- Jingwei Li
- Institute of Medicine, School of Pharmacy, Dali University, Xueren Rd., Dali, 671000, People's Republic of China,
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45
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Bakhshinejad B, Sadeghizadeh M. Bacteriophages and their applications in the diagnosis and treatment of hepatitis B virus infection. World J Gastroenterol 2014; 20:11671-11683. [PMID: 25206272 PMCID: PMC4155358 DOI: 10.3748/wjg.v20.i33.11671] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 02/11/2014] [Accepted: 04/15/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a major global health challenge leading to serious disorders such as cirrhosis and hepatocellular carcinoma. Currently, there exist various diagnostic and therapeutic approaches for HBV infection. However, prevalence and hazardous effects of chronic viral infection heighten the need to develop novel methodologies for the detection and treatment of this infection. Bacteriophages, viruses that specifically infect bacterial cells, with a long-established tradition in molecular biology and biotechnology have recently been introduced as novel tools for the prevention, diagnosis and treatment of HBV infection. Bacteriophages, due to tremendous genetic flexibility, represent potential to undergo a huge variety of surface modifications. This property has been the rationale behind introduction of phage display concept. This powerful approach, together with combinatorial chemistry, has shaped the concept of phage display libraries with diverse applications for the detection and therapy of HBV infection. This review aims to offer an insightful overview of the potential of bacteriophages in the development of helpful prophylactic (vaccine design), diagnostic and therapeutic strategies for HBV infection thereby providing new perspectives to the growing field of bacteriophage researches directing towards HBV infection.
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46
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Bardhan NM, Ghosh D, Belcher AM. M13 virus based detection of bacterial infections in living hosts. JOURNAL OF BIOPHOTONICS 2014; 7:617-23. [PMID: 23576418 PMCID: PMC3989466 DOI: 10.1002/jbio.201300010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Revised: 03/21/2013] [Accepted: 03/23/2013] [Indexed: 05/24/2023]
Abstract
We report a first method for using M13 bacteriophage as a multifunctional scaffold for optically imaging bacterial infections in vivo. We demonstrate that M13 virus conjugated with hundreds of dye molecules (M13-Dye) can target and distinguish pathogenic infections of F-pili expressing and F-negative strains of E. coli. Further, in order to tune this M13-Dye complex suitable for targeting other strains of bacteria, we have used a 1-step reaction for creating an anti-bacterial antibody-M13-Dye probe. As an example, we show anti-S. aureus-M13-Dye able to target and image infections of S. aureus in living hosts, with a 3.7× increase in fluorescence over background.
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Affiliation(s)
- Neelkanth M. Bardhan
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
- The David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Debadyuti Ghosh
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
- The David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Angela M. Belcher
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
- The David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
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47
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Won YW, Bull DA, Kim SW. Functional polymers of gene delivery for treatment of myocardial infarct. J Control Release 2014; 195:110-9. [PMID: 25076177 DOI: 10.1016/j.jconrel.2014.07.041] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 07/18/2014] [Accepted: 07/20/2014] [Indexed: 01/18/2023]
Abstract
Ischemic heart disease is rapidly growing as the common cause of death in the world. It is a disease that occurs as a result of coronary artery stenosis and is caused by the lack of oxygen within cardiac muscles due to an imbalance between oxygen supply and demand. The conventional medical therapy is focused on the use of drug eluting stents, coronary-artery bypass graft surgery and anti-thrombosis. Gene therapy provides great opportunities for treatment of cardiovascular disease. In order for gene therapy to be successful, the development of proper gene delivery systems and hypoxia-regulated gene expression vectors is the most important factors. Several non-viral gene transfer methods have been developed to overcome the safety problems of viral transduction. Some of which include plasmids that regulate gene expression that is controlled by environment specific promoters in the transcriptional or the translational level. This review explores polymeric gene carriers that target the myocardium and hypoxia-inducible vectors, which regulate gene expression in response to hypoxia, and their application in animal myocardial infarction models.
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Affiliation(s)
- Young-Wook Won
- Center for Controlled Chemical Delivery (CCCD), Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA; Division of Cardiothoracic Surgery, Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT, USA
| | - David A Bull
- Division of Cardiothoracic Surgery, Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT, USA
| | - Sung Wan Kim
- Center for Controlled Chemical Delivery (CCCD), Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA.
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48
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Hwang I. Virus outbreaks in chemical and biological sensors. SENSORS (BASEL, SWITZERLAND) 2014; 14:13592-612. [PMID: 25068866 PMCID: PMC4179090 DOI: 10.3390/s140813592] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Revised: 07/08/2014] [Accepted: 07/08/2014] [Indexed: 12/11/2022]
Abstract
Filamentous bacteriophages have successfully been used to detect chemical and biological analytes with increased selectivity and sensitivity. The enhancement largely originates not only from the ability of viruses to provide a platform for the surface display of a wide range of biological ligands, but also from the geometric morphologies of the viruses that constitute biomimetic structures with larger surface area-to-volume ratio. This review will appraise the mechanism of multivalent display of the viruses that enables surface modification of virions either by chemical or biological methods. The accommodation of functionalized virions to various materials, including polymers, proteins, metals, nanoparticles, and electrodes for sensor applications will also be discussed.
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Affiliation(s)
- Inseong Hwang
- The Research Institute of Basic Sciences, Seoul National University, Seoul 147-779, Korea.
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49
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Zhang ZF, Shan X, Wang YX, Wang W, Feng SY, Cui YB. Screening and selection of peptides specific for esophageal cancer cells from a phage display peptide library. J Cardiothorac Surg 2014; 9:76. [PMID: 24779651 PMCID: PMC4018990 DOI: 10.1186/1749-8090-9-76] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Accepted: 04/24/2014] [Indexed: 01/11/2023] Open
Abstract
Background Esophageal cancer is a common malignant tumor of the gastrointestinal tract and is typically diagnosed at an advanced stage due to the absence of early clinical symptoms. Although surgery, chemotherapy, and radiotherapy represent the major treatment methods employed for this cancer, the prognosis of esophageal cancer remains poor. Methods A Ph.D.-12TM Phage Display Peptide Library was screened using an esophageal cancer cell line, Eca109, and a normal esophageal epithelial cell line to identify novel ligands that selectively bind the surface of esophageal cancer cells with high affinity. Results Two polypeptides were isolated that exhibited higher binding affinities and specificity for the Eca109 cells. These peptides were further validated using enzyme-linked immunosorbent assays (ELISAs), immunofluorescence assays, and immunohistochemistry assays. Conclusion Two polypeptides with high binding affinities to esophageal cancer cells were isolated from the Ph.D.-12TM Phage Display Peptide Library. Further studies are needed to characterize the biological effects of these polypeptides and to explore the potential for these peptides to be used for the early screening of esophageal cancer or for cell-targeted therapies that would reduce the toxic side effects of cancer treatment.
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Affiliation(s)
| | | | | | | | | | - You-Bin Cui
- Department of Thoracic Surgery, The First Hospital of Jilin University, 71 Xinmin Street, 130021 Changchun, China.
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50
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Lee YS, Kim SW. Bioreducible polymers for therapeutic gene delivery. J Control Release 2014; 190:424-39. [PMID: 24746626 DOI: 10.1016/j.jconrel.2014.04.012] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 04/09/2014] [Accepted: 04/09/2014] [Indexed: 01/18/2023]
Abstract
Most currently available cationic polymers have significant acute toxicity concerns such as cellular toxicity, aggregation of erythrocytes, and entrapment in the lung capillary bed, largely due to their poor biocompatibility and non-degradability under physiological conditions. To develop more intelligent polymers, disulfide bonds are introduced in the design of biodegradable polymers. Herein, the sustained innovations of biomimetic nano-sized constructs with bioreducible poly(disulfide amine)s demonstrate a viable clinical tool for the treatment of cardiovascular disease, anemia, diabetes, and cancer.
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Affiliation(s)
- Young Sook Lee
- Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, USA.
| | - Sung Wan Kim
- Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, USA; Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea.
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