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功能性高分子在基因/藥物傳遞上之應用 The Research Center of Textile and Fiber Materials National Chung Hsing University 12/10/2014 陳致光 Department of Fiber and Composite Materials Feng Chia University, Taichung Short biography 主要學經歷 89-91:台北科技大學化工學士 91-93:台灣大學化工碩士 94-98:工研院材化所副研究員 98-103:紐約州立大學水牛城分校化工博士 103-now:逢甲大學纖維與複合材料學系助理教授 研究專長 生物可裂解基因載體之設計及合成 以奈米中空微球作為藥物/基因共傳遞載體 奈米微膠囊/纖維複合生醫織物之製備 以靜電紡絲技術製備共聚合物之奈米纖維 Outline Recent developments in polymer chemistry Polymeric materials for biomedical applications Research work in biomedical polymers Summary Acknowledgement What are polymers ? Polymers are macromolecules built up by linking together of large number of much smaller molecules. The small molecules that combine with each other to form polymer molecules are termed as monomers, and the reactions by which they combine are termed polymerization. Oligomers are molecules built up by the linking together of a few monomers. How to classify polymers ? There are several ways to classify polymers. One way to classify polymers is based on how they are produced. Another way to classify polymers is based on whether the repeating units for a polymer are the same. A controlled polymeric architecture by living polymerization Features of living polymerization Controlled molecular weight Narrow size distribution PDI˂1.3 With preserved end functionalities Types of living polymerization techniques Living radical polymerization Living cationic/anionic polymerization Living ring-opening polymerization Biodegradability can be rendered to the backbone http://www.otsukac.co.jp/en/advanced/living/ Click reaction:A powerful tool for building up polymer architectures Azide–alkyne cycloaddition reaction In 2001, Sharpless and coworkers introduced the ‘‘click chemistry’’ concept that defines any reaction which shows the following features Thiol–ene reaction High yield High selectivity Low sensitivity to oxygen and water Simple separation procedures Mild reaction conditions High amenability to starting compounds Thiol–maleimide addition, Thiol–isocyanate addition K. Kempe, A. Krieg, C. R. Becer, U. S. Schubert, Chem Soc Rev 2012, 41, 176. Polymers: an ubiquitous material in everyday life Apparel Electronic devices Cosmetics Automotive parts Medicine (antibodies, protein, excipient, carrier) Just about everywhere Displays Skin care products fibers Drug capsules Polymers for biomedical applications Drug delivery Gene delivery Nanofibers Scaffolds Antimicrobial materials Biomedical Polymers Hydrogels Surgical suture Wound dressings Cancer: a leading cause of mortality in Taiwan General cancer treatments Surgical removal of tumor Radiation therapy Chemotherapy Chemotherapy: the use of anticancer drugs to initiate the apoptosis mechanism by which cancer cells are killed, thereby leading to the tumor shrinkage. http://www.mohw.gov.tw/cht/DOS/Statistic.aspx?f_list_no=312&fod_list_no=1610 Limitations of chemotherapy Example: Paclitaxel (Taxol®)- treats numerous types of cancers Formulated with Cremophor® EL Very high incidence & severity of toxicities Limited therapeutic index Drug exposure to tumor is low Drug exposure to rest of body is high Multi-drug resistance (MDR) Chemotherapy cannot inhibit the tumor growth due to MDR The MDR is caused by two major mechanisms. The first arises from the drug efflux pump protein (P-gp) and the second results from self-anti-apoptosis protein (Bcl-2) Using gene therapy, the expression of these proteins can be effectively suppressed. A safe and efficient gene delivery vector is required. M. Creixell, N. A. Peppas, Nano Today 2012, 7, 367. Using nanocarriers to enhance therapeutic effects of anti-cancer drugs Anti-cancer drugs Pros: An effective modality to combat cancer-related diseases Paclitaxel (PTXL) Nano-sized (EPR effect) Stimuli-responsive feature PEGylation Targeting ability Imaging function Nanotechnology Polymeric Nanomedicine Cons: Doxorubicin (DOX) ✕ ✕ ✕ ✕ ✕ Polymer chemistry Low water solubility Low tumor permeability Fast clearance Adverse effects Non-targeting M. Skwarczynski, Y. Hayashi, Y. Kiso, J Med Chem 2006, 49, 7253. drugs nanocarriers Rational design of polymeric nanoparticles for combating cancer diseases Improved circulation time and stability Increased encapsulation efficiency Various agents can be loaded into nanoparticles Enhanced cell uptake In order to have the EPR effect M. Elsabahy, K. L. Wooley, Chem Soc Rev 2012, 41, 2545. Enhanced permeability and retention (EPR) effect Blood vessels Blood vessels Angiogenesis and enhanced vascular permeability of tumor capillaries and impaired or missing lymphatic clearance of macromolecules result in accumulation of macromolecules (polymers) in tumor tissue. Ulbrich K; Subr V., Adv Drug Delivery Rev 2004, 56, 1023. Materials for gene delivery applications Due to the repeated administration need in gene therapy, the safety and biodegradability of vectors have to be taken into consideration for clinical applications. V. Sokolova, M. Epple, Angew Chem Int Edit 2008, 47, 1382. The applications of polymeric vectors in gene delivery Problems of gene delivery poor cell-uptake low stability rapid clearance DNA or siRNA fragile nature Advantages of polymeric vectors low immune responses biodegradability versatility low cost protecting genes Cationic polymers Nanoplexes Y. C. Chen, S. R. Bathula, J. Li, L. Huang, J Biol Chem 2010, 285, 22639. Polymeric scaffolds for nanomedicines Linear polymerdrug conjugate Polymeric micelle polymeric scaffolds Polymeric nanosphere; nanogel Dendrimer Hyperbrnched polymer Polymeric nanocapsules (NCs) The polymeric scaffolds should have: Significant water solubility or dispersibility Well-controlled nanoparticle sizes for preferred biodistribution Biodegradability to minimize side effects (MW < 45 kDa for complete clearance from circulation) Functionality to link with prodrug, targeting component, detection element, etc. Cationic groups to bind with genes for effective gene delivery. Tong R; Cheng J. Polym Rev, 2007, 47 345. Polymeric materials for drug/gene applications Advantages of polymeric materials • Versatile properties (biodegradability can be designed) • Controllable size • Feasibility of functionalization Drug delivery Gene delivery • Protecting therapeutic genes • Enhancing cell uptake • Avoid rapid clearance • • • • Improved water solubility Long circulation time Enhanced accumulation in tumor Targeting/imaging ability Biodegradable cationic polylactides (CPLAs) and NCs for gene/drug Delivery Goal: To develop novel, safe biodegradable cationic scaffolds for gene and drug delivery. Well-defined structures of CPLA/CPLA NC verified by 1H-NMR, FTIR, GPC, TEM and DLS J. Zou, C. C. Hew, E. Themistou, Y. Li, C.-K. Chen, et al., Adv. Mater. 2011, 23, 4274. C.-K. Chen, W.-C. Law, et al., Adv. Healthcare Mater. 2012, 1, 751. C. H. Jones#, C.-K. Chen#, et al., Mol Pharmaceutics 2013, 10, 1138. CPLA-based nanocomplexes as high efficient vectors for siRNA/pDNA delivery to prostate cancer or macrophage cells siRNA delivery Safe biomaterials TEM image of CPLA/siRNA Cell uptake of nanoplexes pDNA delivery High transfection efficiency in macrophage cells Transfection results Degradable scaffolds TEM image of CPLA/pDNA Strategies for enhancing in vivo applicability of resulting nanocomplexes Stealthy coatings against serum attack 1. Hydrophilic shielding layers Approaches Polyethylene glycol PEG Nanocomplexes 2. Zwitterionic polymers Resistance to nonspecific protein adsorption Improving colloidal stability D. W. Pack, A. S. Hoffman, S. Pun, P. S. Stayton, Nat. Rev. Drug Discovery 2005, 4, 581. J. Ladd, Z. Zhang, S. Chen, J. C. Hower, S. Jiang, Biomacromolecules 2008, 9, 1357. PEGylated CPLAs for for enhanced gene delivery in increasing levels of serum via nanocomplexes Goal: To develop CPLA-based gene vectors to be relevant for clinical applications C.-K. Chen, C.H. Jones, et al. Biomaterials 2013, 34, 9688. Well-defined chemical structures of PEG-b-CPLAs 1H NMR results GPC curves PEG-b-CPLA/gene nanocomplexes PDI = 1.05-1.06 DLS results PEG-b-CPLA-20 TEM image PEG-b-CPLA-50 Gene transfection study in four physiologically distinct cells using PEG-b-CPLAs as vector Advantages of PEGylation for CPLA-based vectors Reduced hemolysis Enhanced serum resistance Synthesis of CPLA NCs and loading the NCs with therapeutic agents Goal: To develop CPLA-based nanocapsules for overcoming MDR and enabling codelivery C.-K. Chen, W.-C. Law et al., Nanoscale 2014, 6, 1567. G. Lin, R. Hu, W.-C. Law, C.-K. Chen, et al., Small 2013, 9, 2757. Overcoming MDR via encapsulation of NCs in MCF7/ADR cells Dox-CPLA-NCs free Dox Enhanced intracellular concentration of Dox via NCs 50% increase in Dox-positive cells Enhanced anti-proliferation effects CPLA NCs as biodegradable carriers for drug/gene codelivery Cell uptake of Dox-CPLA NCs Antiproliferation of PC3 cells Cell uptake of siRNA-CPLA NCs Transfection results Codelivery of siRNA/Dox via NCs Synergetic antitumor effects via codelivery Synthesis of pH-responsive CSNCs via interfacial miniemulsion crosslinking for drug delivery Goal: To develop pH-responsive chitosan nanocapsules (a) Preparation of Dox-loaded chitosan nanocapsules (Dox-CSNCs) via miniemulsion interfacial crosslinking, (b) The acid-labile cross-linkage of CSNCs, (c) The appearance of Dox-loaded CSNC-3 solution. C.-K. Chen, Q. Wang et al., Langmuir 2014, 30, 4111. Well-defined chitosan nanocapsules with pH-responsive feature Tunable size feature pH-dependant drug release Capsular structure Non-toxic and higher antitumor efficacy Summary Nanocomplexs for gene delivery PEGylated Nanocomplexs with high serum resistance CPLAs CPLA NCs H+ pH-responsive chitosan nanocapules for overcoming MDR and enabling gene/drug delivery Acknowledgement Ph.D. advisor Current group members 林威任、黃思傑 Collaborator Dr. Chong Cheng Prof. Blaine Pfeifer, Prof. Paras N. Prasad at UB 國衛院羅履維老師 南洋理工大學Prof. Ken-Tye Yang Funding supports 科技部(MOST 103-2218-E-035 -010) 逢甲大學(startup funding) Thank you for your attention