药用高分子材料-siRNA药物.pptx

姚老师作业：聚乳酸的本体聚合工艺，相应机理和反应方程;第六章 高分子纳米药物-siRNA药物; 抗体: Bind protein, but only extracellular epitopes Low throughput, high cost 反义RNA/核酶: Stop gene expression (production), most proteins Chemical stabilization essential Barriers: sequence selection, potency, toxicities, … RNA干扰: Stop gene expression (production), most proteins Good activity without chemical stabilization Rapidly replacing antisense: really better? ;RNA干扰（RNA interference, RNAi）技术;RNAi 作用机制;Log [Oligo] (M);;Target ID; Company ;难以被细胞摄取：大分子，阴离子;Nature 2010, 468, p487, Nov. 25, 2010;表达siRNA的质粒DNA的传递 病毒（Nature Biotechnology, 2002, 20: 1006-10） 非病毒类载体 化学合成的siRNA的传递 非病毒类载体：脂质体和高分子 物理手段: electroporation, high pressure/high volume injection;脂质类;;;;;Challenge 1: 稳定 Challenge 2: 长循环 Challenge 3: 靶向 Challenge 4: 渗透 Challenge 5: 细胞摄取 Challenge 6: 制剂化;;;脂质体类siRNA纳米载体;Stable Nucleic Acid Lipid Particle (SNALP);Stable Nucleic Acid Lipid Particle (SNALP);siRNA-SNALP with a longer half-life in plasma and liver reduced serum HBV DNA titers in mouse model following intravenous injection;ApoB-siRNA-SNALP resulted in silencing of ApoB mRNA expression in liver and significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels;高分子类 siRNA给药系统;Steric Coat (Inert);NUCLEIC ACIDS RESEARCH 32 (19): Art. No. e149 2004;PNAS 2007, 104, 5715-5721;Cancer Research 2005, 65, 8984-8992;;;Loading siRNA post nanoparticle formation PEG: prolonged blood circulation Biocompatible Degradable, potentially intracellular siRNA release Co-delivery of chemotherapeutic drug for synergistic effect;a;Days post-xenografting;Kim A.Woodrow, W. Mark Saltzman et al., Nature Materials, 2009, 8, 526 – 533 Christopher J. Cheng,?W. Mark Saltzman, Biomaterials, 2011, 32, 6194–6203;Organic phase (polymer/lipid);基于CLAN技术设计的靶向siRNA给药系统;Nature Biotechnol. 23, 709–717 (2005);M Sioud1, Gene Therapy, 2006, 13, 194–195;思考题