基于蛋白冠状物生成控制技术的核酸纳米给药系统在肝纤维化靶向治疗中的应用

发布时间：2018-03-18 19:09

本文选题：纳米颗粒　切入点：冠状物蛋白　出处：《南京大学》2014年硕士论文　论文类型：学位论文

【摘要】：纳米颗粒在药物传输中的作用越来越重要。有报道称当纳米颗粒进入生物环境后,血浆中的蛋白会快速的在它的表面形成一层“冠状物”,这种冠状物给药物载体赋予了新的生物识别能力。蛋白冠状物的种类和数量将决定着载体的运输路线及最终的分布位点。因此,对冠状物蛋白的合理利用在靶向治疗中十分重要。肝纤维化是一种由过度的Ⅰ型胶原蛋白沉积而导致的肝脏疾病,这种胶原蛋白是由活化的肝星状细胞(Hepatic stellate cells,HSCs)分泌的。目前,并没有有效的手段来治疗肝纤维化。通过将反义核苷酸ASO靶向HSCs来抑制Ⅰ型胶原蛋白的表达可能是一种有效的策略。白蛋白作为一种天然的载体能有效的运输生物体内的营养物质,并且还能通过体内过滤系统且不被吞噬。在本文的研究中,我们利用血液中本来就存在的白蛋白来达到靶向HSCs的目的。我们设计了一种运输ASO的载体,即将小分子量的聚乙烯亚胺(PEI,1.3KD)与使用CDI (N,N'-羰基二咪唑)活化的视黄醇(Retinol)连接起来。由于视黄醇结合蛋白(RBP)是视黄醇的单一性载体,HSCs可以有效的吸收血液中的与RBP结合的视黄醇。我们假设这种设计能使药物载体在血液循环中与白蛋白结合,从而可以利用白蛋白的天然运输能力使得载体能免于被身体的过滤系统快速清除；然后,通过视黄醇与RBP的特异性结合,将载体进一步的靶向HSCs。实验结果显示,在CCl4诱导的小鼠肝纤维化模型中,Retinol-c-PEI/ASO复合物(RAP)优先在HSCs中累积；并且,与裸的ASO相比,RAP显著的抑制了Ⅰ型胶原蛋白的表达。
[Abstract]:Nanoparticles play an increasingly important role in drug delivery. It has been reported that when nanoparticles enter the biological environment, The protein in the plasma rapidly forms a "crown" on its surface, which gives the drug carrier a new biometric ability. The type and quantity of the protein crown will determine the transport route and the most important of the carriers. The distribution site of the end. The rational use of coronal proteins is very important in targeted therapy. Hepatic fibrosis is a liver disease caused by excessive deposition of type I collagen, which is secreted by activated hepatic stellate cells (HSCs). There is no effective method to treat hepatic fibrosis. Inhibiting the expression of type I collagen by targeting HSCs with antisense ASO may be an effective strategy. Albumin as a natural carrier can effectively transport raw materials. Nutrients in objects, In this study, we used the already existing albumin in the blood to achieve the goal of targeting HSCs. We designed a carrier to transport ASO. The low molecular weight polyethylene imine (PEI) 1.3KD) was connected with Retinol (Retinoll) activated by CDI (NNN- carbonyl diimidazole). Since retinol binding protein (RBP) is the sole carrier of retinol, it can effectively absorb RBP from the blood. We assume that this design allows the drug carrier to bind to albumin in the blood circulation. It is possible to use the natural transport capacity of albumin to keep the carrier from being quickly cleared by the body's filtration system; then, by the specific binding of retinol to RBP, the carrier can be further targeted at HSCs.Experimental results show that, In CCl4 induced mouse liver fibrosis model, Retinol-c-PEI / ASO complex preferentially accumulated in HSCs, and rap significantly inhibited the expression of type I collagen compared with bare ASO.
【学位授予单位】：南京大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R575.2

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