School of Chemical Engineering, Purdue University, West Lafayette, Indiana 47907, United States.
ACS Nano. 2011 May 24;5(5):3493-505. doi: 10.1021/nn102540y. Epub 2011 Apr 6.
Micelle-based siRNA carriers ("micelleplexes") were prepared from the A-B-C triblock copolymer poly(ethylene glycol)-poly(n-butyl acrylate)-poly(2-(dimethylamino)ethyl methacrylate) (PEG-PnBA-PDMAEMA), and their in vitro performance and in vivo biodistribution properties were compared with the benchmark PEGylated and basic polycation systems PEG-PDMAEMA and PDMAEMA, respectively. The micelle architecture, incorporating increased PEG shielding and a larger particle size (∼50 nm) than polycation-based complexes (polyplexes; ∼10 nm), enhances siRNA delivery performance in two important aspects: in vitro gene silencing efficiency and in vivo tumor accumulation. The in vitro gene silencing efficiency of the micelleplexes (24% in HeLa cells) was significantly better than the statistically insignificant levels observed for PDMAEMA and PEG-PDMAEMA polyplexes under identical conditions. This enhancement is linked to the different mechanisms by which micelleplexes are internalized (i.e., caveolar, etc.) compared to PDMAEMA and PEG-PDMAEMA polyplexes. Folate-functionalization significantly improved micelleplex uptake but had negligible influence on gene-silencing efficiency, suggesting that this parameter is not limited by cellular internalization. In vivo biodistribution analysis revealed that siRNA delivered by micelleplexes was more effectively accumulated and retained in tumor tissues than that delivered by PEGylated polyplexes. Overall, the micelle particle size and architecture appear to improve in vitro and in vivo delivery characteristics without significantly changing other properties, such as cytotoxicity and resistance to enzymes and dissociation. The self-assembled nature of micelleplexes is expected to enable incorporation of imaging modalities inside the hydrophobic micelle core, thus combining therapeutic and diagnostic capabilities. The findings from the present study suggest that the micelleplex-type carrier architecture is a useful platform for potential theranostic and tumor-targeting applications.
基于胶束的 siRNA 载体（“胶束复合物”）是由三嵌段共聚物聚乙二醇-聚正丁基丙烯酰胺-聚（2-二甲氨基乙基甲基丙烯酸酯）（PEG-PnBA-PDMAEMA）制备的，其体外性能和体内生物分布特性分别与基准 PEG 化和碱性聚阳离子系统 PEG-PDMAEMA 和 PDMAEMA 进行了比较。与基于聚阳离子的复合物（聚合物；约 10nm）相比，胶束的结构具有更高的 PEG 屏蔽和更大的粒径（约 50nm），增强了 siRNA 传递性能的两个重要方面：体外基因沉默效率和体内肿瘤积累。胶束复合物（在 HeLa 细胞中为 24%）的体外基因沉默效率明显优于在相同条件下观察到的 PDMAEMA 和 PEG-PDMAEMA 聚合物的统计学上无意义水平。这种增强与胶束复合物（即小窝等）的内化机制与 PDMAEMA 和 PEG-PDMAEMA 聚合物不同有关。叶酸功能化显著提高了胶束复合物的摄取，但对基因沉默效率的影响可以忽略不计，这表明该参数不受细胞内化的限制。体内生物分布分析表明，与 PEG 化聚合物相比，胶束复合物递送的 siRNA 更有效地在肿瘤组织中积累和保留。总的来说，胶束的粒径和结构似乎改善了体外和体内的传递特性，而不会显著改变其他性质，如细胞毒性、对酶的抵抗力和解离。胶束复合物的自组装性质有望使成像模式在疏水性胶束核心内得到整合，从而将治疗和诊断能力结合起来。本研究的结果表明，胶束复合物型载体结构是一种有前途的治疗和肿瘤靶向应用的平台。
