School of Life Sciences and Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China.
ACS Nano. 2012 Jun 26;6(6):4955-65. doi: 10.1021/nn300500u. Epub 2012 Jun 5.
The clinical success of therapeutics of small interfering RNA (siRNA) is still hindered by its delivery systems. Cationic polymer or lipid-based vehicles as the major delivery systems of siRNA cannot sufficiently satisfy siRNA therapeutic applications. It is hypothesized that cationic lipid-polymer hybrid nanoparticles may take advantage of both polymeric and lipid-based nanoparticles for siRNA delivery, while diminishing the shortcomings of both. In this study, cationic lipid-polymer hybrid nanoparticles were prepared by a single-step nanoprecipitation of a cationic lipid (N,N-bis(2-hydroxyethyl)-N-methyl-N-(2-cholesteryloxycarbonyl aminoethyl) ammonium bromide, BHEM-Chol) and amphiphilic polymers for systemic delivery of siRNA. The formed hybrid nanoparticles comprised a hydrophobic polylactide core, a hydrophilic poly(ethylene glycol) shell, and a cationic lipid monolayer at the interface of the core and the shell. Such hybrid nanoparticles exhibited excellent stability in serum and showed significantly improved biocompatibility compared to that of pure BHEM-Chol particles. The hybrid nanoparticles were capable of delivering siRNA into BT474 cells and facilitated the escape of loaded siRNA from the endosome into the cytoplasm. The hybrid nanoparticles carrying polo-like kinase 1 (Plk1)-specific siRNA (siPlk1) remarkably and specifically downregulated expression of the oncogene Plk1 and induced cancer cell apoptosis both in vitro and in vivo and significantly suppressed tumor growth following systemic administration. We demonstrate that this system is stable, nontoxic, highly efficient, and easy to scale up, bringing the clinical application of siRNA therapy one important step closer to reality.
治疗性小干扰 RNA（siRNA）的临床成功仍然受到其递送系统的限制。阳离子聚合物或脂质基载体作为 siRNA 的主要递送系统，不能充分满足 siRNA 治疗应用的需要。有人假设，阳离子脂质-聚合物杂化纳米粒可能利用聚合物和基于脂质的纳米粒的优势来递送 siRNA，同时减少两者的缺点。在这项研究中，通过阳离子脂质（N，N-双（2-羟乙基）-N-甲基-N-（2-胆甾烷氧基羰基氨基乙基）铵溴化物，BHEM-Chol）和两亲聚合物的一步纳米沉淀制备了阳离子脂质-聚合物杂化纳米粒，用于系统递送 siRNA。形成的杂化纳米粒包含疏水性聚乳酸核、亲水性聚乙二醇壳和核与壳界面处的阳离子脂质单层。与纯 BHEM-Chol 颗粒相比，这种杂化纳米粒在血清中表现出优异的稳定性，并且显示出显著改善的生物相容性。杂化纳米粒能够将 siRNA 递送到 BT474 细胞中，并促进负载的 siRNA 从内涵体逃逸到细胞质中。携带 Polo 样激酶 1（Plk1）特异性 siRNA（siPlk1）的杂化纳米粒显著且特异性地下调了致癌基因 Plk1 的表达，并在体外和体内诱导了癌细胞凋亡，并显著抑制了系统给药后的肿瘤生长。我们证明该系统稳定、无毒、高效且易于规模化，使 siRNA 治疗的临床应用更接近现实一步。
