Zhu Xi, Tao Wei, Liu Danny, Wu Jun, Guo Zilei, Ji Xiaoyuan, Bharwani Zameer, Zhao Lili, Zhao Xiaoping, Farokhzad Omid C, Shi Jinjun
Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
National Shanghai Center for New Drug Safety Evaluation and Research, Shanghai, 201203, China.
Theranostics. 2017 May 12;7(7):1990-2002. doi: 10.7150/thno.18136. eCollection 2017.
The present work proposes a unique de-PEGylation strategy for controllable delivery of small interfering RNA (siRNA) using a robust lipid-polymer hybrid nanoparticle (NP) platform. The self-assembled hybrid NPs are composed of a lipid-poly(ethylene glycol) (lipid-PEG) shell and a polymer/cationic lipid solid core, wherein the lipid-PEG molecules can gradually dissociate from NP surface in the presence of serum albumin. The de-PEGylation kinetics of a series of different lipid-PEGs is measured with their respective NPs, and the NP performance is comprehensively investigated and . This systematic study reveals that the lipophilic tails of lipid-PEG dictate its dissociation rate from NP surface, determining the uptake by tumor cells and macrophages, pharmacokinetics, biodistribution, and gene silencing efficacy of these hybrid siRNA NPs. Based on our observations, we here propose that lipid-PEGs with long and saturated lipophilic tails might be required for effective siRNA delivery to tumor cells and gene silencing of the lipid-polymer hybrid NPs after systemic administration.
本研究提出了一种独特的去聚乙二醇化策略，用于使用强大的脂质-聚合物杂化纳米颗粒（NP）平台可控地递送小干扰RNA（siRNA）。自组装的杂化NP由脂质-聚乙二醇（脂质-PEG）外壳和聚合物/阳离子脂质固体核心组成，其中脂质-PEG分子在血清白蛋白存在下可逐渐从NP表面解离。用一系列不同的脂质-PEG及其各自的NP测量去聚乙二醇化动力学，并对NP性能进行全面研究。这项系统研究表明，脂质-PEG的亲脂性尾部决定了其从NP表面的解离速率，从而决定了这些杂化siRNA NP被肿瘤细胞和巨噬细胞的摄取、药代动力学、生物分布以及基因沉默效率。基于我们的观察结果，我们在此提出，为了在全身给药后将siRNA有效递送至肿瘤细胞并实现脂质-聚合物杂化NP的基因沉默，可能需要具有长且饱和亲脂性尾部的脂质-PEG。
