School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Liaoning Province, China.
J Mater Chem B. 2020 Feb 26;8(8):1616-1628. doi: 10.1039/c9tb02764e.
Small interfering RNA (siRNA) has extensive potential for the treatment of non-small cell lung cancer (NSCLC). While both cationic lipids and polymers have demonstrated promise to facilitate siRNA encapsulation, they can also hamper cytosolic siRNA release and induce severe cytotoxicity. To address these issues, a unique polymer hybrid nanoparticle (NP) nanoplatform was developed for multistage siRNA delivery based on both pH-responsive and endo/lysosomal escape characteristics, which was formed via a combination of an electrostatic interactions between the copolymer methoxy poly(ethylene glycol)-poly(l-histidine)-poly(sulfadimethoxine) (mPEG-PHis-PSD, shortened to PHD), dendritic poly-l-lysine (PLL) and PLK1 siRNA (shortened to siPLK1). The biological composition of the proton sponge effect polymer of the PHis chain, which was in position to make efficient endo/lysosomal escape, and the pH-responsive polymer of the PSD fragment, which could accelerate the release of siPLK1. In the present study, the NP illustrated excellent physiochemical properties and rapid endo/lysosomal escape in vitro. Besides this, compared with the PD/PLL/siRNA formulation, the PHD/PLL/siRNA NP indicated higher cellular uptake, and higher cell cytotoxicity in vitro. The in vivo results demonstrated that the PHD/PLL/siRNA NP exhibited the strongest tumor growth inhibition rate and ideal safety compared with the control and other siPLK1-treated formulations, which can be mainly attributed to pH-induced instantaneous dissociation and efficient endo/lysosomal escape arising from the PHD copolymer. Consequently, the above evidence indicates that the PHD/PLL/siRNA NP is a favorable gene delivery system and provides a potential strategy for siRNA delivery.
小干扰 RNA（siRNA）在治疗非小细胞肺癌（NSCLC）方面具有广泛的应用潜力。阳离子脂质体和聚合物都被证明可以促进 siRNA 的包裹，但也会阻碍细胞质中 siRNA 的释放并引起严重的细胞毒性。为了解决这些问题，我们开发了一种独特的聚合物杂化纳米颗粒（NP）纳米平台，用于基于 pH 响应和内体/溶酶体逃逸特性的多阶段 siRNA 递释，该平台是通过静电相互作用形成的共聚物甲氧基聚乙二醇-聚（组氨酸）-聚（磺胺二甲氧嘧啶）（mPEG-PHis-PSD，简称 PHD）、树枝状多聚赖氨酸（PLL）和 PLK1 siRNA（简称 siPLK1）之间的组合。PHis 链中的质子海绵效应聚合物的生物组成有利于有效的内体/溶酶体逃逸，以及 PSD 片段的 pH 响应聚合物，能够加速 siPLK1 的释放。在本研究中，NP 表现出优异的物理化学性质和体外快速的内体/溶酶体逃逸。此外，与 PD/PLL/siRNA 制剂相比，PHD/PLL/siRNA NP 表现出更高的细胞摄取率和体外更高的细胞毒性。体内结果表明，与对照组和其他 siPLK1 处理制剂相比，PHD/PLL/siRNA NP 表现出最强的肿瘤生长抑制率和理想的安全性，这主要归因于 PHD 共聚物的 pH 诱导瞬时解离和高效的内体/溶酶体逃逸。因此，上述证据表明 PHD/PLL/siRNA NP 是一种有前途的基因传递系统，为 siRNA 传递提供了一种潜在的策略。
