Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital , Sun Yat-Sen University , Guangzhou 510120 , P. R. China.
RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital , Sun Yat-Sen University , Guangzhou 510120 , P. R. China.
Nano Lett. 2019 Sep 11;19(9):5967-5974. doi: 10.1021/acs.nanolett.9b01660. Epub 2019 Aug 7.
Nanoparticles (NPs) formulated with cationic lipids and/or polymers have shown substantial potential for systemic delivery of RNA therapeutics such as small interfering RNA (siRNA) for the treatment of cancer and other diseases. While both cationic lipids and polymers have demonstrated the promise to facilitate siRNA encapsulation and endosomal escape, they could also hamper cytosolic siRNA release due to charge interaction and induce potential toxicities. Herein, a unique polymer-prodrug hybrid NP platform was developed for multistage siRNA delivery and combination cancer therapy. This NP system is composed of (i) a hydrophilic polyethylene glycol (PEG) shell, (ii) a hydrophobic NP core made with a tumor microenvironment (TME) pH-responsive polymer, and (iii) charge-mediated complexes of siRNA and amphiphilic cationic mitoxantrone (MTO)-based prodrug that are encapsulated in the NP core. After intravenous administration, the long-circulating NPs accumulate in tumor tissues and then rapidly release the siRNA-prodrug complexes via TME pH-mediated NP disassociation for subsequent tissue penetration and cytosolic transport. With the overexpressed esterase in tumor cells to hydrolyze the amphiphilic structure of the prodrug and thereby induce destabilization of the siRNA-prodrug complexes, the therapeutic siRNA and anticancer drug MTO can be efficiently released in the cytoplasm, ultimately leading to the combinational inhibition of tumor growth via concurrent RNAi-mediated gene silencing and MTO-mediated chemotherapy.
纳米颗粒 (NPs) 由阳离子脂质体和/或聚合物构成，在用于治疗癌症和其他疾病的 RNA 治疗药物（如小干扰 RNA (siRNA)）的系统递送上显示出巨大的潜力。阳离子脂质体和聚合物都具有促进 siRNA 包封和内涵体逃逸的潜力，但由于电荷相互作用，它们也可能阻碍细胞质中 siRNA 的释放，并引起潜在的毒性。本文中，开发了一种独特的聚合物前药杂化 NP 平台，用于多阶段 siRNA 递药和联合癌症治疗。该 NP 系统由 (i) 亲水性聚乙二醇 (PEG) 壳、(ii) 由肿瘤微环境 (TME) pH 响应性聚合物制成的疏水性 NP 核、和 (iii) 包裹在 NP 核中的 siRNA 和两亲性米托蒽醌 (MTO)- 基于前药的电荷介导复合物组成。静脉给药后，长循环 NP 在肿瘤组织中积累，然后通过 TME pH 介导的 NP 解离迅速释放 siRNA-前药复合物，随后进行组织渗透和细胞质转运。由于肿瘤细胞中过表达的酯酶水解前药的两亲性结构，从而导致 siRNA-前药复合物不稳定，治疗性 siRNA 和抗癌药物 MTO 可以在细胞质中有效释放，最终通过 RNAi 介导的基因沉默和 MTO 介导的化疗联合抑制肿瘤生长。
