Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, XueYuan Rd 38, Haidian Dist, Beijing 100191, China; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.
Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, XueYuan Rd 38, Haidian Dist, Beijing 100191, China.
J Control Release. 2019 Dec 28;316:317-330. doi: 10.1016/j.jconrel.2019.11.010. Epub 2019 Nov 13.
Although microRNAs (miRNAs) function as the important tumor gene regulators, they still confront with many challenges in systemic delivery. Here, the amphiphilic gemcitabine-oleic acid prodrugs (GOA) binding miRNAs with hydrogen bond are assembled into nanoparticles (GOA/miR NPs) through hydrophobic interaction via denaturation-annealing processes and nano-precipitation technique. The non-cationic GOA/miR NPs with an average size of ~150 nm and a zeta potential of ~ - 15 mV exhibit a stable encapsulation of miRNAs with non-sequence selectivity. Either miR-122 or miR-34a encapsulated in the GOA/miR NPs is efficiently delivered into HepG2 cells and significantly downregulate the expression levels of target gene after lysosome escape and pH-responsive disassembly. Moreover, in vivo experiments demonstrate that the GOA/miR-122 NPs exhibit higher tumor accumulation. Compared to GOA micelles, GOA/miR-122 NPs displayed stronger tumor inhibition (73% regression) after intravenous injection in nude mice xenografted with HCC, along with rapid clearance in normal liver tissues. Furthermore, there is no significant influence on biochemical indicators and immune factors during the systematic administration of GOA/miR-122 NPs. The non-cationic GOA/miR NPs engineered by hydrogen bond interaction and hydrophobic forces show the enhanced synergistic antitumor efficacy and good biosafety, which will provide a potential nanomedcine for HCC treatment.
尽管 microRNAs（miRNAs）作为重要的肿瘤基因调节剂发挥作用，但在系统传递方面仍面临许多挑战。在这里，通过疏水相互作用，将带正电的吉西他滨-油酸前药（GOA）与 miRNA 进行组装，通过变性-退火过程和纳米沉淀技术形成纳米颗粒（GOA/miR NPs）。非阳离子 GOA/miR NPs 的平均粒径约为 150nm，zeta 电位约为-15mV，对 miRNA 具有非序列选择性的稳定包封。封装在 GOA/miR NPs 中的 miR-122 或 miR-34a 可以有效地递送到 HepG2 细胞中，并在溶酶体逃逸和 pH 响应性解组装后显著下调靶基因的表达水平。此外，体内实验表明，GOA/miR-122 NPs 具有更高的肿瘤积累。与 GOA 胶束相比，GOA/miR-122 NPs 在裸鼠 HCC 异种移植模型中静脉注射后表现出更强的肿瘤抑制作用（73%的肿瘤消退），同时在正常肝组织中快速清除。此外，在系统给予 GOA/miR-122 NPs 期间，对生化指标和免疫因素没有显著影响。通过氢键相互作用和疏水作用力设计的非阳离子 GOA/miR NPs 显示出增强的协同抗肿瘤疗效和良好的生物安全性，可为 HCC 治疗提供一种有潜力的纳米医学方法。
