Centre for Biomedical Engineering, Indian Institute of Technology Delhi , New Delhi 110016, India.
Biomedical Engineering Unit, All India Institute of Medical Sciences , New Delhi 110029, India.
ACS Appl Mater Interfaces. 2017 Nov 15;9(45):39672-39687. doi: 10.1021/acsami.7b11716. Epub 2017 Oct 31.
To overcome the limitations of conventional chemotherapy, nanoparticle-mediated combinatorial delivery of siRNA and drugs represents a new approach to overcome its associated side effects. Designing safe and efficient vehicles for their codelivery has emerged as a potential challenge in the clinical translation of these formulations. Herein, we have demonstrated a novel "two-in-one" polyplex nanosystem developed from redox sensitive, short chain polyethylenimine modified poly[(poly(ethylene)glycol methacrylate]-s-s-polycaprolactone copolymer synthesized by atom-transfer free-radical polymerization (ATRP), which can deliver doxorubicin and polo-like kinase I (plk1) siRNA, simultaneously for an enhanced chemotherapeutic effect. The nanoparticles were found to be stable at physiological buffer with and without fetal bovine serum (FBS). The developed polymeric nanosystem was found to be biocompatible and hemocompatible in vitro and in vivo at repeated dose administrations. The polymer could easily self-assemble into ∼100 nm spherical nanoparticles with enhanced doxorubicin loading (∼18%) and effective siRNA complexation at a polymer to siRNA weight ratio of 15. The doxorubicin loaded nanoparticles exhibited ∼4-fold higher drug release in endosomal pH (pH 5) containing 10 mmol of GSH compared to pH 7.4, depicting their redox-sensitive behavior. The polyplexes were capable of delivering both cargos simultaneously to cancer cells in vitro as observed by their excellent colocalization in the cytoplasm of MDA-MB-231 and HeLa cells using confocal laser microscopy. Moreover, in vitro transfection of the cells with polyplexes exhibited 50-70% knockdown of plk1-mRNA expression in both cell lines. In vivo administration of the drug loaded polyplexes to EAT tumor bearing (EAT, Ehrlich ascites tumor) Swiss albino mice showed a ∼29-fold decrease in percent tumor volume in comparison to the control group. The results highlight the therapeutic potential of the polyplexes as a combined delivery of doxorubicin and plk1-siRNA in cancer therapy.
为了克服传统化疗的局限性，将 siRNA 和药物的纳米颗粒介导的联合递呈代表了克服其相关副作用的一种新方法。设计用于它们共递呈的安全有效的载体已经成为这些制剂临床转化中的一个潜在挑战。在此，我们展示了一种新型的“二合一”聚阳离子纳米系统，该系统由氧化还原敏感的、短链聚乙二醇甲基丙烯酸酯修饰的聚[（聚乙二醇）甲基丙烯酸酯]-s-s-聚己内酯共聚物通过原子转移自由基聚合（ATRP）合成，该共聚物可以同时递呈阿霉素和 Polo 样激酶 I（plk1）siRNA，从而增强化疗效果。在生理缓冲液中和含有或不含有胎牛血清（FBS）的情况下，纳米粒均稳定。在重复剂量给药时，所开发的聚合物纳米系统在体内和体外均具有生物相容性和血液相容性。该聚合物可以很容易地自组装成具有增强的阿霉素负载（约 18%）和约 15 聚合物与 siRNA 重量比的有效 siRNA 复合物的约 100nm 球形纳米粒。与 pH 7.4 相比，在含有 10mmol GSH 的内体 pH（pH 5）下，负载阿霉素的纳米粒的药物释放增加了约 4 倍，表明其具有氧化还原敏感性。聚阳离子能够同时将两种载物递送至体外癌细胞，如通过共聚焦激光显微镜观察到 MDA-MB-231 和 HeLa 细胞的细胞质中良好的共定位。此外，用聚阳离子转染细胞后，在两种细胞系中 plk1-mRNA 表达的敲低率均达到 50-70%。将载药的聚阳离子复合物给药于 EAT 荷瘤（EAT，艾氏腹水瘤）瑞士白化病小鼠后，与对照组相比，肿瘤体积的百分比降低了约 29 倍。结果突出了聚阳离子作为阿霉素和 plk1-siRNA 联合递呈在癌症治疗中的治疗潜力。
