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通过混合胶束实现siRNA与甲氨蝶呤的靶向共递送用于肿瘤治疗

Targeted Co-Delivery of siRNA and Methotrexate for Tumor Therapy via Mixed Micelles.

作者信息

Hao Fei, Lee Robert J, Yang Chunmiao, Zhong Lihuang, Sun Yating, Dong Shiyan, Cheng Ziyuan, Teng Lirong, Meng Qingfan, Lu Jiahui, Xie Jing, Teng Lesheng

机构信息

School of Life Sciences, Jilin University, Changchun 130012, China.

College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.

出版信息

Pharmaceutics. 2019 Feb 21;11(2):92. doi: 10.3390/pharmaceutics11020092.

DOI:10.3390/pharmaceutics11020092
PMID:30795589
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6409946/
Abstract

A combination of chemotherapeutic drugs and siRNA is emerging as a new modality for cancer therapy. A safe and effective carrier platform is needed for combination drug delivery. Here, a functionalized mixed micelle-based delivery system was developed for targeted co-delivery of methotrexate (MTX) and survivin siRNA. Linolenic acid (LA) was separately conjugated to branched polyethlenimine (b-PEI) and methoxy-polyethyleneglycol (mPEG). MTX was then conjugated to LA-modified b-PEI (MTX-bPEI-LA) to form a functionalized polymer-drug conjugate. Functionalized mixed micelles (M-MTX) were obtained by the self-assembly of MTX-bPEI-LA and LA-modified mPEG (mPEG-LA). M-MTX had a narrow particle size distribution and could successfully condense siRNA at an N/P ratio of 16/1. M-MTX/siRNA was selectively taken up by HeLa cells overexpressing the folate receptor (FR) and facilitated the release of the siRNA into the cytoplasm. In vitro, M-MTX/siRNA produced a synergy between MTX and survivin siRNA and markedly suppressed survivin protein expression. In tumor-bearing mice, M-MTX/Cy5-siRNA showed an elevated tumor uptake. In addition, M-MTX/siRNA inhibited tumor growth. Immunohistochemistry and a western blot analysis showed a significant target gene downregulation. In conclusion, M-MTX/siRNA was highly effective as a delivery system and may serve as a model for the targeted co-delivery of therapeutic agents.

摘要

化疗药物与小干扰RNA（siRNA）的联合使用正成为一种新的癌症治疗方式。联合药物递送需要一个安全有效的载体平台。在此，开发了一种基于功能化混合胶束的递送系统，用于甲氨蝶呤（MTX）和生存素siRNA的靶向共递送。将亚麻酸（LA）分别与支链聚乙烯亚胺（b-PEI）和甲氧基聚乙二醇（mPEG）偶联。然后将MTX与LA修饰的b-PEI（MTX-bPEI-LA）偶联，形成功能化聚合物-药物偶联物。通过MTX-bPEI-LA和LA修饰的mPEG（mPEG-LA）的自组装获得功能化混合胶束（M-MTX）。M-MTX具有窄的粒径分布，并且能够以16/1的N/P比成功浓缩siRNA。M-MTX/siRNA被过表达叶酸受体（FR）的HeLa细胞选择性摄取，并促进siRNA释放到细胞质中。在体外，M-MTX/siRNA在MTX和生存素siRNA之间产生协同作用，并显著抑制生存素蛋白表达。在荷瘤小鼠中，M-MTX/Cy5-siRNA显示出肿瘤摄取增加。此外，M-MTX/siRNA抑制肿瘤生长。免疫组织化学和蛋白质印迹分析显示靶基因显著下调。总之，M-MTX/siRNA作为一种递送系统非常有效，可作为治疗剂靶向共递送的模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/0ef13d44eb5e/pharmaceutics-11-00092-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/8647d057fb3f/pharmaceutics-11-00092-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/d5baa496f216/pharmaceutics-11-00092-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/2435e9d80538/pharmaceutics-11-00092-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/bf746228b348/pharmaceutics-11-00092-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/306fc29d0e7d/pharmaceutics-11-00092-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/b9c430b5731e/pharmaceutics-11-00092-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/53b3407d498f/pharmaceutics-11-00092-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/4177e15aa4cb/pharmaceutics-11-00092-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/0ef13d44eb5e/pharmaceutics-11-00092-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/8647d057fb3f/pharmaceutics-11-00092-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/d5baa496f216/pharmaceutics-11-00092-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/2435e9d80538/pharmaceutics-11-00092-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/bf746228b348/pharmaceutics-11-00092-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/306fc29d0e7d/pharmaceutics-11-00092-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/b9c430b5731e/pharmaceutics-11-00092-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/53b3407d498f/pharmaceutics-11-00092-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/4177e15aa4cb/pharmaceutics-11-00092-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed07/6409946/0ef13d44eb5e/pharmaceutics-11-00092-g008.jpg

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