A cationic polymeric prodrug with chemotherapeutic self-sensibilization co-delivering MMP-9 shRNA plasmid for a combined therapy to nasopharyngeal carcinoma
A cationic polymeric prodrug with chemotherapeutic self-sensibilization co-delivering MMP-9 shRNA plasmid for a combined therapy to nasopharyngeal carcinoma
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DOI：
10.1080/10717544.2019.1698674
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发表时间：
2019-01-01
期刊：
影响因子：
6
通讯作者：
Zhang, Siyi
中科院分区：
文献类型：
--
作者：
Liu, Tao;Wu, Xidong;Zhang, Siyi
为了获得一种高效的药物和基因共递送系统来治疗ne -1肿瘤，我们合成了一种由gsh反应的超支化聚胺胺（PAAs）和抗肿瘤药物甲氨蝶呤（MTX）组成的具有化疗增敏性的聚合前药（PAAs-MTX）。然后，将HNE-1细胞的靶向分子转铁蛋白（Tf）偶联形成Tf- paas - mtx。该聚合前药可再次递送MMP-9 shRNA质粒（pMMP-9），形成Tf-PAAs-MTX/pMMP-9的药物和基因共递送体系。该共递送系统对HNE-1细胞具有较高的细胞毒性和基因转染效率，具有有效的药物和基因递送能力。此外，Tf-PAAs-MTX还表现出化疗增敏作用，含有PAAs片段的制剂比游离MTX具有更高的细胞毒性。受益于增敏效应和MTX/pMMP-9共给药策略，该Tf-PAAs-MTX/pMMP-9共给药系统在体外和体内实验中证实了联合给药方式对hcc -1肿瘤的治疗效果显著提高。并对其生物相容性，特别是血液相容性进行了分析。这种高分子前药将药物/基因共给药、化疗致敏和靶向作用于一个平台，提供了一种易于给药的系统，在鼻咽癌治疗中具有广阔的应用前景。
To obtain a high-efficiency drug and gene co-delivery system to HNE-1 tumor therapy, a polymeric prodrug (PAAs-MTX) with chemotherapeutic sensibilization was synthesized consisting of a GSH-response hyperbranched poly(amido amine) (PAAs) and an antitumor drug of methotrexate (MTX). Then, the targeting molecule to HNE-1 cells, transferrin (Tf), was conjugated to form the Tf-PAAs-MTX. This polymeric prodrug could deliver MMP-9 shRNA plasmid (pMMP-9) again to form the drug and gene co-delivery system of Tf-PAAs-MTX/pMMP-9. The co-delivery system showed the effective drug and gene delivery ability with high cytotoxicity and gene transfection efficiency to HNE-1 cells. Besides that, Tf-PAAs-MTX also showed the chemotherapeutic sensibilization effect, the formulation containing PAAs segments showed much higher cytotoxicity than that of free MTX. Benefiting from the sensibilization effect and MTX/pMMP-9 co-delivery strategy, this Tf-PAAs-MTX/pMMP-9 co-delivery system exhibited the significantly improved therapeutic efficacy to HNE-1 tumor in a combined manner which was confirmed by in vitro and in vivo assays. Moreover, its biocompatibility, especially the blood compatibility was analyzed. This polymeric prodrug provided an easily delivery system combining the drug/gene co-delivery, chemotherapeutic sensibilization and targeting into one single platform, which showed a promising application in nasopharyngeal carcinoma therapy.