Zeng Ye, Zhou Zixuan, Fan Minmin, Gong Tao, Zhang Zhirong, Sun Xun
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Mol Pharm. 2017 Jan 3;14(1):81-92. doi: 10.1021/acs.molpharmaceut.6b00726. Epub 2016 Dec 7.
Several targeted drug delivery systems have recently been developed to increase the bioavailability of a drug at its site of action, allowing simultaneous reduction of the total necessary drug dose as well as side effects. Here, we designed a cationic gene vector containing matrix metalloproteinase-2 (MMP2)-cleavable substrate peptides that specifically target tumor sites where MMP2 levels are high. The targeted delivery system is fabricated by linking enzyme-cleavable polyethylene glycol (PEG) derivatives to cationic β-cyclodextrin-polyethylenimine conjugates, which reduce the toxicity of polyethylenimine and condense the therapeutic cargo. In the present study, tumor suppressor microRNA miR-34a, which suppresses onset and progression of many types of cancers, was investigated for its therapeutic potential for treating breast cancer. The PEG coating markedly reduces nonspecific interaction between cationic particles and serum proteins, permitting accumulation at the target site; subsequent peptide cleavage by MMP2 facilitates miR-34a delivery into tumor cells. The nanopreparation shows excellent stability, and its internalization, tumor targeting, and antitumor efficacy in vitro and in vivo are better than those of a nanopreparation containing MMP2-uncleavable peptide.
最近开发了几种靶向给药系统，以提高药物在其作用部位的生物利用度，从而在减少所需药物总剂量的同时降低副作用。在此，我们设计了一种含有基质金属蛋白酶-2（MMP2）可裂解底物肽的阳离子基因载体，该载体可特异性靶向MMP2水平较高的肿瘤部位。靶向给药系统是通过将可酶解的聚乙二醇（PEG）衍生物与阳离子β-环糊精-聚乙烯亚胺缀合物连接而制成的，后者可降低聚乙烯亚胺的毒性并浓缩治疗性药物。在本研究中，对抑制多种癌症发生和发展的肿瘤抑制性微小RNA miR-34a治疗乳腺癌的潜力进行了研究。PEG涂层显著降低了阳离子颗粒与血清蛋白之间的非特异性相互作用，使药物能够在靶位点积累；随后MMP2对肽的裂解促进了miR-34a向肿瘤细胞的递送。该纳米制剂显示出优异的稳定性，其在体外和体内的内化、肿瘤靶向及抗肿瘤功效均优于含有MMP2不可裂解肽的纳米制剂。
