Shen Jianan, Meng Qingshuo, Sui Huiping, Yin Qi, Zhang Zhiwen, Yu Haijun, Li Yaping
Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
Mol Pharm. 2014 Aug 4;11(8):2579-91. doi: 10.1021/mp400576f. Epub 2013 Nov 18.
Multidrug resistance (MDR) is one of the major obstacles in tumor treatment. Herein, we reported an active targeting strategy with peptide-mediated nanoparticles deep into tumor parenchyma, which iRGD conjugated d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) mediated codelivery of paclitaxel (PTX) and survivin shRNA (shSur) for the reversal of lung cancer resistance. Pluronic P85-polyethyleneimine/TPGS complex nanoparticles incorporated with iRGD-TPGS conjugate codelivering PTX and shSur systems (iPTPNs) could induce effective cellular uptake, RNAi effects, and cytotoxicity on A549 and A549/T cells. In particular, iPTPNs showed superiority in biodistribution, survivin expression, tumor apoptosis, and antitumor efficacy by simultaneously exerting an enhanced permeability and retention (EPR) effect and iRGD mediated active targeting effects. iPTPNs significantly enhanced the accumulation of PTX and shSur, down-regulated survivin expression, and induced cell apoptosis in tumor tissue. The in vivo antitumor efficacy showed the tumor volume of iPTPNs group (10 mg/kg) was only 12.7% of the Taxol group. Therefore, the iRGD mediated PTX and shSur codelivery system could be a very powerful approach for the reversal and therapy of lung cancer resistance.
多药耐药（MDR）是肿瘤治疗中的主要障碍之一。在此，我们报道了一种主动靶向策略，即通过肽介导的纳米颗粒深入肿瘤实质，其中整合素靶向肽（iRGD）偶联的聚乙二醇1000维生素E琥珀酸酯（TPGS）介导紫杉醇（PTX）和生存素短发夹RNA（shSur）的共递送以逆转肺癌耐药。载有iRGD-TPGS偶联物共递送PTX和shSur系统（iPTPNs）的普朗尼克P85-聚乙烯亚胺/TPGS复合纳米颗粒可诱导对A549和A549/T细胞的有效细胞摄取、RNA干扰效应和细胞毒性。特别是，iPTPNs通过同时发挥增强的渗透和滞留（EPR）效应和iRGD介导的主动靶向效应，在生物分布、生存素表达、肿瘤凋亡和抗肿瘤疗效方面表现出优势。iPTPNs显著增强了PTX和shSur的积累，下调了肿瘤组织中生存素的表达并诱导细胞凋亡。体内抗肿瘤疗效显示iPTPNs组（10 mg/kg）的肿瘤体积仅为紫杉醇组的12.7%。因此，iRGD介导的PTX和shSur共递送系统可能是一种非常有效的逆转和治疗肺癌耐药的方法。
