iRGD conjugated TPGS mediates codelivery of paclitaxel and survivin shRNA for the reversal of lung cancer resistance.
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.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
Jianan
J
Shen
Qingshuo
Q
Meng
Huiping
H
Sui
Qi
Q
Yin
Zhiwen
Z
Zhang
Haijun
H
Yu
Yaping
Y
Li
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry; D036103:Nanotechnology / Q000379:methods; D009842:Oligopeptides / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage*; D010539:Permeability; D011092:Polyethylene Glycols / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*; D000077022:Survivin; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D034741:RNA, Small Interfering; D000077022:Survivin; D014810:Vitamin E; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid; C014225:tocophersolan; D017239:Paclitaxel