Co-delivery of paclitaxel and survivin shRNA by pluronic P85-PEI/TPGS complex nanoparticles to overcome drug resistance in lung cancer.
Drug resistance is a main obstacle for the successful chemotherapy of lung cancer. In this work, a new co-delivery system, P85-PEI/TPGS/PTX/shSur complex nanoparticles (PTPNs), to overcome paclitaxel (PTX) resistance in A549 human lung cancer was designed and developed. The experimental results showed that PTPNs could facilitate drug into cells and induce survivin shRNA (shSur) into nuclei on A549 and A549/T cells, achieve efficient gene delivery and induce availably RNA interference on A549/T cells. The IC(50) of PTPNs against A549/T cells was 360-fold lower than that of free PTX. The enhanced efficacy of PTPNs against A549/T cells was associated with PTX-induced apoptosis and cell arrest in G2/M phase. Down-regulation of survivin protein by PTPNs could lower the apoptosis threshold of drug resistant cells and render chemotherapeutic agents more effective. Moreover, the inhibition of GST activity by P85 was found to increase PTX accumulation in A549/T cells. The in vivo antitumor efficacy showed that PTPNs were more effective than that of the Taxol. As a result, the co-delivery of PTX and shSur by PTPNs could be a very powerful approach to improve the therapeutic effect of PTX in resistant lung cancer.
Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
Jianan
J
Shen
Qi
Q
Yin
Lingli
L
Chen
Zhiwen
Z
Zhang
Yaping
Y
Li
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007097:Imines / Q000737:chemistry*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*; D011060:Poloxalene / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011095:Polyethylenes / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D000077022:Survivin; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry
C107489:BIRC5 protein, human; D007097:Imines; D051034:Inhibitor of Apoptosis Proteins; D011095:Polyethylenes; D034741:RNA, Small Interfering; D000077022:Survivin; C422648:pluronic block copolymer p85; C505405:poly(ethylene imine); D014810:Vitamin E; D011092:Polyethylene Glycols; D011060:Poloxalene; C014225:tocophersolan; D017239:Paclitaxel