Redox-Activatable ATP-Depleting Micelles with Dual Modulation Characteristics for Multidrug-Resistant Cancer Therapy.
A fast adenosine triphosphate (ATP)-depleting micellar system that is activated by intracellular redox for the codelivery of anticancer drug paclitaxel (PTX) and small interference RNA (siRNA) targeting polo-like kinase1 (PLK1) is developed to address the key challenges of multidrug-resistant (MDR) cancer therapy. The ATP-depleting micelle is self-assembled from a redox-responsive amphiphilic polymer (termed as bPEG-SS-P123-PEI (PSPP)) that is composed of biocompatible branched polyethylene glycol (PEG) with 8 arms (bPEG), ATP-depleting Pluronic P123 (P123), and cationic low molecular weight polyethylenimine (PEI) blocks. Upon critical micelle concentration, the PSPP unimer self-assembles into a well-ordered multilayered nanostructure and is able to load PTX and siRNA targeting PLK1. The cleavage of disulfide linkages at intracellular glutathione-rich reduction milieu not only promotes PTX and siRNA release, but also activates the fast ATP-depletion action that is critical in preventing intracellular PTX efflux by multidrug-resistant cancer cells. The combination of ATP depletion and siRNA inhibition by PSPP micelles is found to provide dual modulations for resensitizing multidrug-resistant cancer cells for PTX treatment. As a result, the codelivery of PTX and PLK1 siRNA exerts a stronger combinational effect against tumor growth in MDR tumor models in vivo. The development of fast ATP-depleting nanomicelle represents an original delivery strategy for the distinctive dual modulation of cancer MDR with spatial and temporal control.
Department of Chemistry, Zhejiang University, Hangzhou, 310028, China.|College of life Sciences, Tarim University, Alar, 843300, China.
Hebin
H
Wang
Department of Chemistry, Zhejiang University, Hangzhou, 310028, China.
Yang
Y
Li
Department of General Surgery, Ningbo Li Huili Hospital, Medical School of Ningbo University, Ningbo, 315040, China.
Miaozun
M
Zhang
Department of Chemistry, Zhejiang University, Hangzhou, 310028, China.
Di
D
Wu
Center for Bionanoengineering and State Key Laboratory for Chemical Engineering, Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, China.
Youqing
Y
Shen
Department of Chemistry, Zhejiang University, Hangzhou, 310028, China.
Guping
G
Tang
School of Materials Science and Engineering, Nanyang Technological University, Singapore, 639798, Singapore.
Yuan
Y
Ping
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D017239:Paclitaxel / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology*; D000097869:Polo-Like Kinase 1
D000255:Adenosine Triphosphate; D018797:Cell Cycle Proteins; D008823:Micelles; D017239:Paclitaxel; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1
PEGylation; anticancer drug delivery; combination therapy; nanomedicine; stimuli-responsive polymeric micelles