期刊
COLLOIDS AND SURFACES B-BIOINTERFACES
卷 145, 期 -, 页码 716-727出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.colsurfb.2016.05.088
关键词
pH-sensitive nanoparticles; Intracellular sequential release; Autophagy; Endosome escape; Nuclear drug delivery; Multidrug resistance
资金
- National Natural Science of China [81172721]
- National Natural Science Foundation of China for Talents Training in Basic Science of the People's Republic of China [J1103507, J1210025]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
Development of novel nano-drug delivery systems (NDDS) that can transport anticancer drugs into cell nuclei is still a highly desirable strategy for reversing multi-drug resistance (MDR) in cancer therapy. Herein, we designed and prepared a novel NDDS, designated S@L NPs, in which several smaller nanoparticles are contained within a larger nanoparticle. Our S@L NPs (CS/PAA/VP-16@TPGS/PLGA NPs) possess a structure in which smaller nanoparticles (Chitosan-Poly(acrylic acid) nanoparticles, CS/PAA NPs) containing the drug etoposide (VP-16) are loaded within a larger nanoparticle (Vitamin E d-a-tocopheryl polyethylene glycol 1000 succinate-modified poly(lactic-co-glycolic acid) nanoparticles, TPGS/PLGA NPs). The system utilizes intracellular pH gradients to achieve pH-sensitive sequential release within different intracellular domains of MDR cells. S@L NPs could be triggered to degrade and release CS/PAA/VP-16 NPs in the acid environment of the cytosol, endosomes or lysosomes, and CS/PAA/VP16 NPs were capable of entering the nucleus through nucleopores. It is significant that CS/PAA/VP-16 NPs exhibit disaggregation in the alkaline environment of the nucleus and thereby release the contained anticancer drug. Further mechanistic studies showed that CS/PAA/VP-16 NPs escaped retention and degradation within lysosomes and protected the drug from P-glycoprotein-induced efflux. Simultaneously, S@L NPs enhanced the anticancer effect of the loaded drug by inducing autophagy and apoptosis of MDR cells. This novel NDDS may provide a promising platform for nuclear drug delivery for reversing MDR. (C) 2016 Elsevier B.V. All rights reserved.
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