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Engineering of cell microenvironment-responsive polypeptide nanovehicle co-encapsulating a synergistic combination of small molecules for effective chemotherapy in solid tumors

Title
Engineering of cell microenvironment-responsive polypeptide nanovehicle co-encapsulating a synergistic combination of small molecules for effective chemotherapy in solid tumors
Author
최한곤
Keywords
Polypeptide; Doxorubicin; Quercetin; Nanovehicle; Combination; POLYELECTROLYTE COMPLEX MICELLES; CANCER-CELLS; QUERCETIN PHARMACOKINETICS; MULTIDRUG-RESISTANCE; CONTROLLED DELIVERY; ANTICANCER DRUGS; BREAST-CANCER; THERAPY; NANOPARTICLES; DOXORUBICIN
Issue Date
2017-01
Publisher
ELSEVIER SCI LTD
Citation
ACTA BIOMATERIALIA, v. 48, Page. 131-143
Abstract
In this study, we report a facile method to construct a bioactive (poly(phenylalanine)-b-poly(t-histidine)-b-poly(ethylene glycol) polypeptide nanoconstruct to co-load doxorubicin (DOX) and quercetin (QUR) (DQ-NV). The smart pH-sensitive nanovehicle was fabricated with precisely tailored drug-to-carrier ratio that resulted in accelerated, sequential drug release. As a result of ratiometric loading, QUR could significantly enhance the cytotoxic potential of DOX, induced marked cell apoptosis; change cell cycle patterns, inhibit the migratory capacity of sensitive and resistant cancer cells. In particular, pro-oxidant QUR from DQ-NV remarkably reduced the GSH/GSSG ratio, indicating high oxidative stress and damage to cellular components. DQ-NV induced tumor shrinkage more effectively than the single drugs in mice carrying subcutaneous SCC-7 xenografts. DQ-NV consistently induced high expression of caspase-3 and PARP and low expression of Ki67 and CD31 immunomarkers. In summary, we demonstrate the development of a robust polypeptide-based intracellular nanovehicle for synergistic delivery of DOX/QUR in cancer chemotherapy. Statement of Significance In this study, we report a facile method to construct bioactive and biodegradable polypeptide nanovehides as an advanced platform technology for application in cancer therapy. We designed a robust (poly (phenylalanine)-b-poly(L-histidine)-b-poly(ethylene glycol) nanoconstruct to co-load doxorubicin (DOX) and quercetin (QUR) (DQ-NV). The conformational changes of the histidine block at tumor pH resulted in accelerated, sequential drug release. QUR could significantly enhance the cytotoxic potential of DOX, induce marked cell apoptosis, change cell cycle patterns, and inhibit the migratory capacity of sensitive and resistant cancer cells. DQ-NV induced tumor shrinkage more effectively than the single drugs and the 2-drug cocktail in tumor xenografts. In summary, we demonstrate the development of an intracellular nanovehicle for synergistic delivery of DOX/QUR in cancer chemotherapy. (C) 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
URI
https://www.sciencedirect.com/science/article/pii/S1742706116305621https://repository.hanyang.ac.kr/handle/20.500.11754/71611
ISSN
1742-7061; 1878-7568
DOI
10.1016/j.actbio.2016.10.034
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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