PUBLICATION

Synergistic effects of A-B-C-type amphiphilic copolymer on reversal of drug resistance in MCF-7/ADR breast carcinoma

Authors
Zhang, L., Lu, J., Qiu, L.
ID
ZDB-PUB-161028-8
Date
2016
Source
International Journal of Nanomedicine   11: 5205-5220 (Journal)
Registered Authors
Keywords
P-glycoprotein, doxorubicin, micelle, multidrug resistance, zebrafish
MeSH Terms
  • ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
  • Animals
  • Antibiotics, Antineoplastic/chemistry
  • Antibiotics, Antineoplastic/pharmacology*
  • Apoptosis/drug effects
  • Breast Neoplasms/drug therapy*
  • Breast Neoplasms/pathology
  • Doxorubicin/chemistry
  • Doxorubicin/pharmacology*
  • Drug Resistance, Multiple/drug effects*
  • Drug Resistance, Neoplasm/drug effects*
  • Embryo, Nonmammalian/cytology
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/metabolism
  • Female
  • Humans
  • MCF-7 Cells
  • Micelles
  • Polyethylene Glycols/chemistry
  • Polymers/chemistry
  • Polymers/pharmacology*
  • Xenograft Model Antitumor Assays
  • Zebrafish/growth & development
  • Zebrafish/metabolism
  • beta-Cyclodextrins/chemistry
PubMed
27785023 Full text @ Int. J. Nanomedicine
Abstract
P-glycoprotein (P-gp) overexpression has become the most common cause of occurrence of multidrug resistance in clinical settings. We aimed to construct a micellar polymer carrier to sensitize drug-resistant tumors to doxorubicin (DOX). This A-B-C-type amphiphilic copolymer was prepared by the sequential linkage of β-cyclodextrin, hydrophobic poly(d,l-lactide), and hydrophilic poly(ethylene glycol). Upon incubation of the DOX-loaded micelles with DOX-resistant human breast carcinoma MCF-7/ADR cells, significantly enhanced cytotoxicity and apoptosis were achieved. A series of studies on the action mechanism showed that the polymer components such as β-cyclodextrin, hydrophobic poly(d,l-lactide) segment, and poly(ethylene glycol) coordinatively contributed to the improved intracellular ATP depletion and ATPase activity, increased intracellular uptake of P-gp substrates via competitive binding to P-gp, and decreased P-gp expression in MCF-7/ADR cells. More interestingly, a similar phenomenon was observed in the zebrafish xenograft model, resulting in ~64% inhibition of MCF-7/ADR tumor growth. These results implied that the polymeric micelles displayed great potentials as P-gp modulators to reverse DOX resistance in MCF-7/ADR breast carcinoma.
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