Chemosensitization of doxorubicin in multidrug-resistant cells by unimolecular micelles via increased cellular accumulation and apoptosis

J Pharm Pharmacol. 2016 Mar;68(3):333-41. doi: 10.1111/jphp.12528. Epub 2016 Feb 19.

Abstract

Objectives: Unimolecular micelles were prepared by modification of polyamidoamine (PAMAM) dendrimers using Pluronic F127 (PF127), which is expected to reverse multidrug resistance (MDR). And the reversal mechanisms have been studied.

Methods: Characterization of the products was carried on. MTT assay was used to evaluate the cytotoxicity of the DOX-loaded conjugates. Cellular uptake study was measured by confocal laser scanning microscope and flow cytometry. Apoptosis assay was identified by Annexin V-FITC/PI apoptosis assay and Hoechst 33 342 staining.

Key findings: Improved cytotoxicity of DOX-loaded conjugates in MCF-7/ADR cells (as much as 33-fold according to the IC50 values) was observed in contrast with that of free DOX. The DOX-loaded conjugates induced a much quicker and 100% uptake in MCF-7/ADR cells, and more than fivefold accumulation of DOX-loaded conjugates was observed compared with free DOX. Apoptosis assay showed that DOX-loaded conjugates decreased the cell viability from 81.87 ± 5.94% to 54.83 ± 3.63% (DOX concentration 2 μg/ml). At 48 h, more accumulation and distribution in the nuclei were observed after treatment with DOX-loaded conjugates.

Conclusions: PF127-PAMAM conjugates showed superiority in the treatment of MCF-7/ADR, which implied the potential vehicles of anticancer drugs for the reversal of MDR.

Keywords: PAMAM dendrimer; doxorubicin; drug resistance; pluronic; unimolecular micelle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dendrimers / administration & dosage
  • Dendrimers / chemistry
  • Doxorubicin / administration & dosage*
  • Doxorubicin / chemistry*
  • Drug Carriers / chemistry
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • MCF-7 Cells
  • Micelles
  • Poloxamer / chemistry
  • Rabbits

Substances

  • Antineoplastic Agents
  • Dendrimers
  • Drug Carriers
  • Micelles
  • Poloxamer
  • Doxorubicin