Biodegradable hybrid polymer micelles for combination drug therapy in ovarian cancer

Swapnil S. Desale, Samuel Monroe Cohen, Yi Zhao, Alexander V. Kabanov, Tatiana K Bronich

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

The co-delivery of drug combination at a controlled ratio via the same vehicle to the cancer cells is offering the advantages such as spatial-temporal synchronization of drug exposure, synergistic therapeutic effects and increased therapeutic potency. In an attempt to develop such multidrug vehicle this work focuses on functional biodegradable and biocompatible polypeptide-based polymeric micelles. Triblock copolymers containing the blocks of ethylene glycol, glutamic acid and phenylalanine (PEG-PGlu-PPhe) were successfully synthesized via NCA-based ring-opening copolymerization and their composition was confirmed by 1H NMR. Self-assembly behavior of PEG-PGlu 90-PPhe25 was utilized for the synthesis of hybrid micelles with PPhe hydrophobic core, cross-linked ionic PGlu intermediate shell layer, and PEG corona. Cross-linked (cl) micelles were about 90 nm in diameter (ξ-potential = -20 mV), uniform (narrow size distribution), and exhibited nanogels-like behavior. Degradation of cl-micelles was observed in the presence of proteolytic enzymes (cathepsin B). The resulting cl-micelles can incorporate the combination of drugs with very different physical properties such as cisplatin (15 w/w% loading) and paclitaxel (9 w/w% loading). Binary drug combination in cl-micelles exhibited synergistic cytotoxicity against human ovarian A2780 cancer cells and exerted a superior antitumor activity by comparison to individual drug-loaded micelles or free cisplatin in cancer xenograft model in vivo. Tunable composition and stability of these hybrid biodegradable micelles provide platform for drug combination delivery in a broad range of cancers.

Original languageEnglish (US)
Pages (from-to)339-348
Number of pages10
JournalJournal of Controlled Release
Volume171
Issue number3
DOIs
StatePublished - Nov 10 2013

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Keywords

  • Cisplatin
  • Combination drug delivery
  • Controlled release
  • Cross-linked polymer micelles
  • Ovarian cancer
  • Paclitaxel

ASJC Scopus subject areas

  • Pharmaceutical Science

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