Dual temperature-and pH-responsive polymeric micelle for selective and efficient two-step doxorubicin delivery

Yuki Hiruta, Yuki Kanda, Naoya Katsuyama, Hideko Kanazawa

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)


We report a polymeric micelle drug delivery system, which enables selective intracellular uptake with external thermal stimulation, and effective release of a drug at internal acidic endosomal pH. We developed a dual temperature-and pH-responsive polymeric micelle composed of a temperature-responsive corona segment with poly(N-isopropylacrylamide-co-dimethylacrylamide) [P(NIPAAm-co-DMAAm)] and a pH-responsive core segment with poly[2-(diisopropylamino)ethyl methacrylate] (PDPA). A dual temperature-and pH-responsive amphiphilic diblock copolymer was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. The dithiobenzoate end-group was removed with radical-induced ester exchange. This copolymer formed nano-sized micelles in aqueous solution, and encapsulated anti-cancer agent, doxorubicin (DOX). The resultant micelles exhibited a temperature-dependent phase transition at a temperature slightly higher than body temperature, and intracellular uptake of encapsulated DOX was accelerated above the phase transition temperature. A transition from neutral to positive charge, leading to micelle disassembly, accelerated the release of Nile red as a model drug. The cytotoxicity of doxorubicin (DOX)-loaded dual temperature-and pH-responsive micelles against human cervical cancer HeLa cells was significantly greater at 42 °C than at 37 °C, while no significant temperature-dependent cytotoxicity was observed with DOX-loaded micelles that were only temperature-responsive. This proof-of-concept synergistic two-step delivery system with enhanced intracellular uptake upon external thermal stimulation and rapid release of DOX at internal acidic endosomal pH was effective against tumor cells in vitro.

Original languageEnglish
Pages (from-to)29540-29549
Number of pages10
JournalRSC Advances
Issue number47
Publication statusPublished - 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)


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