Temperature-triggered on-demand drug release enabled by hydrogen-bonded multilayers of block copolymer micelles

Zhichen Zhu, Ning Gao, Hongjun Wang, Svetlana A. Sukhishvili

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

We report on hydrogen-bonded layer-by-layer (LbL) films as a robust, reusable platform for temperature-triggered "on-demand" release of drugs. Films with high drug loading capacity, temperature-controlled on-off drug release, and stability at physiological conditions were enabled by assembly of tannic acid (TA) with temperature-responsive block copolymer micelles (BCMs), which were pre-formed by heating solutions of a neutral diblock copolymer, poly(N-vinylpyrrolidone)-b-poly(N-isopropylacrylamide) (PVPON-b-PNIPAM), to a temperature above the lower critical solution temperature (LCST) of PNIPAM. The BCM/TA films exhibited temperature-triggered swelling/deswelling transitions at physiological conditions (swelling ratios of 1.75 and 1.2 at 37 °C and 20 °C, respectively). A model drug, doxorubicin (DOX) was incorporated into the film at a high drug-to-matrix ratio (∼9.3 wt.% of DOX per film mass), with a total loading capacity controlled by the film thickness. At 37 °C, DOX was efficiently retained within the hydrophobic BCM cores of BCM/TA films, whereas exposure to a lower temperature (20 °C) triggered fast DOX release. While neither bare BCM-containing films nor films loaded with DOX showed cytotoxicity at 37 °C, drug released from films at lower temperature exhibited high potency against breast cancer cells. Repeated on/off drug release was demonstrated with 1.5-um-thick DOX-loaded films, allowing at least three 30-min cooling cycles with consistent DOX (∼12-16% of loaded DOX released for each cycle) released over a 4-day period. Despite significant stress associated with multiple swelling/deswelling cycles, films maintained their structural integrity in PBS, and each film could be repeatedly loaded with drug and used more than 15 times with only ∼ 7% loss in film thickness and no obvious changes in reloading capacity or release profiles. This work presents the first proof-of-concept utility of temperature-responsive BCM-containing films for repeated on-demand release of a drug.

Original languageEnglish
Pages (from-to)73-80
Number of pages8
JournalJournal of Controlled Release
Volume171
Issue number1
DOIs
StatePublished - 2013

Keywords

  • Block copolymer micelles
  • Drug release
  • Layer-by-layer
  • Poly(N-isopropylacrylamide)
  • Temperature responsive

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