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

Journal of controlled release : official journal of the Controlled Release Society (2013-07-09)
Zhichen Zhu, Ning Gao, Hongjun Wang, Svetlana A Sukhishvili
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 (~9.3wt.% 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-μm-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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Poly(N-isopropyl acrylamide), NHS ester end functionalized, average Mn 5,000
Sigma-Aldrich
1-Vinyl-2-pyrrolidinone, contains sodium hydroxide as inhibitor, ≥99%
Sigma-Aldrich
Poly(N-isopropylacrylamide), carboxylic acid terminated, average Mn 10,000
Sigma-Aldrich
Poly(N-isopropylacrylamide), Mn ~40,000