title: Temperature-triggered on-demand drug release enabled by hydrogen-bonded multilayers of block copolymer micelles.
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.
authors.affiliation: Department of Chemistry, Chemical Biology and Biomedical Engineering, Stevens Institute of Technology, Hoboken 07030, USA.
authors.forename: Zhichen
authors.initials: Z
authors.lastname: Zhu
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
authors.forename: Hongjun
authors.initials: H
authors.lastname: Wang
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Sukhishvili
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry*; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry*; D016503:Drug Delivery Systems; D006801:Humans; D006859:Hydrogen; D061986:MCF-7 Cells; D008823:Micelles; D011760:Pyrrolidinones / Q000737:chemistry*; D013634:Tannins / Q000737:chemistry*; D013696:Temperature
chemical_list: D000180:Acrylic Resins; D000903:Antibiotics, Antineoplastic; D008823:Micelles; D011760:Pyrrolidinones; D013634:Tannins; C052970:poly-N-isopropylacrylamide; C042670:N-vinyl-2-pyrrolidinone; D006859:Hydrogen; D004317:Doxorubicin
keywords: Block copolymer micelles; Drug release; Layer-by-layer; Poly(N-isopropylacrylamide); Temperature responsive