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Unimolecular Micelle-Based Hybrid System for Perivascular Drug Delivery Produces Long-Term Efficacy for Neointima Attenuation in Rats

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† ‡ †Department of Materials Science and Engineering, and Wisconsin Institute for Discovery and ‡Department of Biomedical Engineering and Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53715, United States
§ §Department of Surgery, 5151 Wisconsin Institutes for Medical Research and ⊥McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States
# Department of Surgery, Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute and #Department of Surgery, College of Medicine, The Ohio State University, Columbus, Ohio 43210, United States
*E-mail: [email protected]. Phone: 614-292-2600.
*E-mail: [email protected]. Phone: +1 608 316 4311.
*E-mail: [email protected]. Phone: 614-292-5276.
*E-mail: [email protected]. Phone: +1 608 262 6269. Fax: +1 608 262 3330.
Cite this: Biomacromolecules 2017, 18, 7, 2205–2213
Publication Date (Web):June 14, 2017
https://doi.org/10.1021/acs.biomac.7b00617
Copyright © 2017 American Chemical Society
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    Abstract

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    At present, there are no clinical options for preventing neointima-caused (re)stenosis after open surgery such as bypass surgery for treating flow-limiting vascular disease. Perivascular drug delivery is a promising strategy, but in translational research, it remains a major challenge to achieve long-term (e.g., > 3 months) anti(re)stenotic efficacy. In this study, we engineered a unique drug delivery system consisting of durable unimolecular micelles, formed by single multiarm star amphiphilic block copolymers with only covalent bonds, and a thermosensitive hydrogel formed by a poly(lactide-co-glycolide)–poly(ethylene glycol)–poly(lactide-co-glycolide) triblock copolymer (abbreviated as triblock gel) that is stable for about 4 weeks in vitro. The drug-containing unimolecular micelles (UMs) suspended in Triblock gel were able to sustain rapamycin release for over 4 months. Remarkably, even 3 months after perivascular application of the rapamycin-loaded micelles in Triblock gel in the rat model, the intimal/medial area ratio (a restenosis measure) was still 80% inhibited compared to the control treated with empty micelle/gel (no drug). This could not be achieved by applying rapamycin in Triblock gel alone, which reduced the intimal/medial ratio only by 27%. In summary, we created a new UM/Triblock gel hybrid system for perivascular drug delivery, which produced a rare feat of 3-month restenosis inhibition in animal tests. This system exhibits a real potential for further translation into an anti(re)stenotic application with open surgery.

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