Chen Guojun, Shi Xudong, Wang Bowen, Xie Ruosen, Guo Lian-Wang, Gong Shaoqin, Kent K Craig
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.
Biomacromolecules. 2017 Jul 10;18(7):2205-2213. doi: 10.1021/acs.biomac.7b00617. Epub 2017 Jun 14.
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.
目前，对于治疗限流性血管疾病的开放性手术（如搭桥手术）后预防新生内膜导致的（再）狭窄，尚无临床可用方案。血管周围给药是一种很有前景的策略，但在转化研究中，要实现长期（如>3个月）的抗（再）狭窄疗效仍是一项重大挑战。在本研究中，我们构建了一种独特的给药系统，该系统由耐用的单分子胶束组成，其由仅含共价键的单臂多星型两亲性嵌段共聚物形成，以及由聚（丙交酯-共-乙交酯）-聚（乙二醇）-聚（丙交酯-共-乙交酯）三嵌段共聚物（简称为三嵌段凝胶）形成的热敏水凝胶组成，该水凝胶在体外约4周内稳定。悬浮在三嵌段凝胶中的含药单分子胶束（UMs）能够持续释放雷帕霉素超过4个月。值得注意的是，即使在大鼠模型中血管周围应用负载雷帕霉素的胶束于三嵌段凝胶中3个月后，与用空胶束/凝胶（无药物）处理的对照组相比，内膜/中膜面积比（一种再狭窄指标）仍被抑制了80%。单独在三嵌段凝胶中应用雷帕霉素无法实现这一点，其仅使内膜/中膜比降低了27%。总之，我们创建了一种用于血管周围给药的新型UM/三嵌段凝胶混合系统，该系统在动物试验中实现了罕见的3个月再狭窄抑制效果。该系统具有进一步转化为开放性手术抗（再）狭窄应用的实际潜力。
