聚合物纤维制控释载药胶束及靶向作用机制

Anticancer drugs and their formulations are currently confronted with challenges in improving the targeting capabilities and continuous availability with effective concentrations. Electrospun fibers provide customizable drug loading contents and flexible interconnected pores to regulate drug release, while micelles are characterized with significant alleviation of drug resistance effect and high sensitivity to environmental signals. In this proposal electrospun fibers with micelle loadings are constructed at three incremental levels to include drug-containing micelles, drug-conjugated micelle carriers, and copolymers of drug-conjugated carrier and fiber matrix molecules, respectively, which is aimed to develop principles and methods for sustainable release and targeting action of anticancer drugs. The fiber matrices are designed to release drug-loading micelles in response to the acidic pH and enzymes of tumor microenvironment, followed by the release of therapeutics from micelles in response to the reducible signals in cytoplasm after targeting delivery into tumor cells. The molecular structure of micelle carrier and fiber matrix is optimized to efficiently modulate the release behaviors of micelles and drugs at different stages. The overall regulation and fine tune-up of drug release form micelle-lading fibers are supposed to delivery multiple drugs with optimal concentration and ratios into tumor cells, and the synergistic enhancement of therapeutic efficiency against tumors are explored both in vitro and in vivo. The distribution of micelles in tumor tissues and the interactions with tumor cells are determined in tumor-bearing animals to reflect the local release from and targeting therapy of implanted fibers. The suppression of tumor growth in tumor-bearing animals and the inhibition of tumor development in tumor-removed animals are evaluated after implantation of micelle-loading fibers, which is attempted to define a feasible strategy for cancer treatment.

围绕抗肿瘤药物制剂在体内靶向性、释药稳定性和持续性等方面面临的困难，在前期研究基础上，本项目从三个层次构建载胶束的纤维制剂，即纤维中分别包含载药胶束、载药胶束载体分子、载药胶束载体分子和纤维基质分子间键合的共聚物，目标是发展一类持续缓释、靶向作用制剂的构建方法和控释机制。以纤维基质和胶束载体的结构设计为重点，全面揭示释放行为的调控机制，包括基于响应肿瘤的微酸性和酶环境，利用降解速度的差异，纤维基质释放或形成胶束；基于靶向细胞和响应细胞内环境，键合药物的胶束释放药物。利用载药胶束纤维全程调控释放行为的手段，实现多种药物按最佳剂量比作用于细胞，探究药物联用的协同增效。在建立的肿瘤、切除肿瘤动物模型中，阐明释放胶束在肿瘤组织中的分布、靶向细胞和细胞内释药；基于载胶束纤维的响应释放和靶向作用机制，结合药物联用的协同增效，抑制肿瘤生长或再生、降低全身毒副作用，为丰富和发展癌症的治疗手段提供技术支撑。

为解决载药胶束在肿瘤组织中聚集度、释药持续性等问题，本项目将载药胶束整合到电纺纤维中，瘤内植入纤维后，赋予制剂的局部靶向性。通过设计纤维基质材料的组成或结构，调节胶束的释放和形成，赋予对肿瘤环境的敏感性和载药胶束释放的持续性；同时通过设计胶束载体材料，赋予胶束的细胞靶向性、药物释放对细胞内环境的敏感性。研究内容一是合成了共价接枝药物的胶束载体材料，包括以聚乙二醇-聚己内酯共聚物、四臂聚乙二醇和聚己内酯的星形共聚物、透明质酸为载体，通过二硫键接枝喜树碱。二是研究了胶束与细胞的作用机制及抗肿瘤效果，实现了细胞对胶束的高效吞噬、还原性环境下药物的敏感释放、胶束对肿瘤细胞生长的有效抑制、药物联用的协同增效等。三是研究了载药纤维的释药机制、在肿瘤中的分布和抗肿瘤效果，包括针对肿瘤生长的特点实施联合用药的协同机制，载药短纤维经静脉和瘤内注射后在肿瘤中的分布等。四是研究了载胶束纤维的胶束释放机制、释放胶束在肿瘤组织的分布和抗肿瘤效果。通过合成响应肿瘤微环境发生降解的纤维基质材料、在纤维基质中添加水溶性高分子改变其组成等手段，可有效调控胶束的释放和形成，提升了抗肿瘤效果；采用基于聚集诱导发光效应的胶束载体聚合物研究表明，其释放后在肿瘤组织中自组装成胶束。通过上述研究，掌握了载胶束纤维制剂的构建方法，获得了不同类型载胶束纤维中胶束释放速度和释放物特征的调控手段，阐明了载体材料结构、纤维特征、药物联用方案等对胶束释放、组织分布、靶向细胞释放药物、抑制肿瘤生长或再生的影响机制，项目研究达到了预期研究目标，可为研究一种有效治疗肿瘤的药物制剂提供技术支撑。基于上述研究结果，项目主持人以通讯作者发表SCI收录论文29篇，影响因子均大于3.0，其中1篇论文为封面文章，1篇论文被选为ACS Editors’ Choice论文，项目完成期间主持人以第一完成人获得教育部自然科学奖二等奖1项。