“MSC-前药酶/前药”脑肿瘤精确给药系统

Commonly, brain tumor is protected by "Blood-Brain-Barrier" and easy to metastasize, which leads to the poor result of clinical therapy. So a novel brain-targeted delivery system is urgently needed. Mesenchymal stem cells are recently emerging as cell-based delivery carriers, which show specific migration trend toward brain tumor, track microscopic tumor deposits and infiltrate tumor cells. In our researches, we try to design a kind of nano-enzyme, produced by the self-assembly of enzymes, which could easily transfer into MSC. Then according to cell migration, nano-enzyme might directly reach the tumor region in brain. Here, lots of pro-drug would be transformed into cell-toxic metabolites under the enzyme catalysis. As a result, the growth of brain tumor would be significantly inhibited. In our designed system, the enzyme would be directly delivered into brain and no gene engineering approach might be needed, which greatly improve the therapeutic safety of MSC. Also, during the treatment, the "enzyme/prodrugs" system is flexible to change due to drug sensitivity for patients' therapy, called as "individual therapy", which would be significantly helpful for tumor therapy. This strategy would arouse a new research tendency for targeted therapy of brain tumor, and also improve the clinical efficiency.

脑肿瘤的"血脑屏障"保护、高转移等特点，严重限制了其临床治疗疗效，故亟待开展新型、安全、有效的脑肿瘤靶向给药系统。间充质干细胞（Mesenchymal stem cells，MSC）作为新型药物递送载体，其具有高度的脑肿瘤趋向性，可主动迁移穿越 "血脑屏障"，准确到达肿瘤部位。本课题首次提出利用MSC趋化优势，将自组装构建的活性前药酶纳米颗粒内吞入MSC，经细胞主动迁移直接靶向输送到脑肿瘤区域，提高小分子前药的生物转化率，实现脑肿瘤的"脉冲式"杀伤并降低毒副作用。有别于传统体系，本课题避免了基因工程改造对MSC的生物活性、治疗安全性的潜在影响；同时治疗中可依据患者临床指征、药物敏感性等，灵活更替"前药酶/前药"体系，利于患者自体细胞、个体化治疗的实现，改善肿瘤疗效、降低副作用、提高治疗安全性。本新型治疗体系的建立为攻克脑肿瘤提供了一条新的研究思路。

在基金的支持下，课题组出色完成了项目的既定目标，并在预设基础上有了更深入的发展。课题组完成了酶活性蛋白的自组装，“MSC-前药酶”的初步构建及其优化，主要包括间充质干细胞三维体系的建立，载模型代谢酶MSC体系构建及体内外活性评价。基于以上工作，我们创新性提出了细胞膜结合纳米技术，进一步改进“MSC-前药酶”的药物递送体系，使体系的尺寸控制在纳米级，经血管给药在肿瘤组织内可实现分布、扩散、迁移，从而实现瘤内的有效微分布，提高潜在疗效，为肿瘤的治疗提供新的思路。 . 团队在基金的支持下，在肿瘤靶向纳米研究领域取得了突出的进步，发表了Nature子刊等SCI论文10余篇，其中关于抗肿瘤纳米组装的文章，被国际著名药学期刊J Pharm Sci作为“最具有创新性和最重要的科学发现”在其官网首页推送；基金支持期间，获得有关抗肿瘤纳米药物的发明专利授权3项（美国、日本专利各1项），团队研制的抗肿瘤靶向纳米制剂（白蛋白紫杉醇纳米制剂），获得国家食品药品监督管理局批准进入临床试验。在基金支持下，培养了研究生10名以上，多名研究生获得国家奖学金。在基金支持期间，团队获两项国自然青年基金，获多个省博士及博士后基金。总之，在基金帮助下我们团队在肿瘤纳米药物研究领域已进入了国内外领先行列。