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EGFR-targeted polyglycerol-shelled multifunctional micellar drug conjugates for precision cancer chemotherapy

EGFR靶向聚甘油壳多功能胶束药物缀合物用于精准癌症化疗

基本信息

批准号：
392192146
负责人：
Professor Dr. Rainer Haag
金额：
--
依托单位：
Mivenion GmbH
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2018
资助国家：
德国
起止时间：
2017-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/392192146?language=en
关键词：
EGFR targeted polyglycerol shelled multifunctional

项目摘要

Intelligent delivery of highly potent drugs is the next cornerstone in the design of novel therapeutics. With this project, we seek to develop a particulate drug delivery system which combines the strengths of antibody-drug conjugates with the versatility of micellar nanoparticles. We synthesize block-copolymers which assemble to defined micelles comprising self-cross-linked cores based on biodegradable copolymers of dithiolane-functionalized trimethylene carbonate (DTC) with caprolactone (CL) or trimethylene carbonate (TMC). To the DTC structures the toxic highly potent drugs auristatin and maytansine are covalently linked and released only upon reductively triggered decomposition of the micelle. The hydrophilic exterior of the micelle consists of highly tolerable next generation polyglycerol polymers, which provide a multihydroxylated surface of either linear or dendritic architecture. The micelles carry a peptidic targeting ligand, GE11, to accomplish targeting of the EGF receptor overexpressing tumors. This type of architecture allows a translation of approved highly potent drugs of antibody conjugates towards applications using much easier and fully synthetic drug targeting systems. Our micellar systems address the major obstacle of toxicity due to free drug molecules in the circulation, which is avoided by the intelligent design. This project involving the synthesis of novel block-copolymers, formation and characterization of EGFR-targeted micellar drug conjugates, selectivity and anticancer activity toward EGF-receptor expressing lung and breast cancer cells, as well as in vivo treatment of lung and metastatic breast tumors in nude mice, uniquely combines the expertise of both groups between China (Prof. Zhong) and Germany (Prof. Haag/Dr. Licha).

高效药物的智能输送是设计新疗法的下一个基石。通过这个项目，我们寻求开发一种结合了抗体-药物结合物的强度和胶束纳米颗粒的多功能性的颗粒药物输送系统。我们合成了基于二硫杂环戊烷功能化的三亚甲基碳酸酯(DTC)与己内酯(CL)或三亚甲基碳酸酯(TMC)的可生物降解共聚物，这些嵌段共聚物组装成定义的胶束，包括自交联核。对于DTC结构，有毒的高效力药物奥立斯汀和美丹辛是共价连接的，只有在还原引发胶束分解时才会释放。胶束的亲水性外部由高度耐受的下一代聚甘油聚合物组成，这些聚合物提供了线状或树枝状结构的多羟化表面。胶束携带多肽靶向配体Ge11，以完成对过度表达EGF受体的肿瘤的靶向。这种类型的体系结构允许将已批准的高效力抗体结合物药物转化为使用更容易和完全合成的药物靶向系统的应用。我们的胶束系统解决了由于循环中的游离药物分子而造成的主要毒性障碍，这是通过智能设计避免的。该项目涉及新型嵌段共聚物的合成、针对表皮生长因子受体的胶束药物结合物的形成和表征、对表达EGF受体的肺癌和乳腺癌细胞的选择性和抗癌活性，以及对裸鼠肺癌和转移性乳腺癌的体内治疗，独一无二地结合了中国(钟教授)和德国(哈格/利查博士)两个小组的专业知识。