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

高效药物的智能递送是新疗法设计的下一个基石。通过这个项目，我们寻求开发一种微粒药物递送系统，该系统结合了抗体-药物缀合物的优势和胶束纳米颗粒的多功能性。我们合成嵌段共聚物，其组装成限定的胶束，所述胶束包括基于二硫戊环官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）的可生物降解的共聚物的自交联核。对于DTC结构，毒性高效力药物澳瑞他汀和美登素共价连接并且仅在胶束的还原触发分解时释放。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，其提供线性或树枝状结构的多羟基化表面。胶束携带肽靶向配体GE 11，以实现EGF受体过表达肿瘤的靶向。这种类型的架构允许将已批准的高效抗体缀合物药物转化为使用更容易且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导致的毒性的主要障碍，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、EGFR靶向胶束药物偶联物的形成和表征、对表达EGF受体的肺癌和乳腺癌细胞的选择性和抗癌活性，以及裸鼠体内肺和转移性乳腺肿瘤的治疗，独特地结合了中国（钟教授）和德国（Haag教授/Licha博士）两个小组的专业知识。

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).