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

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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).