Mixed Polymer Nanoassemblies for Tunable Combination Drug Delivery to Lung Cancer Tumors

Chemotherapy is the most widely used for treatment of cancer. In order to reduce the side toxic effects and increase efficacy, anticancer drugs are generally given to patients in combination. Synergistic effects of combination chemotherapy are dependent on combination settings such as concentrations, ratios and injection sequence of multiple drugs. Despite the potential, there are no currently available drug formulations that can fix such optimal combination settings in vivo because each drug shows different distribution and metabolism patterns in the body. This proposal suggests a promising method to achieve safe and effective combination therapy for lung cancer in vivo by using mixed polymer nanoassemblies that can entrap and release multiple drugs in a pH-controlled fashion. Tumor tissues as well as intracellular vesicles called endosomes and Iysosomes are known acidic. Mixed polymer nanoassemblies that deliver heat shock protein 90 (HSP90) inhibitors along with other anticancer drugs used currently for cancer treatment (doxorubicin (DOX)) will be designed to release drugs selectively in acidic environments. This approach will allow the mixed nanoassemblies to remain stable in the blood stream yet to release drugs in tumor tissues. Synergistic drug actions are expected by the combined use of HSP90 inhibitors and DOX. HSP90 is known responsible for regulation of cancer cell viability by refolding denatured vital proteins for cell survival. Therefore, inhibition of HSP90 is believed to render cancer cells more sensitive to DOX. This project will test our hypothesis that mixed nanoassemblies can deliver HSP90 inhibitors and DOX to cancer cells at a fixed ratio for the maximum synergistic effect. In order to optimize drugloading and release efficiency, biocompatible poly(ethylene glycol)-poly(amino acid) block copolymers will be synthesized and used as a building block for preparation of mixed nanoassemblies. Drugbinding linkers of hydrazone conjugation between anticancer drugs and polymers will be studied by modulating their hydrolysis rates in various different acidic conditions. Cytotoxicity of the mixed polymer nanoassemblies will be tested in human lung cancer cells, such as GLC4, H82, PC-14, A549, Lu-99 and H460, in various disease states. Obtained results will lead to further development of mixed polymer nanoassembly for preclinical applications that can reduce side effects and improve efficacy of combination chemotherapy for lung cancers.