Mumlti-stimuli Sensitive Platinum (IV) Micells for Programmed Drug Delivery

Cisplatin is a first line chemotherapeutic drug routinely used in clinics for cancer management. The cisplatin mode of action is based on the inhibition of DNA repair mechanisms to induce apoptosis. However, cisplatin usage has side effects such as nephrotoxicity, ototoxicity, and neurotoxicity. Also, the tumor cell was showed to rapidly develop resistance due to the overuse of cisplatin, thereby lowering the survival rate. Over the years, many efforts have been made to improve the effectiveness of this chemotherapeutical drug. Several prodrugs have been synthesized with the hope of enhancing its anti-cancer performance while minimizing non-specific toxicity. The downside of delivery of chemotherapeutics to cancer cells account for the heterogeneity and complex cellular network in tumors which is comprised of fibroblast, stroma cells, immune cells and cancer cells. In addition, the distinct physiological conditions of a tumor microenvironment such as hypoxia, acidic pH, and interstitial pressure make drug delivery to cancer cells highly challenging. To tackle these problems, we designed platinum (IV)-based micelle that can be activated under a unique tumor physiological environment. We hypothesize that the key features of a tumor microenvironment such as bio-reduction, hypoxia, and pH can trigger the release of cisplatin from the proposed platinum (IV) micelles at the target site. To achieve this goal, we first converted cisplatin into oxoplatin [Pt(IV)(OH)2] through an oxidation reaction. The Pt(IV)(OH)2 was subsequentially substituted with a hypoxia-sensitive molecule and pH-responsive polymer chain. Via this design consideration, an amphipathic molecule undergoes self-assembly to form a micelle. The micelle provides protection to the platinum bioactive agent and will only be released in the tumor. Using the proposed strategy, the chemotherapeutic delivery efficiency will be improved while reducing the non-specific side effects