Plasma Membrane-anchored Platinum(IV) Anticancer Photooxidants to Reduce Drug Resistance

Despite the continuing emergence of new antineoplastic modalities, such as immunotherapy, conventional chemotherapeutic agents remain the standard treatment for most cancers in the clinic. One of the major reasons for the failure of chemotherapy is drug resistance, which can arise via multiple mechanisms. In case of DNA-damaging agents, such as platinum-based drugs, several parallel mechanisms, including reduced uptake, increased efflux, enhanced DNA damage repair, and failure to induce apoptosis, are used by cancer cells to detoxify the drugs. Targeting one of these mechanisms alone may not be able to effectively overcome drug resistance. As such, a novel strategy that can bypass these intracellular resistance pathways is highly demanded, and such complexes with new action modes may also represent a direction for future development. Our preliminary data showed that a platinum(IV) complex based on carboplatin, a clinically-used platinum(II) drug, did not enter cancer cells but accumulated well in the plasma membrane where the complex remained stable prior to activation. In contrast to classical platinum(IV) prodrugs, upon irradiation with near-infrared light, our platinum(IV) complex acted as a photooxidant to oxidize lipids and proteins, releasing the original platinum(II) drug and axial ligands. Consequently, cell death occurred due to the loss of cell membrane integrity, and the platinum(IV) photooxidant exhibited significantly augmented photocytotoxicity compared with carboplatin, especially in platinum-refractory cancer cells. Based on this preliminary study, we will first design and synthesize analogues of the platinum(IV) photooxidant. The photooxidative properties and photoreduction processes of these complexes will be examined. Subsequently, in vitro evaluation and cellular mechanistic study on the membrane-targeted platinum(IV) photooxidants will be performed. We will also investigate the toxicity and antitumor efficacy of the lead compounds in vivo. Our proposed research represents a possible direction for developing photoactivatable platinum coordination complexes with novel modes of action; this strategy of anchoring platinum(IV) photooxidants to the cell membrane to inflict damage in a controllable fashion will likely lead to the discovery of several anticancer platinum(IV) coordination complexes that can trigger intracellular signaling cascades and effectively overcome platinum resistance. Such complexes will also broaden the family of organelle-targeted metallodrugs with controllable activation properties.