Photocaged Platinum Anticancer Prodrugs Targeting the Endoplasmic Reticulum to Conquer Drug Resistance
DescriptionDrug resistance remains one of the biggest challenges in the clinical application of chemotherapeutic drugs and it is a primary cause of treatment failure. Additionally, systematic toxicity is another obstacle from conventional small-molecule anticancer drugs. Novel anticancer agents utilizing unique mechanisms of action are in high demand, as such agents have the potential to overcome drug resistance. Recently, we have made significant progress in the development of controllably activated platinumbased anticancer prodrugs, with the aim of reducing the toxicity associated with the conventional platinum drugs that are extensively used in the clinic. Our preliminary study indicates that we have successfully obtained a photocaged platinum prodrug that can accumulate efficiently in the endoplasmic reticulum (ER) of cancer cells. Upon irradiation with near-infrared light, the photocage is activated via two-photonactivation, releasing the original platinum drug to exert its cytotoxic effects, and the cell death mode is different than that from the original drug. This prodrug is significantly effective in platinum-refractory human cancer cells. Based on our preliminary data, weplan to design and synthesize several photocaged and ER-targeting platinum prodrugs. The stability of the prodrugs under physiological conditions and their photoactivation properties will be investigated. After confirming the subcellular localization of thesynthetic complexes, their photocytotoxicity will be assessed, particularly in platinumresistant cells including cancer stem cells. We will further investigate their possible mechanisms of action in cancer cells, including their ability to trigger immune response.In vivo evaluation of the prodrugs will also be carried out. The project will generate several new platinum-based anticancer agents targeting the ER, an emerging anticancer drug target. These new complexes are likely to utilize a distinct mode of action to killcancer cells and thus, conquer drug resistance. A greater understanding of these compounds’ mechanism of action may also shed light on the contribution of the ER to the cytotoxicity of the original platinum-based drugs.
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