Synthesis and Anticancer Evaluation of Near-infrared-activatable Platinum Photooxidants
DescriptionPhotodynamic therapy is emerging as a promising technique for cancer treatment. Several photodynamic therapeutic agents have been applied in clinical settings. The process involves the combined use of light, photosensitizers, and oxygen to executeenergy or electron transfer, generating reactive oxygen species to eradicate tumor cells. However, traditional photosensitizers indirectly damage biomolecules in an oxygendependent manner, limiting their therapeutic efficacy in the hypoxic (oxygen-starved)tumor microenvironment. In addition, the short excitation wavelengths of classical photosensitizers limit the tumor types that can be cured by photodynamic therapy. In this proposed project, we aim to address the limitations of the current light-driven cancer treatments by developing a class of near-infrared (NIR)-activatable photooxidants that can directly damage survival-related intracellular biomolecules in an oxygen-independent manner. Our preliminary data show that when a Pt(IV) moiety isconjugated with a photosensitive ligand, the Pt(IV) complex but not the ligand displays remarkably strong photooxidative capability. Without the need of oxygen, the photooxidant can oxidize a variety of biomolecules that traditional oxidants cannot oxidize. More importantly, the photooxidant is able to enter cells efficiently, be activated by NIR light in a controllable fashion, and effectively oxidize intracellular biomolecules, leading to more than 222-fold increased photocytotoxicity compared with the clinical drug carboplatin in drug-resistant human cancer cells. Based on these preliminary data, we plan to design and synthesize a small class of Pt(IV) photooxidants in which different types of photosensitive ligands are conjugated at various positions of Pt(IV) motifs. The stability and photooxidative ability of the photooxidants will be examined. The cellular uptake, photocytotoxicity, and oxidative ability in drug-resistant cells, including cancer stem cells, will be determined. We will also investigate the cell death mechanism inducedby these photooxidants. Moreover, the antitumor activity of any lead compound in vivo will be studied. The proposed research may provide a new paradigm in anticancer phototherapy by developing NIR-activatable Pt-based photooxidants with a distinctmode of action. Such new phototherapeutic modality to directly oxidize intracellular biomolecules may address the limitations of conventional photosensitizers, achieve improved therapeutic efficacy, and circumvent drug resistance. In addition, our proposedresearch may highlight the importance of the photooxidative ability of photoactivatable metal complexes and the resulting applications of this ability to anticancer chemotherapy.
|Effective start/end date||1/01/23 → …|