Synthesis and Biological Evaluation of Near-Infrared-II Activatable Platinum Anticancer Prodrugs
Project: Research
Description
Photoactivated chemotherapy (PACT) has emerged as a promising approach for cancer treatment, as it combines the advantages of photochemical processes and chemotherapeutics to enable tumor eradication in a spatiotemporally controlled manner. Photoactivatable Pt(IV) anticancer prodrugs have been extensively reported, and these Pt-based PACT agents have exhibited remarkable anticancer effects both in vitro and in vivo. The activation wavelengths of the majority of these agents fall within the UV-visible region, which greatly limits their biomedical applications as UV-visible light has poor tissue penetrating capabilities. Recently, we reported small-molecule Pt-based anticancer prodrugs that can be activated by near-infrared (NIR)-I light via two-photon excitation; however, NIR-I light still has relatively shallow tissue penetration depth, limited maximum permissible exposure (MPE), and unsatisfactory fluorescence bioimaging quality. In this proposed project, we will aim to address these limitations by developing small-molecule Pt-based prodrugs that can be activated by NIR-II light, which has strong tissue penetrating capability, a high MPE limit, great biosafety, and high-contrast bioimaging properties. Although it can be challenging to utilize NIR-II light to achieve specific chemical bond cleavage, our preliminary results have shown proof-of-concept for the efficient activation of a small-molecule Pt(IV) prodrug using NIR-II light via one-photon excitation, resulting in the release of the Pt(II) drug and NIR-II ligand. By building on our extensive experience in the synthesis and evaluation of Pt(IV) prodrugs, we propose the synthesis of Pt(IV) prodrugs that contain various Pt(II) cores and NIR-II-responsive ligands. The associated photoactivation properties and processes will be scrutinized. Cell-based assays will be performed to reveal photocytotoxicity and the underlying mechanisms. We will also utilize animal models to study the antitumor activity of the prodrugs in vivo. The success of the proposed project will yield leading Pt(IV) prodrugs that can be activated by NIR-II light, enhancing therapeutic outcomes and expanding their application potential; such prodrugs may also serve as theragnostic agents, combining fluorescence and photoacoustic imaging contrast properties with a high signal-to-background ratio to guide the in vivo therapeutic interventions. The strategy used to produce NIR-II-activated Pt coordination compounds may also shed light on the design of NIR-II-responsive PACT agents based on other metals.Detail(s)
Project number | 9043735 |
---|---|
Grant type | GRF |
Status | Active |
Effective start/end date | 1/01/25 → … |