Development and Biological Evaluation of Ultrasound-activatable Platinum(IV) Anticancer Prodrugs
DescriptionAlthough small-molecule anticancer drugs such as platinum drugs are effective against a variety of tumor types, the adverse effects and drug resistance significantly limit their broader clinical applications. One promising solution is to develop novel Pt coordination compounds with controllable activation properties, which enable the drug to be activated in a spatially and temporally controlled fashion with minimized “off-target” effects. Along this line, photoactivatable Pt(IV) prodrugs, including diazido-Pt(IV) complexes and Pt(IV) compounds bearing axial photoactivators, have been extensively developed and explored. However, the light penetration depth remains a limiting factor, and photoactivatable Pt(IV) prodrugs may not be suitable for non-invasive therapy against tumors deep beneath the skin. In this proposal, we aim to address this problem by developing Pt(IV) anticancer prodrugs that can be controllably activated by ultrasound, which can penetrate deeply into the human body. Our preliminary study indicates that a carboplatin-based Pt(IV) prodrug bearing a sonosensitizer at the axial position can be activated by ultrasound, and this prodrug can also effectively kill cancer cells upon sono-activation. Based on this proof-of-concept, we plan to synthesize and characterize several types of ultrasound-activatable Pt(IV) complexes including those that are highly resistant to reducing agents. Stable prodrugs will be tested for their sono-activation properties under optimized ultrasound treatment conditions. The cellular accumulation levels, cytotoxicity, and cell death mechanism will be examined in vitro. Any lead compounds will be further evaluated to determine their in vivo antitumor activities. The success of the proposed project will lead to the discovery of Pt(IV) anticancer prodrugs that can be controllably activated by ultrasound and have strong antitumor activity both in vitro and in vivo. This discovery may also contribute significantly to the emerging field of sono-sensitized chemotherapy (SSCT). Such prodrugs represent a novel therapeutic modality independent of the penetration depth, and therefore may significantly expand the range of tumor types that can be treated, compared with those treatable by conventional photoactivatable anticancer drugs.
|Effective start/end date||1/01/22 → …|