Exploring the Impact of Head Group Modifications on the Anticancer Activities of Fatty-Acid-like Platinum(IV) Prodrugs: A Structure-Activity Relationship Study.

We conducted the first comprehensive investigation on the impact of head group modifications on the anticancer activities of fatty-acid-like Pt(IV) prodrugs (FALPs), which are a class of platinum-based metallodrugs that target mitochondria. We created a small library of FALPs (1-9) with diverse head group modifications. The outcomes of our study demonstrate that hydrophilic modifications exclusively enhance the potency of these metallodrugs, whereas hydrophobic modifications significantly decrease their cytotoxicity. To further understand this interesting structure-activity relationship, we chose two representative FALPs (compounds 2 and 7) as model compounds: one (2) with a hydrophilic polyethylene glycol (PEG) head group, and the other (7) with a hydrophobic hydrocarbon modification of the same molecular weight. Using these FALPs, we conducted a targeted investigation on the mechanism of action. Our study revealed that compound 2, with hydrophilic modifications, exhibited remarkable penetration into cancer cells and mitochondria, leading to subsequent mitochondrial and DNA damage, and effectively eradicating cancer cells. In contrast, compound 7, with hydrophobic modifications, displayed a significantly lower uptake and weaker cellular responses. The collective results present a different perspective, indicating that increased hydrophobicity may not necessarily enhance cellular uptake as is conventionally believed. These findings provide valuable new insights into the fundamental principles of developing metallodrugs.

Visible light-activatable platinum(IV) prodrugs harnessing CD36 for ovarian cancer therapy.

We hereby engineered photoactivatable Pt(IV) metallodrugs that harness CD36 to target ovarian cancer cells. Pt(IV) compounds mimic the structure of fatty acids and take advantage of CD36 as a "Trojan horse" to gain entry into the cells. We confirmed that CD36-dependent entry occurs using graphite furnace atomic absorption spectroscopy with ovarian cancer cells expressing different levels of CD36 and a CD36 inhibitor, SSO. Once the Pt(IV) metallodrugs enter the cancer cells, they can be activated to form Pt(II) with characteristics of cisplatin under visible light (490 nm) irradiation, promoting photoinduced electron transfer from the attached fluorophore to the metal center. This light-induced activation can increase the cytotoxicity of the Pt(IV) metallodrugs by up to 20 times toward ovarian cancer cells, inducing DNA damage and enabling efficient elimination of drug-resistant cancer cells.