Preventing oxaliplatin-induced peripheral neuropathy with a Pt(IV)-Mn(II) prodrug: Toxicity, behavioral and X-ray...

Although widely used in chemotherapeutic treatments, platinum (Pt)-based drugs -namely cisplatin (Cis), oxaliplatin (Ox), and carboplatin- encounter several drawbacks that significantly limit their clinically applicable doses, such as the development of various side effects. These toxicities, including nephrotoxicity and neurotoxicity associated with Cis and Ox, respectively, arise from the lack of selectivity of these drugs toward cancer cells. While numerous alternative treatments -some employing a Pt(IV) prodrug strategy- have been investigated in preclinical settings for their anticancer activity, studies evaluating their systemic toxicities remain scarce. However, assessing these toxicities is crucial for the development of improved therapies. This study aimed to evaluate the systemic toxicities induced by PtC5Mn, a novel Pt(IV)-Mn(II) prodrug reported to exhibit anticancer activity in both in vitro and in vivo models of colorectal cancer, as well as Mn1C5, its corresponding Mn(II) complex that mimics superoxide dismutase (SOD) activity, in combination with Ox. Additionally, their potential protective effects against Ox-induced peripheral neuropathy were explored through behavioral studies and mapping of Pt localization in sciatic nerves sections by Synchrotron-based Scanning X-Ray Fluorescence microscopy. Our results support the use of Pt(IV) prodrugs and redox modulation by SOD mimics for the mitigation of oxaliplatin-associated off-target effects.