Multitargeting Pt(IV) Derivatives of Cisplatin or Oxaliplatin Inhibit Tumor Growth in Mice without Inducing Neuropathic Pain

Cisplatin and oxaliplatin are Pt(II) anticancer agents that are used to treat several cancers, usually in combination with other drugs. Their efficacy is diminished by dose-limiting peripheral neuropathy (PN) that affects ∼70% of patients. PN is caused by selective accumulation of the platinum drugs in the dorsal root ganglia (DRG), which overexpress transporters for cisplatin and oxaliplatin. To date, no drug is recommended for the prevention of PN. We report that Pt(IV) prodrugs of cisplatin or oxaliplatin do not induce neuropathic pain in mice, likely due to the lower accumulation of platinum in the DRG compared with Pt(II) drugs. Moreover, the multitargeting prodrug that combines cisplatin with paclitaxel, both strong inducers of PN, efficiently inhibited tumor growth in vivo without inducing neuropathic pain. The high antitumor efficacy of Pt(IV) prodrugs and their micellar counterparts and the low level of neuropathic pain associated with them make them ideal candidates for clinical use in cancer therapy.