UCSF

Most cancer chemotherapeutics are administered at or near their maximum tolerated dose, yet poor efficacy and insufficient therapeutic index remain major causes of attrition in oncology drug development. New pharmacological approaches that selectively target tumor cells are therefore of significant interest. Emerging evidence suggests that an augmented pool of intracellular labile Fe(II) is a metabolic signature of many cancers and thus may represent a targetable chemical environment. We have leveraged Fe(II)-dependent, Fenton-type reactivity of the 1,2,4-trioxolane ring to develop highly selective, reactivity-based probes of the ferrous iron pool and a prototypical scaffold for Fe(II)-dependent drug delivery of chemotherapeutics. These probes reveal higher reactive Fe(II)-pools in cancer cells as compared to non-tumorigenic cells, changes that can be linked to alteration of iron metabolism. Our findings suggest that many cancers alter iron metabolism to increase intracellular Fe(II)-pools and these changes can be exploited for cell-selective drug delivery. By using this scaffold to mask a highly potent DNA-alkylator we illustrate that this prodrug system is capable of stabilizing and selectively delivering such potent cytotoxins in vivo. Overall our results establish that Fe(II)-dependent prodrug/delivery strategies can be used to enhance the therapeutic index of cancer chemotherapeutics. Encouraged by these results further efforts were made to apply trioxolane-based systems as novel, tumor-selective cleavable linkers for antibody-drug conjugate strategies. Preliminary results indicate trioxolane-based linkers are capable of efficiently releasing drugs from ADC’s in cancer cells but optimization will be required before further development.