Imidazoquinoline glycoconjugate prodrugs activated by acquired anthracycline resistance 4683

Abstract Description Irregular carbohydrate metabolism and drug efflux are mechanisms of acquired drug resistance common to a myriad of end-stage cancers. Orthogonal to these mechanisms, imidazoquinoline immunotherapeutics induce tumoricidal immune responses; however, they also cause inflammatory toxicity. Objective: Establish imidazoquinoline glycoconjugate prodrugs with minimal inflammatory toxicity that are activated by the irregular metabolism and drug efflux of multidrug-resistant (MDR) cancers. Methods Prodrugs were optimized for conversion within MDR cancer cells, and efflux of the resulting imidazoquinoline metabolite. Immunogenicity following conversion and efflux was tested in MDR cancer cell lines (B16-F10 melanoma and TRAMP-C2 prostate cancer). In-vivo, dose escalation (up to 5 mg / day, I.P.) was conducted alongside measuring inflammatory cytokines in Black 6 mice. Tumoricidal efficacy was examined by treating mice with TRAMP tumors over 10 days (1 mg / mouse, I.T.) followed by monitoring tumor growth delay to 30 days. Results Prodrugs were well tolerated to 50 times the lethal dose of unaltered parent drug. Mice administered prodrug exhibited reduction in tumor volume and durable growth delay through day 30. Histology revealed a tumoricidal immune response consistent with the immunological fingerprint elicited by the parent drug. Conclusion Caging imidazoquinolines as glycoconjugate prodrugs enables safe delivery at increased doses with comparably enhanced tumoricidal effects. Funding Sources This work was supported by the National Cancer Institute of the National Institutes of Health R01CA234115, the Arnold & Mabel Beckman Foundation, and the Washington Research Foundation. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)