Bioorthogonal chemistry-based prodrug strategies for enhanced biosafety in tumor treatments: current progress and challenges

Cancer is a significant global health challenge, and while chemotherapy remains a widely used treatment, its non-specific toxicity and broad distribution can lead to systemic side effects and limit its effectiveness against tumors. Therefore, the development of safer chemotherapy alternatives is crucial. Prodrugs hold great promise, as they remain inactive until they reach the cancer site, where they are selectively activated by enzymes or specific factors, thereby reducing side effects and improving targeting. However, subtle differences in the microenvironments between tumors and normal tissue may still result in unintended cytotoxicity. Bioorthogonal reactions, known for their selectivity and precision without interfering with natural biochemical processes, are gaining attention. When combined with prodrug strategies, these reactions offer the potential to create highly effective chemotherapy drugs. This review examines the safety and efficacy of prodrug strategies utilizing various bioorthogonal reactions in cancer treatment.