Challenging and new opportunities for prodrug technology.

Research on prodrug technology has opened new avenues for site-directed chemotherapy rather than systemic chemotherapy. This distinctive strategy allows drug delivery to be activated by light-, irradiation-, or ultrasound (US)-tunable chemistries, which have been termed photopharmacology, radiopharmacology, and sonopharmacology, respectively. Prodrugs have emerged as a main strategy for improving pharmacokinetics, reducing side effects, and thus enhancing the therapeutic efficacy of drugs. This review summarizes stimuli-responsive drug release systems and the latest progress in exogenous stimuli-responsive prodrug activation, e.g., light, irradiation, and US, with a focus on the activation of small molecule prodrugs, antibody‒drug conjugates, and prodrug nanosystems. In addition, challenges encountered by Pt drugs and Pt(IV) prodrug nanotherapeutics are summarized and discussed. Moreover, this review presents the current state of precise treatment and discusses the opportunities and challenges for the clinical translation of these strategies.