What blocks more anticancer platinum complexes from experiment to clinic: Major problems and potential strategies from drug design perspectives

Encouraged by the worldwide success of cisplatin in the field of cancer chemotherapy, intensive works have been conducted to explore more platinum coordination complexes as antitumor drugs over half a century. Although a significant number of promising platinum complexes with multiple structural motifs have been emerging during this period, most of them failed to enter clinical applications. Abandoned reasons for platinum antitumor candidates from experiment to clinic are complicated, and corresponding strategies were proposed during the last decades to deal with those issues. In recent years, with the rapid development of targeted therapy, immunotherapy and so on, anticancer platinum drugs have gained new opportunities and challenges. In this review, we first overviewed the major problems associated with current platinum anticancer drugs including drug resistance, toxicity and side effects to “know our enemies”, and then described recent progresses in rational design of specific-targeted platinum complexes, immune response therapy, tumor microenvironment regulation, light-responsive stimulation, and theranostic therapy as promising strategies to cross these barriers. This review at the interface of chemistry, biology, and medicine points out main problems for current platinum drug development from their action mechanisms, and provides up-to-date potential strategies from drug design perspectives to circumvent those drawbacks, and it is supposed to enlighten researchers with more ideas for future development of highly efficient platinum antitumor complexes.