Emerging platinum(iv) prodrugs to combat cisplatin resistance: from isolated cancer cells to tumor microenvironment.

Cisplatin plays a pivotal role in the treatment of various malignant tumors, but its therapeutic effects are hampered by drug resistance. Pt(iv) prodrugs represent a promising class of "non-conventional" platinum-based anticancer agents to circumvent drug resistance, which can be easily functionalized with other bioactive ligands. One strategy is to build "dual-action" and "multi-action" Pt(iv) prodrugs that not only damage DNA but also perturb other pathways related to cisplatin resistance to achieve combinatorial therapeutic effects. Another way to overcome the shortcomings of cisplatin is to deliver Pt(iv) prodrugs via nanocarriers. Most studies in this area have focused on designing prodrugs based on the mechanism of cisplatin resistance within isolated cancer cells. Recent findings, however, reveal that the tumor microenvironment also plays important roles in the development of cisplatin resistance. This perspective focuses on various types of novel cisplatin-based Pt(iv) complexes, including Pt-loaded nanostructures, to overcome cisplatin resistance. Special attention will be devoted to complexes that target the tumor microenvironment, which is a new area for the development of effective Pt(iv) prodrugs. Our summary and outlook may have a hope to help researchers in the field generate new ideas and strategies to develop more potent Pt(iv) prodrugs to combat cisplatin resistance.