Recent advances in antitumor Pt(IV) complexes: Dual targeting and chemoimmunotherapy

The design of Pt(IV) prodrugs is aimed at overcoming key drawbacks of conventional Pt(II)-based therapy, such as multidrug resistance of tumors and toxic side effects. The introduction of bioactive ligands into the axial position of the Pt(IV) complex opens a way to develop various novel platinum agents with multitargeting antitumor mechanisms by the incorporation of desired functional groups at the axial positions. A new promising emerging trend in the field of Pt-based anticancer drugs is the development of chemoimmunotherapeutic Pt(IV) prodrugs capable of not only high synergetic therapeutic efficacy but also the ability to induce immunological memory and prevent tumor recurrence, which greatly enhances these Pt(IV) prodrugs over clinically used Pt(II) agents. In the present review, we highlighted 2 main approaches utilized in Pt(IV)-based anticancer drug development for the past 4 years. First, multi-action Pt(IV) prodrugs that trigger cell death via multiple pathways are discussed. The main focus of the second part is advances in the design of Pt(IV) prodrugs for chemoimmunotherapy and the mechanisms with which immune response is stimulated are reviewed. The goal of this review is to highlight the most promising approaches towards a new generation of efficient Pt-based anticancer therapeutics and hopefully, to inspire further development of anticancer metal-based drugs. • Recently reported Pt(IV) prodrugs with chemo- or chemoimmunotherapeutic modes of action are reviewed • Two main approaches towards novel Pt(IV)-based anticancer agents are highlighted: multi-action Pt(IV) prodrugs, Pt(IV) prodrugs for chemoimmunotherapy • Within each section, the Pt(IV) prodrugs are discussed according to their molecular mode of action in cancer cells and tumor microenvironment. • Special emphasis in the review is made on how the design of Pt(IV)-based anticancer agents impacts their performance in vivo.