Luminescence-activated Pt(IV) prodrug for in situ triggerable cancer therapy

Anticancer platinum prodrugs that can be controllably activated are highly desired for personalized precision medicine and patient compliance in cancer therapy. However, the clinical application of platinum(IV) prodrugs (Pt(IV)) is restricted by tissue penetration of external irradiation. Here, we report a novel Pt(IV) activation strategy based on endogenous luminescence of tumor microenvironment responsiveness, which completely circumvents the limitation of external irradiation. The designed Pt(IV)Lu, a mixture of trans, trans, trans-[Pt(N3)2(OH)2(py)2] and luminol (Lu), has controllable activation property: it remains inert in reductant environment and normal tissues, but under tumor microenvironment, Lu will be oxidized to produce blue luminescence, which rapidly reduce Pt(IV) to Pt(II) without the need of any external activator. Pt(IV)Lu shows excellent responsive antitumor ability both in vitro and in vivo. Compared to cisplatin, the median lethal dose in BALB/c mice increased by an order of magnitude. Our results suggest that Pt(IV)Lu exhibits highly controllable activation property, superior antitumor activity, and good biosafety, which may provide a novel strategy for the design of platinum prodrugs. A promising prodrug activation strategy of Pt(IV) based on endogenous luminescence of tumor microenvironment responsiveness, which completely avoids the tissue penetration limitation of external irradiation, and has good antitumor activity and safety. [Display omitted]