DNA alkylating agents generally kill
tumor cells by covalently binding with
DNA to form interstrand or intrastrand cross-links. However, in the case of
cisplatin, only a few
DNA adducts (<1%) are highly toxic irreparable interstrand cross-links. Furthermore,
cisplatin is rapidly detoxified by high levels of intracellular
thiols such as
glutathione (GSH). Since the discovery of its mechanism of action, people have been looking for ways to directly and efficiently remove intracellular GSH and increase interstrand cross-links to improve drug efficacy and overcome resistance, but there has been little breakthrough. Herein, we hypothesized that the anticancer efficiency of
cisplatin can be enhanced through iodo-
thiol click chemistry mediated GSH depletion and increased formation of
DNA interstrand cross-links via mild
hyperthermia triggered by near-infrared (NIR) light. This was achieved by preparing an amphiphilic
polymer with
platinum(IV) (Pt(IV))
prodrugs and pendant
iodine atoms (
iodides). The
polymer was further used to encapsulate IR780 and assembled into Pt-I-IR780 nanoparticles. Induction of mild
hyperthermia (43 °C) at the
tumor site by NIR light irradiation had three effects: (1) it accelerated the GSH-mediated reduction of Pt(IV) in the
polymer main chain to
platinum(II) (Pt(II)); (2) it boosted the iodo-
thiol substitution click reaction between GSH and
iodide, thereby attenuating the GSH-mediated detoxification of
cisplatin; (3) it increased the proportion of highly toxic and irreparable Pt-
DNA interstrand cross-links. Therefore, we find that mild
hyperthermia induced via NIR irradiation can enhance the killing of
cancer cells and reduce the
tumor burden, thus delivering efficient
chemotherapy.