Hypoxia-triggered tumor specific glutamine inhibition for reversing cisplatin resistance of chemotherapy

Cisplatin resistance of tumors significantly impedes the therapeutic effect of cisplatin chemotherapy. Excessive glutathione (GSH) that is produced by tumor cells with abnormal metabolism is the main reason for cisplatin resistance, which would inactivate intracellular cisplatin and cause tumor resistance. Intracellular GSH can be massively synthesized by glutamine (Gln) through enzymatic biochemical reactions. Therefore, inhibiting the metabolism of Gln would reduce intracellular GSH and restore the anti-tumor activity of cisplatin. Another vital feature of cisplatin-resistant tumors is the heavy hypoxia microenvironment, which is beneficial for developing hypoxia-activated drug delivery systems to realize specific drug release in tumors. Herein, we constructed a hypoxia-triggered tumor-metabolism inhibiting nanomedicine (denoted as PD@HN NPs) for high-effective cisplatin therapy. PD@HN NPs were formulated with the chemotherapy drug cisplatin, Gln inhibitor (DON), and a hypoxia-responsive carrier 2-nitroimidazole modified hyaluronic acid (HA-NI). Consequently, the PD@HN NPs demonstrate excellent anti-tumor effect on cisplatin-resistant tumors in both cisplatin-resistant cell lines and patient-derived xenograft tumor models. In general, this work presents a novel nanomedicine that reverses the cisplatin resistance of tumors and significantly enhances the therapeutic effect of cisplatin by precisely mediating the intracellular GSH metabolism under a hypoxia environment, inspiring more insights into the development of high-effective cisplatin therapy.