Glucose transporter 1 (GLUT1)-targeting and hypoxia-activated mitochondria-specific chemo-thermal therapy via a glycosylated poly(amido amine)/celastrol (PAMAM/Cel) complex

Mitochondria are appealing targets in cancer therapy for providing a suitable microenvironment and energy supply. Herein, we constructed a glycosylated poly(amido amine)/celastrol (PAMAM/Cel) complex for hypoxia-activated mitochondria-specific drug delivery and chemothermal therapy to inhibit tumor growth and metastasis. The complex was characterized by high photothermal conversion efficiency, hypoxia-sensitive polyethylene glycol (PEG) outer layer detachment, and alkaline-sensitive drug release. The complex showed specific cellular uptake in glucose transporter 1 (GLUT1)-overexpressing tumor cells and mitochondrial accumulation in a hypoxic environment. Combined with near-infrared (NIR) laser irradiation, the complex exhibited higher cytotoxicity, apoptosis induction, and metastasis inhibition rates due to the synergistic chemothermal effect. Similarly, the complex also targeted tumors and accumulated in mitochondria in tumor-bearing nude mice, resulting in superior inhibitory effects on tumor growth and metastasis as well as low systematic toxicity. Further mechanistic studies discovered that the complex impaired the mitochondrial membrane, reduced adenosine triphosphate (ATP) content, and regulated metastasis-related protein expression. Thus, the present study provides a promising nanomedicine for tumor therapy.