Hypoxia-responsive theranostic nanoplatform with intensified chemo-photothermal/photodynamic ternary therapy and fluorescence tracing in colorectal cancer ablation

Photothermal therapy (PTT) is an emerging cancer therapeutic modality displaying the great potential to clinical patients. However, the conventional PTT is suffering from restrictions of heat resistance of tumor cells (e.g. the overexpression of heat shock proteins, HSPs) and adverse effects to normal cells. To break the shackles, herein, a hypoxia-responsive theranostic nanoplatform (GA/BN LIP) was designed for achieving synergistic chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT) through overcoming heat-shock response, while enabling fluorescence tracing. The GA/BN LIP consisted of a hypoxia-responsive liposomal material (DSPE-AZO-PEG) as the shell, surface-functionalized with cRGD peptides targeted binding to integrin α_Vβ₃ receptor expressed in tumors. The GA/BN LIP co-delivered gambogic acid (GA) as HSP90 inhibitor and hypoxia-responsive photosensitizer Bcy-NO₂. After GA/BN LIP entering tumor cells by integrin α_Vβ₃ receptor-mediated endocytosis, drugs were specifically released in response to hypoxic conditions due to lysis of liposomes. GA not only directly killed tumor cells to realize chemotherapy, but also sensitized tumor cells to PTT by downregulating HSP90 protein expression, meantime Bcy-NO₂ targeted mitochondria for combined PTT and PDT. Intriguingly, the reduction of Bcy-NO₂ by nitroreductase (NTR) resulted in the restoration of fluorescence, achieving real-time monitoring of the theranostic process in live cells. In conclusion, this theranostic system, designed to target the hypoxic tumor microenvironment, utilized a sensitization mechanism to enhance the synergistic effects of chemo/PTT/PDT therapy, resulting in improved antitumor efficacy in both in vitro and in vivo studies.