Photodynamic creation of artificial tumor microenvironments to collectively facilitate hypoxia-activated chemotherapy delivered by coagulation-targeting liposomes

Abstract Creation of artificial tumor microenvironments is promising to avoid tumor heterogeneity induced variation of cancer therapeutic efficacy. Herein, a type of cooperative liposomal delivery systems based on photodynamic liposomes and coagulation-targeting liposomes is proposed to collectively suppress tumor growth. We uncover that the first-wave mild photodynamic treatment, mediated by photosensitizer hydrophobic chlorin e6 loaded liposomes (hCe6-liposomes), can effectively damage tumor blood vessels to trigger intratumoral coagulation, as vividly confirmed by recording blood signals using photoacoustic imaging. Such newly-formed blood clot is then utilized as a tumor-localized target to promote the tumor homing of second-wave coagulation-targeting peptide GNQEQVSPLTLLKXC (A15) conjugated liposomes (A15-liposomes). Meanwhile, it is shown that the first-wave photodynamic treatment also rapidly exhausts intratumoral oxygen to worsen tumor hypoxia, thereby enable prolonged activation of AQ4N, a hypoxia-activated chemotherapy delivered by A15-liposomes. As the result, the tumors grown on Balb/c mice treated by the cooperative hCe6-liposome and A15-AQ4N-liposomes would be collectively suppressed. Therefore, this work highlights a profound strategy to enable photodynamic manipulation of tumor vasculature, which can simultaneously create a tumor-localized target and worsen hypoxic microenvironment to benefit the tumor accumulation and activation of AQ4N delivered by A15-liposomes, realizing collective suppression on tumor growth.