Prodrug-based strategy with a two-in-one liposome for Cerenkov-induced photodynamic therapy and chemotherapy

Cerenkov radiation induced photodynamic therapy (CR-PDT) can tackle the tissue penetration limitation of traditional PDT. However, co-delivery of radionuclides and photosensitizer may cause continuous phototoxicity in normal tissues during the circulation. 5-aminolevulinic acid (ALA) which can intracellularly transform into photosensitive protoporphyrin IX (PpIX) is a cancer-selective photosensitizer with negligible side effect. However, the hydrophilic nature of ALA and the further conversion of PpIX to photoinactive Heme severely hinder the therapeutic benefits of ALA-based PDT. Herein, we developed an ⁸⁹Zr-labeled, pH responsive ALA and artemisinin (ART) co-loaded liposome (⁸⁹Zr-ALA-Liposome-ART) for highly selective cancer therapy. ⁸⁹Zr can serve as the internal excitation source to self-activate PpIX for CR-PDT, and the photoinactive Heme can activate the chemotherapeutic effect of ART. The ⁸⁹Zr-ALA-Liposome-ART exhibited excellent tumor inhibition capability in subcutaneous 4T1-tumor-bearing Balb/c mice via CR-PDT and chemotherapy. Combined with anti-PD-L1, the ⁸⁹Zr-ALA-Liposome-ART elicited strong antitumor immunity to against tumor recurrence.