The clinical ionizable lipid SM-102 enhances photochemical immunogenic cell death by verteporfin-conjugated liposomes and improves survival in vivo

Light activation of photosensitizers, including verteporfin-conjugates entrapped in liposomes, can induce photochemical immunogenic cell death (ICD) in cancer cells by exposing damage-associated molecular patterns (DAMPs) under specific conditions. In this study, we investigated how incorporation of the clinical ionizable lipid SM-102 into light-activated liposomes containing the verteporfin-conjugate 20:0 BPD-PC effects key photochemical and photobiological attributes we previously identified to be strongly associated with photochemical ICD. We show that SM-102 incorporation increases the ratio of Type I (hydroxyl radical and peroxynitrite anion)-to-Type II (singlet oxygen) reactive oxygen species by ~ 2.5-fold, increases mitochondrial localization, and improves CT1BA5 mouse pancreatic cancer cell uptake by 7-fold and phototoxicity by 10-fold. These result in more potent photochemical ICD responses with up to 8-fold increases in the exposure of the DAMPs calreticulin, HSP-70, and HMGB1 following 690 nm light activation. In an immune-cold syngeneic mouse PDAC model, 690 nm light activation of SM-102-containing liposomes slowed tumor growth by up to 56% and extended survival by 40%. Together, these findings suggest that integrating SM-102 into light-activated liposomes is a simple and robust strategy to enhance photochemical ICD and may improve therapeutic outcomes in immunotherapy-based combinations that utilize liposomal drug delivery systems.