Liposomal and PLGA Nanoparticles Differentially Facilitate Chlorin e6-Mediated Sonodynamic Therapy in Ovarian Cancer

Abstract Sonodynamic therapy (SDT) is an emerging strategy that uses ultrasound-mediated activation of a sonosensitizer to kill tumor cells via reactive oxygen species generation. While SDT has shown promise across multiple cancer types, its use in ovarian cancer remains largely unexplored. Chlorin e6 (Ce6) is an FDA-approved small molecule and well-established sonosensitizer. As the hydrophobicity of Ce6 limits its bioavailability, nanoparticle (NP)-based delivery is often required for sufficient bioaccumulation at target sites. While various nanocarriers have been explored for Ce6 delivery in ovarian cancer, such as graphene nanoribbons and inorganic metal oxides, these platforms face significant challenges for clinical translation. In this study, we evaluated two clinically relevant NP platforms, liposomes and poly(lactic-co-glycolic acid) (PLGA) NPs, in ovarian cancer spheroids and noncancerous human LP-9 mesothelial cells to compare Ce6 uptake, tumor specificity, and SDT efficacy. Liposome-Ce6 showed substantially higher uptake in OVCAR8 ovarian cancer spheroids relative to PLGA-Ce6 and free Ce6 at a Ce6 concentration of 0.3 µg/mL, with similar results observed in OVCAR3 and ID8 cancer models. Notably, liposome-Ce6 accumulated 76-fold higher in OVCAR8 spheroids than in LP-9 cells. This selective accumulation drove effective SDT-mediated tumor cell killing, with liposome-Ce6 eliminating 95 ± 4% of cancer cells following ultrasound irradiation while exhibiting significantly lower toxicity toward LP-9 cells. PLGA-Ce6 also enabled SDT-mediated tumor cell killing, though it required a 10-fold higher Ce6 dose than liposomes to achieve similar efficacy, increasing off-target toxicity toward LP-9 cells. Upon surface modification with poly-L-aspartic acid or hyaluronic acid, which are of interest for in vivo ovarian cancer targeting via layer-by-layer assembly, liposome-Ce6 maintained 8–11-fold higher tumor accumulation in OVCAR8 versus LP-9 cells and strong SDT efficacy. Overall, this study demonstrates that liposomes are a promising nanocarrier platform for further development of SDT approaches for treatment of ovarian cancer.