Dr. Michael M. Gottesman Profile

Dr. Michael M. Gottesman

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Proceedings Article | 24 May 2022 Presentation

Clinically relevant pure porphyrin nanoparticles for photodynamic therapy and priming applications

Collin Inglut, Jillian Stable, Brandon Gaitan, Wen-An Chiou, Baktiar Karim, Nina Connolly, Robert Robey, Graeme Woodworth, Michael Gottesman, Huang-Chiao Huang

Proceedings Volume PC12146, PC1214606 (2022) https://doi.org/10.1117/12.2618159

KEYWORDS: Photodynamic therapy, Nanoparticles, Tumors, Plasma display panels, Cancer, Brain, Photomedicine, Luminescence, Animal model studies, Tumor growth modeling

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Liposomes have revolutionized the field of photomedicine. Photodynamic therapy (PDT) using Visudyne®, a liposomal photosensitizer formulation, has helped many patients globally. Since the FDA approved Visudyne® in 2002, countless studies have examined strategies to further improve the therapeutic index of lipid-based photosensitizing nanoconstructs. While liposomes can improve the pharmacokinetics of hydrophobic photosensitizers, they could also modulate cellular uptake and singlet oxygen production. Furthermore, it is evident that there are other immunological and toxicological considerations for the design of liposomal drugs. Accordingly, there is now an emerging trend to engineer carrier-free nanodrugs. Here, we developed a pure-drug nanoparticle using the clinically used verteporfin photosensitizer (termed nanoVP) for photodynamic applications. We validated the effects of nanoVP in three contexts: 1) cytotoxic PDT, 2) subtherapeutic PDT, and 3) dark toxicity. Using a brain cancer murine model, we showed that light activation of nanoVP reduced tumor volume by up to 54% compared to liposomal VP. Fluorescence imaging revealed that nanoVP had a superior tumor-to-liver tissue ratio (~0.92) compared to liposomal VP (~0.4). We further studied nanoVP-mediated PDT at subtherapeutic doses to achieve photodynamic priming (PDP). PDP has been shown to enhance drug delivery, activate antitumor immunity, and sensitize tumors to chemotherapy. This approach is particularly relevant in the brain, where high doses of PDT can result in edema, neurotoxicity, and even animal death. Using a rat model, we demonstrated that nanoVP-assisted PDP improved blood-brain barrier permeability and accumulation of a model drug (Evans Blue dye) in rat brains by >5 fold. Minimal to no brain damage was observed. Lastly, under dark conditions, we validated that nanoVP significantly reduced viability while liposomal VP stimulated cancer cell growth. Results from this work demonstrate the utility of nanoVP for cancer treatment. The development of pure-drug photosensitizing nanoparticles for photodynamic applications could further revolutionize the field of photomedicine.

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