Abstract 2523: Porphyrin-lipid nanoparticle-based multifunctional cancer: from cell to patient

Abstract Background: Porphysomes (PS) are first-in-class organic porphyrin-lipid nanoparticles with unprecedented intrinsic multifunctionality that enables a range of complementary imaging, image-guided interventions and therapies. Examples are presented in a range of preclinical tumor models, including head & neck, lung and gynecological cancers, demonstrating progress towards first-in-human trials. Methods & Results: High-density packing of the porphyrin-lipid monomers in the nanoparticle bilayer enables efficient light absorption and conversion to heat for enhanced photoacoustic imaging (PAI) and photothermal therapy (PTT). Using wide-band acoustic detection at low frequencies multispectral PAI can quantify PS concentration in tumors that span sub-mucosal disease to several cm depth. A novel method has also been developed for direct temperature mapping to monitor PS-mediated PTT delivery. Upon structural dissociation following cell uptake, the fluorescence (FL) and photodynamic therapy (PDT) activity of the porphyrin monomers are restored. Corresponding diffuse optical spectroscopy (DOS) has measured longitudinal PS pharmacokinetics in vivo. This will allow identification of residual tumor during surgical resection and also serve as a component of PDT dosimetry. FL imaging of tumor-targeted PS has been demonstrated in veterinary clinical trials of oral cancer, showing efficacy in tumor localization and surgical guidance. AI-assisted spatial-frequency-domain FL imaging in particular shows promise in measuring tumor depth prior to resection and tumor extent during resection. Attaching gadolinium to the PS lipid chains enables combined intra-operative surgical planning and guidance, using Gd-contrast MRI for pre-resection planning and higher-resolution FGS during resection. We are evaluating MR-FGS in pre-clinical models, comparing PS localization using MRI and DOS to pathology and surgical resection outcomes. Finally, PS chelated with 64Cu for PET imaging of tumors has been demonstrated in several large animal models and serves as the key modality to assess PS pharmacokinetics in first-in-human studies in advanced ovarian cancer, leading to first therapeutic trials. 64CuPS imaging will also be used for planning and dosimetry of 67CuPS radioisotope therapy of disseminated disease. Conclusions: Porphysomes provide unique multifunctional imaging and theranostic capabilities for cancer detection, localization and personalized therapy, both stand-alone and combined with standard modalities. Citation Format: Robert A. Weersink, Theo Husby, Ivan Kosik, Michael Daly, Jason Townson, Ben Motx, Alessandra Ruaro, Juan Chen, Christine Demore, Stephanie Lheureux, Amit Oza, Jonathon Irish, Gang Zheng, Brian C. Wilson. Porphyrin-lipid nanoparticle-based multifunctional cancer: from cell to patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2523.