Water-Soluble Truncated Fatty Acid–Porphyrin Conjugates Provide Photo-Sensitizer Activity for Photodynamic Therapy in Malignant Mesothelioma

Abstract

Clinical trials evaluating intrapleural photodynamic therapy (PDT) are ongoing for mesothelioma. Several issues still hinder the development of PDT, such as those related to the inherent properties of photosensitizers. Herein, we report the synthesis, photophysical, and photobiological properties of three porphyrin-based photosensitizers conjugated to truncated fatty acids (C5SHU to C7SHU). Our photosensitizers exhibited excellent water solubility and high PDT efficiency in mesothelioma. As expected, absorption spectroscopy confirmed an increased aggregation as a consequence of extending the fatty acid chain length. In vitro PDT activity was studied using human mesothelioma cell lines (biphasic MSTO-211H cells and epithelioid NCI-H28 cells) alongside a non-malignant mesothelial cell line (MET-5A). The PDT effect of these photosensitizers was initially assessed using the colorimetric WST-8 cell viability assay and the mode of cell death was determined via flow cytometry of Annexin V-FITC/PI-stained cells. Photosensitizers appeared to selectively localize within the non-nuclear compartments of cells before exhibiting high phototoxicity. Both apoptosis and necrosis were induced at 24 and 48 h. As our pentanoic acid-derivatized porphyrin (C5SHU) induced the largest anti-tumor effect in this study, we put this forward as an anti-tumor drug candidate in PDT and photo-imaging diagnosis in mesothelioma.

Imaging of Light-Enhanced Extracellular Vesicle-Mediated Delivery of Oxaliplatin to Colorectal Cancer Cells via Laser Ablation, Inductively Coupled Plasma Mass Spectrometry

“…Due to its better loading profile, C5SHU PS was used to assess whether the PSs could impact the delivery of oxaliplatin from EVs by co-loading C5SHU and oxaliplatin. Using the oxaliplatin loading efficiency of 18.7% to normalize treatments ( Figure 2 C), EVs were co-incubated with 187 µM oxaliplatin either alone or in combination with 25 µM or 250 µM C5SHU to develop oxa-C5S-EVs with effective concentrations close to the oxaliplatin EC50 of 10 µM ( Figure 2 A) and the bioactive concentration of C5SHU [ 41 ]. SW480 CRC cells were then incubated with oxa-C5SHU-EVs, and delivery was monitored using the LA-ICP-MS platform.…”

“…Porphyrins and other PSs are known to be cytotoxic and are used for photodynamic therapy [ 41 , 49 ] as they have radical-producing activity outside of cells. We observed that C5SHU porphyrins did not influence the viability of EVs even after exposure to light, and more interestingly, did not significantly influence the release of chemotherapy agents from EVs after light exposure—although a trend towards increased release of co-loaded oxaliplatin was noted.…”

“…Finally, using this quantitative analytical platform, we assessed whether the use of photosensitizer agents could promote the release of oxaliplatin from EVs, allowing more efficient control of release rate, delivery and distribution and improving subsequent chemotoxicity. We have previously reported the synthesis and phototoxicity of novel porphyrin-based photosensitizers [ 41 ]. We therefore assessed the impact of co-loading porphyrins with oxaliplatin into EVs and subsequent photoexposure using LA-ICP-MS to assess oxaliplatin release and delivery and chemotoxicity assays to assess the impact of photosensitizer-linked EV-mediated oxaliplatin delivery for the targeting of CRC cells.…”