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Abstract P‐glycoprotein (P‐gp, ABCB1) is a well‐researched ATP‐binding cassette (ABC) drug efflux transporter linked to the development of cancer multidrug resistance (MDR). Despite extensive studies, approved therapies to safely inhibit P‐gp in clinical settings are lacking, necessitating innovative strategies beyond conventional inhibitors or antibodies to reverse MDR. Photodynamic therapy is a globally approved cancer treatment that uses targeted, harmless red light to activate non‐toxic photosensitizers, confining its cytotoxic photochemical effects to disease sites while sparing healthy tissues. This study demonstrates that photodynamic priming (PDP), a sub‐cytotoxic photodynamic therapy process, can inhibit P‐gp function by modulating cellular respiration and ATP levels in light accessible regions. Using chemoresistant (VBL‐MDA‐MB‐231) and chemosensitive (MDA‐MB‐231) triple‐negative breast cancer cell lines, we showed that PDP decreases mitochondrial membrane potential by 54.4% ± 30.4 and reduces mitochondrial ATP production rates by 94.9% ± 3.46. Flow cytometry studies showed PDP can effectively improve the retention of P‐gp substrates (calcein) by up to 228.4% ± 156.3 in chemoresistant VBL‐MDA‐MB‐231 cells, but not in chemosensitive MDA‐MB‐231 cells. Further analysis revealed that PDP did not alter the cell surface expression level of P‐gp in VBL‐MDA‐MB‐231 cells. These findings indicate that PDP can reduce cellular ATP below the levels that is required for the function of P‐gp and improve intracellular substrate retention. We propose that PDP in combination with chemotherapy drugs, might improve the efficacy of chemotherapy and overcome cancer MDR. 

Abstract Glioblastoma (GBM) is hard to treat due to cellular invasion into functioning brain tissues, limited drug delivery, and evolved treatment resistance. Recurrence is nearly universal even after surgery, chemotherapy, and radiation. Photodynamic therapy (PDT) involves photosensitizer administration followed by light activation to generate reactive oxygen species at tumor sites, thereby killing cells or inducing biological changes. PDT can ablate unresectable GBM and sensitize tumors to chemotherapy. Verteporfin (VP) is a promising photosensitizer that relies on liposomal carriers for clinical use. While lipids increase VP's solubility, they also reduce intracellular photosensitizer accumulation. Here, a pure‐drug nanoformulation of VP, termed “NanoVP”, eliminating the need for lipids, excipients, or stabilizers is reported. NanoVP has a tunable size (65–150 nm) and 1500‐fold higher photosensitizer loading capacity than liposomal VP. NanoVP shows a 2‐fold increase in photosensitizer uptake and superior PDT efficacy in GBM cells compared to liposomal VP. In mouse models, NanoVP‐PDT improved tumor control and extended animal survival, outperforming liposomal VP and 5‐aminolevulinic acid (5‐ALA). Moreover, low‐dose NanoVP‐PDT can safely open the blood‐brain barrier, increasing drug accumulation in rat brains by 5.5‐fold compared to 5‐ALA. NanoVP is a new photosensitizer formulation that has the potential to facilitate PDT for the treatment of GBM.