CHRONOTHERAPY-ENHANCED PHOTODYNAMIC THERAPY DEMONSTRATES TIME-DEPENDENT VARIATIONS IN PDT EFFICACY ON GLIOBLASTOMA

SUÁREZ AI; FORNASIER SJ; GONZÁLEZ GRAGLIA MA; WAGNER PM; GUIDO, ME; MIRETTI M; PRUCCA CG

Córdoba

Congreso; LX Annual Meeting of the Argentine Society for Biochemistry and Molecular Biology Research (SAIB); 2024

Glioblastoma (GBM) is the most aggressive and deadliest tumor of the central nervous system, originating from glialcells and characterized by its infiltrative capacity and rapid progression. The current treatment follows the Stuppprotocol, which involves surgical removal of the tumor mass followed by chemotherapy and radiotherapy sessions.Even with treatment, a patient diagnosed with GBM typically survives for only about 14 months, underscoring theurgent need for innovative therapeutic approaches. Photodynamic therapy (PDT) represents a promising approach thatutilizes a photosensitizer (PS), light at the excitation wavelength of the PS, and oxygen. Individually harmless, thesecomponents together generate reactive oxygen species, hydroxyl radicals, and singlet oxygen, creating a redoximbalance in cells that leads to cell death. Emerging research has shown that the efficacy of cancer therapies can beinfluenced by the biological clock inherent in each cell, which synchronizes multiple metabolic functions. Disruptionsin genes associated with this molecular clock have been linked to the development of various cancers, including GBM.Given the intricate connection between the biological clock and cancer cell progression, integratingchronopharmacology with existing treatments, such as PDT, could enhance therapeutic outcomes. In this study, weexplore the novel combination of PDT and chronotherapy in GBM cells, using PSs from the phthalocyanine family(ZnPc and ClAlPc), sodium talaporfin (NPe6), and 5-aminolevulinic acid (5-ALA), the latter being an FDA-approvedPS precursor. Initial experiments tested the dark toxicity of the PSs, confirming that none were toxic within theconcentration ranges evaluated. Phototoxicity assays were then performed in dexamethasone-synchronized cells, wherethe PS was delivered at various post-synchronization times. These assays revealed a time-dependent differentialresponse in GBM cell viability after PDT, suggesting that the timing of PS administration can enhance PDT efficacy.Subsequent analysis using mathematical algorithms (JTK, ARS, and RAIN) determined the periodicity of each PS usedin the PDT assays, showing that each had a unique period. Uptake assays for ZnPc and 5-ALA demonstrated a phaseshift to cell viability, indicating lower PS uptake during periods of increased resistance. This study represents apioneering effort to explore the potential of combining PDT and chronopharmacology in the treatment of glioblastoma,offering hope for an improved prognosis for those affected by this devastating tumor.