NIR pH-Responsive PEGylated PLGA Nanoparticles as Effective Phototoxic Agents in Resistant PDAC Cells

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide due to its resistance to conventional therapies that is attributed to its dense and acidic tumor microenvironment. Chemotherapy based on gemcitabine usually lacks efficacy due to poor drug penetration and the metabolic characteristics of the cells adapted to grow at a more acidic pH_e, thus presenting a more aggressive phenotype. In this context, photodynamic therapy (PDT) offers a promising alternative since it generally does not suffer from the same patterns of cross-resistance observed with chemotherapy drugs. In the present work, a novel bromine-substituted heptamethine-cyanine dye (BrCY7) was synthesized, loaded into PEG-PLGA NPs, and tested on the pancreatic ductal adenocarcinoma cell line cultured under physiological (PANC-1 CT) and acidic (PANC-1 pH selected) conditions, which promotes the selection of a more aggressive phenotype. The cytotoxicity of BrCY7-PEG-PLGA is dose-dependent, with an IC₅₀ of 2.15 µM in PANC-1 CT and 2.87 µM in PANC-1 pH selected. Notably, BrCY7-PEG-PLGA demonstrated a phototoxic effect against PANC-1 pH selected cells but not on PANC-1 CT, which makes these findings particularly relevant since PANC-1 pH selected cells are more resistant to gemcitabine as compared with PANC-1 CT cells.