Peripheral benzodiazepine receptor ligand-PLGA polymer conjugates potentially useful as delivery systems of apoptotic agents.

Poly(d,l-lactic-co-glycolic acid) (PLGA) polymers having different average molecular weights were chemically conjugated to two imidazopyridinacetamides (1 and 2), chosen as model Peripheral Benzodiazepine Receptor (PBR) ligands, via an ester or amide linkage. It is in order to evaluate these conjugates as delivery systems of PBR ligands endowed with apoptosis inducing activity. Various coupling reaction conditions were tested to optimize the conjugation process. After purification by extensive dialysis procedures, the macromolecular conjugates were characterized by FT-IR, UV, (1)H NMR spectroscopy, DSC and the average molecular weights of synthesized conjugates were determined by GPC. PBR ligand released from these conjugates occurred in human serum and in 0.1 N HCl solution at a faster rate than that observed in phosphate buffer, pH 7.4. Moreover, the macromolecular conjugates displayed high affinity and selectivity for PBR. Cytotoxicity studies demonstrated that PBR ligand-PLGA polymer conjugates induce survival inhibition in rat C6 glioma cell line. Fluorescence microscopy studies evidenced the cellular uptake of FITC-conjugated probes 10 and 11 and moreover, the mitochondrial morphology modification induced by compounds 1 and 4a. Therefore, this study demonstrates that this PBR ligand-PLGA combination may provide a new mitochondrial targeted approach useful for improved cancer chemotherapy.