oregon-green-488-carboxylic-acid and 1-2-didodecanoyl-glycero-3-phosphocholine

Glioblastoma (GBM) is the most malignant primary brain tumor in adults, and its prognosis remains very limited despite decades of research. Enhanced drug delivery to GBM using liposomes represents a promising therapeutic strategy. In this study, we describe a novel cationic and pH-sensitive liposome formulation composed of DPPC:DC-Chol:DOPE:DHPE Oregon Green producing efficient internalization and intracellular delivery to F98 and U-118 GBM cells. With a series of derived modifications of the lipid composition, we investigated the impact of membrane fluidity, steric stabilization and loss of both cationic and pH-sensitive components on cellular uptake and intracellular release kinetics by flow cytometry and confocal microscopy, respectively. DPPC:DC-Chol:DOPE:DHPE Oregon Green liposomes were strongly internalized in both cell lines within 6h. Following cellular uptake, liposomes traveled towards the nucleus (12h) and gradually released their cargo in the cytosol (over 24h). Modifications in liposomal composition of our original formulation had detrimental consequences on both the uptake and intracellular release kinetics in the two tested cell lines. Thus, we report a novel potent liposomal formulation for efficient cytosolic delivery of intracellular therapeutics such as chemotherapy agents and siRNAs to GBM cells.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Animals; Biological Transport; Brain Neoplasms; Carboxylic Acids; Cell Line, Tumor; Chemistry, Pharmaceutical; Cholesterol; Flow Cytometry; Glioma; Humans; Hydrogen-Ion Concentration; Kinetics; Lipid Metabolism; Liposomes; Membrane Fluidity; Microscopy, Confocal; Microscopy, Electron, Transmission; Particle Size; Phosphatidylethanolamines; Phosphatidylglycerols; Polyethylene Glycols; Rats