Systemic study of solvent-assisted active loading of gambogic acid into liposomes and its formulation optimization for improved delivery

• Published in: Biomaterials Vol. 166; pp. 13 - 26
• Main Authors: Tang, Wei-Lun, Tang, Wei-Hsin, Szeitz, Andras, Kulkarni, Jayesh, Cullis, Pieter, Li, Shyh-Dar
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.06.2018
• Subjects: Ammonium copper acetate gradient; Animals; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Drug Compounding - methods; Drug Delivery Systems; Female; Gambogic acid; Humans; Insoluble weakly acidic drugs; Liposomes; Liposomes - chemistry; Mice; Mice, Inbred BALB C; Miscible solvents; Remote loading; Solvents - chemistry; Xanthones - pharmacology; Insoluble weakly acidic drugs; Miscible solvents; Gambogic acid; Liposomes; Remote loading; Ammonium copper acetate gradient
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2018.03.004

The solvent-assisted active loading technology (SALT) was developed for encapsulating a water insoluble weak base into the liposomal core in the presence of 5% DMSO. In this study, we further examined the effect of various water miscible solvents in promoting active loading of other types of drugs into liposomes. To achieve complete drug loading, the amount of solvent required must result in complete drug solubilization and membrane permeability enhancement, but must be below the threshold that induces liposomal aggregation or causes bilayer disruption. We then used the SALT to load gambogic acid (GA, an insoluble model drug that shows promising anticancer effect) into liposomes, and optimized the loading gradient and lipid composition to prepare a stable formulation (Lipo-GA) that displayed >95% drug retention after incubation with serum for 3 days. Lipo-GA contained a high drug-to-lipid ratio of 1/5 (w/w) with a mean particle size of ∼75 nm. It also displayed a prolonged circulation half-life (1.5 h vs. 18.6 h) and enhanced antitumor activity in two syngeneic mice models compared to free GA. Particularly, complete tumor regression was observed in the EMT6 tumor model for 14 d with significant inhibition of multiple oncogenes including HIF-1α, VEGF-A, STAT3, BCL-2, and NF-κB. [Display omitted]