RESUMEN

Glycyrrhetinic acid is a bioactive compound extracted from licorice that exhibits inhibition effect on various cancers. However, its hydrophobicity results in low bioavailability that limits application. We aim to overcome this barrier, the present research was performed to prepare glycyrrhetinic acid proliposomes mediated mannosylated ligand (mannose-diester lauric diacid-cholesterol, MDC) and to evaluate its physicochemical characterizations, environmental stability and bioactivity. In preliminary optimization studies of glycyrrhetinic acid proliposomes mediated MDC (MDC-GA-PL), four optimum operating parameters, cryoprotectant of glucose and mannitol, the mixed cryoprotectant ratio (glucose/mannitol) of 1:1, a cryoprotectant/egg phosphatidylcholine mass ratio of 10/1, and -60 â„ƒ pre-freezing temperature, were obtained after investigation. Under the optimum lyophilization conditions, MDC-GA-PL was freeze-dried and reconstituted proliposomes were characterized. These proliposomes showed that MDC-GA-PL were well-dispersible spherical particles with an average particle size of 120.80 nm, a polydispersity index about 0.095, a zeta potential of -33.15 mV, encapsulation efficiency of 85.9% and drug loading of 6.38%. In vitro drug release study showed that glycyrrhetinic acid release of MDC-GA-PL conforms to the Higuchi release model. In addition, these proliposomes were stable during six months at 4 â„ƒ. Moreover, acute toxicity assay revealed no substantial safety concern for MDC-GA-PL. Finally, in vitro bioactivity of proliposomes was evaluated. Cytotoxicity effect and apoptosis efficiency of MDC-GA-PL by HepG2 cells was significantly higher than that of glycyrrhetinic acid proliposomes without MDC, demonstrating that MDC has a desirable effect on liver target. Overall, we have reason to believe that MDC-GA-PL would be a promising target delivery to improve therapeutic against hepatic diseases.

Asunto(s)

Ácido Glicirretínico , Colesterol , Glucosa , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacología , Ligandos , Liposomas/química , Manitol , Manosa , Tamaño de la Partícula , Fosfatidilcolinas

RESUMEN

This research was performed to optimize the enzymatic synthesis of mannosylated ligand with which to prepare mannosy-lated liposomes and investigate their bioactivity. Based on single-factor studies, lipase dose, substrate molar ratio (diester lauric diacid-cholesterol to mannose) and temperature were identified as significant parameters, and optimal reaction conditions were determined through response surface methodology (RSM) with central composite design. The optimum operating parameters, 61.23 mg of lipase, a substrate molar ratio of 5.36, and 56.64 °C temperature offered a predicted yield (71.11%) which was consistent with the actual yield (69.08%). Drug-free mannosylated liposomes were prepared film-dispersion. The characterizations of these liposomes showed that mannosylated liposomes were well-dispersible spherical particles with an average particle size of 142.3 nm, the polydispersity index of 0.16, and a zeta potential of -19.8 mV. Pyrogen examination, hemolytic studies and cytotoxicity assays revealed no substantial safety concern for drug-free mannosylated liposomes. Cellular uptake efficiency of mannosylated liposomes by HepG2 cells was significantly higher than that of unmodified liposomes, demonstrating that mannosylated ligands have a positive effect on liver targeting. Overall, mannosylated liposomes could be active drug delivery system for combatting the therapy of hepatic diseases.

Asunto(s)

Liposomas , Manosa , Sistemas de Liberación de Medicamentos , Ligandos , Hígado , Tamaño de la Partícula

RESUMEN

In this study, novel glycyrrhetinic acid (GA) liposomes modified with a liver-targeting galactosylated derivative ligand (Gal) were prepared using a film-dispersion method. To characterize the samples, particle size, zeta potential, drug loading, and encapsulation efficiency were performed. Moreover, plasma and tissues were pre-treated by liquid-liquid extraction and analyzed by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results showed that the mean residence times (MRTs) and the area under the curve (AUC) of GA liposomes with Gal (Gal-GA-LP), and GA liposomes (GA-LP) were higher than the GA solution (GA-S) in plasma. The tissue (liver) distribution of Gal-GA-LP was significantly different in contrast to GA-LP. The relative intake rate (Re) of Gal-GA-LP and GA-LP in the liver was 4.752 and 2.196, respectively. The peak concentration ratio (Ce) of Gal-GA-LP and GA-LP in the liver was 2.796 and 1.083, respectively. The targeting efficiency (Te) of Gal-GA-LP and GA-LP in the liver was 48.193% and 34.718%, respectively. Taken together, the results indicate that Gal-GA-LP is an ideal complex for liver-targeting, and has great potential application in the clinical treatment of hepatic diseases. Drug loading and releasing experiments also indicated that most liposomes are spherical structures and have good dispersity under physiologic conditions, which could prolong GA release efficiency in vitro.