Preparation, Characterization, and In Vitro Pharmacodynamics and Pharmacokinetics Evaluation of PEGylated Urolithin A Liposomes.

Urolithin A (Uro-A), a metabolite of ellagitannins in mammals' intestinal tract, displays broad biological properties in preclinical models, including anti-oxidant, anti-inflammatory, and anti-tumor effects. However, the clinical application of Uro-A is restricted because of its low aqueous solubility and short elimination half-life. Our purpose was to develop a delivery system to improve the bioavailability and anti-tumor efficacy of Uro-A. To achieve this goal, urolithin A-loaded PEGylated liposomes (Uro-A-PEG-LPs) were prepared for the first time and its physicochemical properties and anti-tumor efficacy in vitro were evaluated. The morphology of Uro-A-PEG-LPs displayed a uniform sphere under transmission electron microscope. The particle size, polydispersity index, zeta potential, and encapsulation efficiency of Uro-A-PEG-LPs were 122.8 ± 7.4 nm, 0.25 ± 0.16, - 25.5 ± 2.3 mV, and 94.6 ± 1.6%, respectively. Moreover, Uro-A-PEG-LPs possessed higher stability and could be stably stored at 4°C for a long time. In vitro release characteristics indicated that Uro-A-PEG-LPs possessed superior sustained release properties. The results of confocal laser scanning microscopy experiment showed that the coumarin 6-loaded PEGylated liposomes (C6-PEG-LPs) have superior cellular uptake than that of conventional liposomes. In addition, in vitro tests demonstrated that Uro-A-PEG-LPs elevated cytotoxicity and pro-apoptotic effect in human hepatoma cells comparing with free Uro-A. Furthermore, the results of pharmacokinetic experiments showed that the t1/2, AUC0-t, and MRT0-t of Uro-A-PEG-LPs increased to 4.58-fold, 2.33-fold, and 2.43-fold than those of free Uro-A solution, respectively. Collectively, these manifested that PEGylated liposomes might be a potential delivery system for Uro-A to prolonging in vivo circulation time, promoting cellular uptake, and enhancing its anti-tumor efficacy.