Enhanced pharmacokinetics and anti-tumor efficacy of PEGylated liposomal rhaponticin and plasma protein binding ability of rhaponticin.

Rhaponticin (RA) extracted from many medicinal plants has been demonstrated to possess a variety of pharmacological activities including potent antitumor, antitumor-promoting, antithrombotic, antioxidant and vasorelaxant activities. However, its poor solubility and bioavailability restricted the clinical application greatly. In this work, surface modification of liposome with polyethylene glycol (PEG) was developed with the purpose of improving the pharmacokinetics and anti-tumor efficacy of RA. PEGylated liposomal RA (PEGL-RA) was prepared by dry-film method. Its mean particle size was 89.3 +/- 8.7 nm, mean zeta potential was -4.1 mV and encapsulation efficiency was 67.4 +/- 6.4%. Moreover, the results of pharmacokinetic analysis showed that the time of maximum plasma concentration (Tmax) of PEGL-RA was about 4.5 times higher than that of free RA after oral administration due to the lower distribution into the gastrointestinal tract. The mean T1/2 value of PEGL-RA and free RA were 350.12 +/- 0.87 min and 180.02 +/- 1.96 min, respectively. The AUC0-->infinity ratio of PEGL-RA to free RA was about 2.41-fold (93.23 microg/mLmin/40.81 microg/mLmin). Plasma protein binding ability of RA was also studied. The results showed that RA with 33.6 microg/mL concentrations in human plasma and HSA achieved the percent of bound 39.23 +/- 3.78% and 22.28 +/- 2.34%, respectively. In the in vivo studies utilizing solid tumor-bearing rat, it was confirmed that PEGL-RA delivered remarkably larger amount of RA to tumor tissue and provided more significant anti-tumor activity than free RA. Furthermore, the cytotoxicity and fluorescence microscopic studies showed higher intracellular uptake of PEGL-RA than that of RA. In conclusion, PEGylated liposome was an effective delivery formulation for RA to increase the pharmacokinetics and therapeutic efficacy.