No abstract

Effective chemotherapy for clinical treatment of brain diseases is still lacking due to the poor penetration of the blood-brain barrier (BBB). The aim of this study was to construct a folate modified pterostilbene (Pt) loaded polymeric micellar delivery system (F-Pt/M) with mPEG-PCL as carrier material to aim at penetrating the BBB for brain tissue targeting via receptor-mediated endocytosis. In this study, F-Pt/M was prepared using thin-film hydration method and then optimized by response surface methodology (RSM) with the entrapment efficiency (EE), drug loading (DL) and hydrodynamic diameter (HD) as indexes. The average hydrodynamic diameter and zeta potential of optimal F-Pt/M were 133.2 nm and 24.6 mV, respectively. DL (18.3%) and EE (98.6%) made the solubility of Pt in water about 25 times higher than that of crude Pt. Results of DSC evaluation revealed that drugs were successfully encapsulated inside the polymeric micelles. TEM images showed that homogeneous spherical micellar structures with a narrow size distribution were developed. The release result in vitro showed that F-Pt/M presented sustained release behavior compared to control free Pt solution. Compared to non-targeted Pt/M, F-Pt/M had a significantly higher cytotoxicity against FR-overexpressing A172 cells. In vitro cellular uptake tests illustrated that the micellar delivery system could significantly improve the accumulation of drugs in target cells via receptor-mediated endocytosis. BBB penetration value (P) of F-Pt/M was about 4 folds higher than that of free Pt group. In addition, drug targeting index (DTI) was calculated to determine targeting of F-Pt/M to the brain which was found to be 4.89, implying improved brain targeting was achieved. Hence, the developed F-Pt/M exhibited great potential for delivering more drug molecules across the BBB for the treatment of brain diseases.

Background: Scoparone, the principal natural active ingredient of Artemisia capillaries (Yin Chen), can effectively treat cholestatic diseases, but the pharmacokinetic properties of scoparone are rarely studied in intrahepatic cholestatic rats. Objective: A sensitive and rapid LC-MS/MS method was established to detect scoparone and its metabolite of scopoletin in rat plasma and then compare their plasma pharmacokinetic differences between the normal and ANIT-induced cholestasis rats. Methods: Positive ionization was used to separate scoparone and scopoletin using acetonitrile and 0.1 % formic acid water as the mobile phase on a Hypersil ODS-BP column. Results: The calibration curves presented good linearity (R=0.9983 and 0.9989) in the concentration range of 10-10000 ng/mL and 0.5-500 ng/mL for scoparone and scopoletin, respectively. The precision of ≤ 9.4% and the accuracy ranged from -6.4% to 6.8% were recorded over three validation runs, and the recovery was higher than 83.9%. Under different storage conditions, scoparone and scopoletin were stable. Therefore, we studied the pharmacokinetic properties of scoparone and scopoletin in rats after a single oral administration with the above method. According to the results, the pharmacokinetic parameters of AUC, t1/2, and Cmax values of scoparone in the ANIT group were increased by 106%, 75%, and 44%, respectively, while these values of scopoletin were increased by 142%, 62%, and 65%. Conclusion: The findings indicated that the pharmacokinetic properties of scoparone and scopoletin were significantly different between the normal and ANIT-induced cholestasis rats, which suggested that the clinical application dosage of scoparone should be adjusted according to the liver function of patients.

Background: rLj-RGD3, a new member of RGD-motif toxin protein family derived from Lampetra japonica by means of DNA recombinant technique, has been demonstrated to be a platelet fibrinogen receptor antagonist. Researches over the years have shown that rLj-RGD3 has great value in developing as a useful antithrombotic and antitumor agent. Therefore, the study of pharmacokinetics is essential, so its quantification in plasma becomes a prerequisite. The present article aims to report a validated highly sensitive and specific double sandwich biotin-avidin enzyme linked immunosorbent assay (BA-ELISA) in order to provide a bio-analytical method for its pharmacokinetic (PK) study. Results: The concentration of rLj-RGD3 in rat plasma was measured at a picogram level by the developed BA-ELISA method, which used two different mouse anti-rLj-RGD3 monoclonal antibodies as capture antibody and detection antibody, respectively, directed at different epitopes. The method was validated to be highly specific (no interference with the detection from blank plasma), precise (within day and between day RSD <10%) and accurate (94%-104%). The absolute recovery was as high as 94%-105%. The calibration curve showed good linearity ranging from 50 to 1600 pg/mL with regression equation of Y = 0.0011X + 0.0328 (r2 = 0.9981), the LOQ was found to be as low as 50 pg/mL. The above validated assay was successfully employed for the assessment of PK disposition of rLj-RGD3 in rats. After i.v. and s.c. dosing 30 µg/kg the rLj-RGD3 plasma concentration declined biexponentially with time, which could be best fitted by the two-compartment model. The drug PK behavior could be characterized by rapid elimination, extensive metabolism and low s.c. bioavailability. Conclusions: The BA-ELISA method reported here was proved to completely meet requirements for PK study of rLj-RGD3, a toxin protein with effective pharmacological dose at µg/kg BW level.