Sustained-release study on Exenatide loaded into mesoporous silica nanoparticles: in vitro characterization and in vivo evaluation.

BACKGROUND: Exenatide (EXT), the first glucagon-like peptide-1 receptor agonist, has been approved as an adjunctive therapy for patients with type 2 diabetes. Due to EXT's short half-life, EXT must be administrated by continuous subcutaneous (s.c.) injection twice daily. In previous studies, many studies on EXT loaded into polymer materials carriers for sustained release had been reported. However, these carriers have some defects, such as hydrophobicity, low surface energy, low mechanical strength, and poor chemical stability. Therefore, this study aims to develop a novel drug delivery system, which is EXT loaded into well-ordered hexagonal mesoporous silica structures (EXT-SBA-15), to control the sustainability of EXT. METHODS: SBA-15 was prepared by hydrothermal method with uniform size. Morphology of SBA-15 was employed by transmission electron microscopy. The pore size of SBA-15 was characterized by N2 adsorption-desorption isotherms. The in vitro drug release behavior and pharmacokinetics of EXT-SBA-15 were investigated. Furthermore, the blood glucose levels of diabetic mice were monitored after subcutaneous injection of EXT-Sol and EXT-SBA-15 to evaluate further the stable hypoglycemic effect of EXT-SBA-15. RESULTS: EXT-SBA-15 showed a higher drug loading efficiency (15.2 ± 2.0%) and sustained-release features in vitro. In addition, pharmacokinetic studies revealed that the EXT-SBA-15 treatment group extended the half-life t 1/2(ß) to 14.53 ± 0.70 h compared with that of the EXT solution (EXT-Sol) treatment group (0.60 ± 0.08 h) in vivo. Results of the pharmacodynamics study show that the EXT-SBA-15 treatment group had inhibited blood glucose levels below 20 mmol/L for 25 days, and the lowest blood glucose level was 13 mmol/L on the 10th day. CONCLUSIONS: This study demonstrates that the EXT-SBA-15 delivery system can control the sustainability of EXT and contribute to improve EXT clinical use.

RGD conjugated liposome-hollow silica hybrid nanovehicles for targeted and controlled delivery of arsenic trioxide against hepatic carcinoma.

The aim of our study was to construct an Arg-Gly-Asp (RGD)-conjugated liposome-hollow silica hybrid nanovehicle for targeted delivery and controlled release of arsenic trioxide (ATO), whose anti-solid tumor effect was hampered by poor pharmacokinetics and dose-limited toxicity. Hydrophobic interactions were used to attach intact lipid membrane to the surface of chlorodimethyloctadecylsilane-modified hollow mesoporous silica nanoparticles. The prepared nanovehicles (RGD-LP-CHMSN) were characterized for uniform structure (silica core of ∼140nm in diameter and liposomal shell of ∼6nm), comparable drug loading efficiency (6.76%), desirable stability and strengthened controlled release. In vitro, RGD-LP-CHMSN showed good biocompatibility and low toxicity on HepG2, MCF-7 and LO2 cells. The targeted delivery of ATO by nanocarriers (RGD-LP-CHMSN-ATO) was demonstrated by an enhanced cellular uptake and a reduced half maximal inhibitory concentration (IC50) value. In pharmacokinetic studies, the RGD-LP-CHMSN-ATO group, compared to the free ATO group, prolonged the half time (t1/2ß) by 1.7 times and increased the area under curve (AUC) by 2.4 times. In addition, in a H22 tumor-xenograft mouse model, nanovehicles improved the targeting efficiency and anticancer potential of ATO. In conclusion, the strategy of constructing a nanocarrier with targeted delivery and controlled release characteristics is prospective to enhance the antitumor effect of ATO.