Study on in vivo pharmacokinetics and in vitro anti-inflammatory effects of cannabidiol-cholesterol succinate monoester-g-carboxymethyl chitosan nano-micelles
OBJECTIVE To study the pharmacokinetics and tissue distribution of cannabidiol(CBD)-cholesterol succinate monoester-g-carboxymethyl chitosan (CCMC) nano-micelles in rats,and to evaluate its anti-inflammatory effect. METHODS CBD-CCMC nano-micelles were prepared by dialysis method and the properties were characterized. SD rats were divided into CBD group and CBD-CCMC nano-micelles group with 6 rats in each group. The rats were given 100 mg/kg CBD and CBD-CCMC nano-micelle by intragastric administration,respectively (based on the CBD load). Blood was collected from the posterior ophthalmic venous plexus at 0.5,1,1.33,1.5,1.75,2,4,8,24,48 h after administration. The heart,liver,spleen,lung,kidney and muscle tissues of rats were separated at 0.25,1.5,10 and 24 h after administration of CBD and CBD-CCMC nano-micelle with the same dose. The drug content in plasma and tissues was determined,the pharmacokinetic parameters were calculated,and the tissue distribution was analyzed. The inflammatory model of Caco-2 cells was induced by lipopolysaccharide,after 24 h of treatment with 5,10,and 15 µg/mL CBD and CBD-CCMC nanomicelles (based on loaded CBD),its anti-inflammatory activity was investigated by measuring cell viability,transepithelial electrical resistance (TEER) and inflammatory cytokines IL-1β,IL-8 and TNF-α. RESULTS The prepared CBD-CCMC nano-micelles had a particle size of (230.6±1.8) nm,a polydispersity index of 0.170±0.053,a Zeta potential of (-13.5±1.2) mV,an encapsulation rate of (86.35±0.56)％ and a drug loading of (9.18±0.32)％,respectively;the solubility was 68.240 μg/mL. The pharmacokinetic results showed that the AUC0-48 h,AUC0-∞,half-life time and peak concentration of CBD-CCMC nano-micelle group were significantly increased/extended compared with CBD group (P<0.05 or P<0.01). The results of the tissue distribution study showed that at the same time point,the drug distribution concentration of CBD-CCMC nanomicelles in the rat tissue was higher than that in the CBD group. Research on anti-inflammatory effects shows that compared with CBD of the same mass concentration,CBD-CCMC nano-micelles can significantly increase cell viability (P<0.05 or P<0.01),enhance TEER,and reduce the levels of IL-8,IL-1β and TNF-α in cells (P<0.01),and the secretion levels of inflammatory cytokines IL-8,IL-1β and TNF-α were significantly decreased (P<0.01). CONCLUSIONS CBD-CCMC nano-micelles can increase the plasma concentration and tissue distribution concentration of CBD,and improve anti-inflammatory activity of CBD.
万方数据
维普
