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大麻二酚-胆甾醇琥珀酸单酯-g-羧甲基壳聚糖纳米胶束体内药动学及体外抗炎作用研究
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| 篇名： | 大麻二酚-胆甾醇琥珀酸单酯-g-羧甲基壳聚糖纳米胶束体内药动学及体外抗炎作用研究 |
| TITLE： | Study on in vivo pharmacokinetics and in vitro anti-inflammatory effects of cannabidiol-cholesterol succinate monoester-g-carboxymethyl chitosan nano-micelles |
| 摘要： | 目的 研究大麻二酚（CBD）-胆甾醇琥珀酸单酯-g-羧甲基壳聚糖（CCMC）纳米胶束在大鼠体内的药动学及组织分布特性，并初步评价其体外抗炎作用。方法采用透析法制备CBD-CCMC纳米胶束，并对其性能进行表征。将SD大鼠分为CBD组和CBD-CCMC纳米胶束组，每组6只，分别灌胃100mg/kgCBD和CBD-CCMC纳米胶束（以负载的CBD计）；于给药后0.5、1、1.33、1.5、1.75、2、4、8、24、48h眼眶采血，计算药动学参数。另取大鼠同法分组、给药，每组24只；分别于给药后0.25、1.5、10、24h，每组取6只大鼠分离其心、肝、脾、肺、肾、肌肉组织，分析药物的组织分布情况。采用脂多糖诱导来建立Caco-2细胞炎症模型，分别以终质量浓度为5、10、15μg/mL的CBD和CBD-CCMC纳米胶束（以负载的CBD计）作用24h后，检测细胞活力、跨膜电阻（TEER）和炎症刺激下细胞产生的炎症因子[白细胞介素1β（IL-1β）、IL-8、肿瘤坏死因子α（TNF-α）]水平。结果所制CBD-CCMC纳米胶束的平均粒径为（230.6±1.8）nm，多分散性指数为0.170±0.053，Zeta电位为（－13.5±1.2）mV，包封率及载药量分别为（86.35±0.56）%、（9.18±0.32）%；溶解度为68.240μg/mL。药动学结果显示，与CBD组比较，CBD-CCMC纳米胶束组大鼠的药时曲线下面积（AUC）0-48h、AUC0-∞、半衰期、峰浓度均显著增加/延长（P＜0.05或P＜0.01）。组织分布研究结果表明，在同一时间点，CBD-CCMC纳米胶束组大鼠组织中药物的分布浓度均高于CBD组。抗炎作用研究结果显示，与同质量浓度的CBD相比，CBD-CCMC纳米胶束可显著提高细胞活力（P＜0.05或P＜0.01），升高TEER，降低细胞中IL-8、IL-1β、TNF-α水平（P＜0.01）。结论CBD-CCMC纳米胶束能够增加CBD血药浓度和组织分布浓度，提高CBD的抗炎活性。 |
| ABSTRACT： | 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. |
| 期刊： | 2024年第35卷第23期 |
| 作者： | 李睿；路丽艳；许楚；郝瑞；田湘涵；阮文辉；王颖莉 |
| AUTHORS： | LI Rui，LU Liyan，XU Chu，HAO Rui，TIAN Xianghan，RUAN Wenhui，WANG Yingli |
| 关键字： | 大麻二酚；纳米胶束；胆甾醇琥珀酸单酯；羧甲基壳聚糖；药动学 |
| KEYWORDS： | cannabinol； nano-micelles； cholesterol succinate monoester； carboxymethyl chitosan； pharmacokinetics |
| 阅读数： | 3 次 |
| 本月下载数： | 2 次 |
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