Baicalin lipid nanocapsules for treatment of glioma: characterization, mechanistic cytotoxicity, and pharmacokinetic evaluation

Baicalin is a promising anticancer nutraceutical compound, but its application is hindered by its low water solubility and bioavailability, which can be remedied by its encapsulation in nanoparticles. Lipid nanocapsules (LNCs) were developed to enhance baicalin delivery via intravenous and intranasal routes, and potentiate its therapeutic activity in treatment of glioma. LNCs displayed a particle size of 17.76 nm and sustained release of 74.36% after 24 h. The IC50 of baicalin LNCs (13 ± 5 µg/ml) was 60 times lower than free baicalin (780 ± 107 µg/ml) on human glioblastoma multiform cell line U87, with adequate cellular uptake as delineated by confocal laser microscopy. Both baicalin and LNCs induced cell cycle arrest at S and G2/M phases, with significant up-regulation in P21 gene, and decline in Nrf-2, HO-1 and VEGF gene expression. LNCs increased baicalin’s bioavailability, either after intravenous (AUC0-24 h 10.94 ± 0.28 vs 3.53 ± 0.09 µg/ml*h), or intranasal administration (AUC0-24 h 6.26 ± 0.11 vs 3.17 ± 0.04 µg/ml*h). They also bypassed the blood brain barrier and achieved significantly higher brain delivery compared to free baicalin (drug targeting efficiency 160.73% vs 52.9%). Baicalin LNCs is a promising treatment modality for glioma, when administered through intravenous or intranasal routes.黄芩苷（Baicalin）是一种极具潜力的抗癌营养药用复合物，但其水溶性与生物利用度较低，极大限制了其临床应用，而将其包封于纳米颗粒中可有效改善这一缺陷。脂质纳米胶囊（Lipid nanocapsules，LNCs）被开发用于通过静脉与鼻内给药途径增强黄芩苷的递送，并强化其在神经胶质瘤治疗中的治疗活性。该脂质纳米胶囊的粒径为17.76 nm，24小时内的药物累积缓释率可达74.36%。在人多形性胶质母细胞瘤细胞系U87中，载黄芩苷脂质纳米胶囊的半数抑制浓度（IC50）为(13 ± 5) µg/mL，较游离黄芩苷的(780 ± 107) µg/mL低60倍；经共聚焦激光显微镜观测证实，该纳米制剂具备良好的细胞摄取能力。黄芩苷与脂质纳米胶囊均可诱导细胞周期阻滞于S期与G2/M期，同时显著上调P21基因的表达，并下调Nrf-2、HO-1及VEGF基因的表达。脂质纳米胶囊可提升黄芩苷的生物利用度：静脉给药时，其0-24小时血浆药物浓度-时间曲线下面积（Area Under the Curve，AUC）为(10.94 ± 0.28) µg·mL⁻¹·h，显著高于游离黄芩苷的(3.53 ± 0.09) µg·mL⁻¹·h；鼻内给药时，其AUC0-24h为(6.26 ± 0.11) µg·mL⁻¹·h，同样高于游离黄芩苷的(3.17 ± 0.04) µg·mL⁻¹·h。此外，相较于游离黄芩苷，脂质纳米胶囊可有效跨越血脑屏障（Blood Brain Barrier，BBB），实现更高的脑部药物递送效率，其药物靶向效率达160.73%，远高于游离黄芩苷的52.9%。综上，通过静脉或鼻内给药途径施用载黄芩苷脂质纳米胶囊，是一种极具开发潜力的神经胶质瘤治疗方案。