Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, People's Republic of China.
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, People's Republic of China.
Int J Nanomedicine. 2022 Aug 17;17:3655-3670. doi: 10.2147/IJN.S368528. eCollection 2022.
We designed a novel isoliquiritigenin (ISL) loaded micelle prepared with DSPE-PEG as the drug carrier modified with the brain-targeting polypeptide angiopep-2 to improve the poor water solubility and low bioavailability of ISL for the treatment of acute ischemic stroke.
Thin film evaporation was used to synthesize the ISL micelles (ISL-M) modified with angiopep-2 as the brain targeted ligands. The morphology of the micelles was observed by the TEM. The particle size and zeta potential were measured via the nanometer particle size analyzer. The drug loading, encapsulation and in vitro release rates of micelles were detected by the HPLC. The UPLC-ESI-MS/MS methods were used to measure the ISL concentrations of ISL in plasma and main tissues after intravenous administration, and compared the pharmacokinetics and tissue distributions between ISL and ISL-M. In the MCAO mice model, the protective effects of ISL and ISL-M were confirmed via the behavioral and molecular biology experiments.
The results showed that the drug loading of ISL-M was 7.63 ± 2.62%, the encapsulation efficiency was 68.17 ± 6.23%, the particle size was 40.87 ± 4.82 nm, and the zeta potential was -34.23 ± 3.35 mV. The in vitro release experiments showed that ISL-M had good sustained-release effect and pH sensitivity. Compared with ISL monomers, the ISL-M could significantly prolong the in vivo circulation time of ISL and enhance the accumulation in the brain tissues. The ISL-M could ameliorate the brain injury induced by the MCAO mice via inhibition of cellular autophagy and neuronal apoptosis. There were no the cellular structural damages and other adverse effects for ISL-M on the main tissues and organs.
The ISL-M could serve as a promising and ideal drug candidate for the clinical application of ISL in the treatment of acute ischemic stroke.
我们设计了一种新型的大豆异黄酮（ISL）载药胶束，以 DSPE-PEG 为药物载体，修饰具有脑靶向多肽血管生成素-2（angiopep-2），以提高 ISL 治疗急性缺血性脑卒中的水溶性差和生物利用度低的问题。
采用薄膜蒸发法合成载药胶束（ISL-M），并对其进行脑靶向修饰。用透射电镜观察胶束的形态。用纳米粒度分析仪测量胶束的粒径和 zeta 电位。用高效液相色谱法（HPLC）检测载药率、包封率和体外释放率。采用超高效液相色谱-电喷雾串联质谱法（UPLC-ESI-MS/MS）检测静脉给药后 ISL 在血浆和主要组织中的浓度，比较 ISL 和 ISL-M 的药代动力学和组织分布。在大脑中动脉闭塞（MCAO）小鼠模型中，通过行为学和分子生物学实验证实了 ISL 和 ISL-M 的保护作用。
结果表明，ISL-M 的载药量为 7.63±2.62%，包封率为 68.17±6.23%，粒径为 40.87±4.82nm，zeta 电位为-34.23±3.35mV。体外释放实验表明，ISL-M 具有良好的缓释效果和 pH 敏感性。与 ISL 单体相比，ISL-M 能明显延长 ISL 的体内循环时间，增强其在脑组织中的蓄积。ISL-M 可通过抑制细胞自噬和神经元凋亡改善 MCAO 小鼠的脑损伤。ISL-M 对主要组织和器官无细胞结构损伤等不良反应。
ISL-M 可作为 ISL 治疗急性缺血性脑卒中的临床应用有前景和理想的药物候选物。
