Wu Xiaomei, Yuan Renxiang, Xu Yichong, Wang Kai, Yuan Hong, Meng Tingting, Hu Fuqiang
Department of Pharmacy, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200000, China.
College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, China.
Asian J Pharm Sci. 2024 Apr;19(2):100904. doi: 10.1016/j.ajps.2024.100904. Epub 2024 Mar 12.
The challenge in the clinical treatment of Parkinson's disease lies in the lack of disease-modifying therapies that can halt or slow down the progression. Peptide drugs, such as exenatide (Exe), with potential disease-modifying efficacy, have difficulty in crossing the blood-brain barrier (BBB) due to their large molecular weight. Herein, we fabricate multi-functionalized lipid nanoparticles (LNP) Lpc-BoSA/CSO with BBB targeting, permeability-increasing and responsive release functions. Borneol is chemically bonded with stearic acid and, as one of the components of Lpc-BoSA/CSO, is used to increase BBB permeability. Immunofluorescence results of brain tissue of 15-month-old C57BL/6 mice show that Lpc-BoSA/CSO disperses across the BBB into brain parenchyma, and the amount is 4.21 times greater than that of conventional LNP. Motor symptoms of mice in Lpc-BoSA/CSO-Exe group are significantly improved, and the content of dopamine is 1.85 times (substantia nigra compacta) and 1.49 times (striatum) that of PD mice. α-Synuclein expression and Lewy bodies deposition are reduced to 51.85% and 44.72% of PD mice, respectively. Immunohistochemical mechanism studies show AKT expression in Lpc-BoSA/CSO-Exe is 4.23 times that of PD mice and GSK-3β expression is reduced to 18.41%. Lpc-BoSA/CSO-Exe could reduce the production of α-synuclein and Lewy bodies through AKT/GSK-3β pathway, and effectively prevent the progressive deterioration of Parkinson's disease. In summary, Lpc-BoSA/CSO-Exe increases the entry of exenatide into brain and promotes its clinical application for Parkinson's disease therapy.
帕金森病临床治疗的挑战在于缺乏能够阻止或减缓疾病进展的疾病修饰疗法。诸如艾塞那肽（Exe）等具有潜在疾病修饰功效的肽类药物，因其分子量较大而难以穿过血脑屏障（BBB）。在此，我们制备了具有血脑屏障靶向、增渗和响应释放功能的多功能脂质纳米颗粒（LNP）Lpc-BoSA/CSO。冰片与硬脂酸化学键合，作为Lpc-BoSA/CSO的成分之一，用于增加血脑屏障的通透性。对15月龄C57BL/6小鼠脑组织的免疫荧光结果显示，Lpc-BoSA/CSO穿过血脑屏障分散到脑实质中，其含量是传统LNP的4.21倍。Lpc-BoSA/CSO-Exe组小鼠的运动症状明显改善，多巴胺含量分别是帕金森病小鼠黑质致密部的1.85倍和纹状体的1.49倍。α-突触核蛋白表达和路易小体沉积分别降至帕金森病小鼠的51.85%和44.72%。免疫组化机制研究表明，Lpc-BoSA/CSO-Exe中AKT表达是帕金森病小鼠的4.23倍，GSK-3β表达降至18.41%。Lpc-BoSA/CSO-Exe可通过AKT/GSK-3β途径减少α-突触核蛋白和路易小体的产生，并有效防止帕金森病的进行性恶化。总之，Lpc-BoSA/CSO-Exe增加了艾塞那肽进入脑内的量，促进了其在帕金森病治疗中的临床应用。
