Chaulagain Bivek, Singh Jagdish
Department of Pharmaceutical Sciences, School of Pharmacy, College of Health and Human Sciences, North Dakota State University, Fargo, North Dakota 58105, United States.
Mol Pharm. 2025 Jan 6;22(1):154-167. doi: 10.1021/acs.molpharmaceut.4c00811. Epub 2024 Nov 26.
Inflammation is emerging as a critical player in the disease progression of Alzheimer's disease (AD) by its interaction with amyloid beta plaques in a feed-forward loop. There is also a decline in the nourishment and enriching neurotrophic factor, brain-derived neurotrophic factor (BDNF), in the brain. Therefore, supplementing the brain with BDNF by gene delivery and delivering the anti-inflammatory agent, cannabidiol (CBD) in this case, to mitigate inflammation-induced disease cascade offers an attractive treatment strategy. To achieve the brain localization of CBD and pBDNF, lipid nanoparticles (LNPs) functionalized with mannose and penetratin were utilized. CBD and pBDNF were successfully encapsulated in the LNPs (more than 80%) with a size less than 180 nm, polydispersity index less than 0.25, and zeta potential of 23 mV. CBD was released from the formulation over a period of a week. The dual-functionalized LNPs demonstrated higher cellular uptake of CBD and expressed a significantly higher amount of BDNF (-value <0.05) after transfection than their nonmodified counterparts in four brain cell lines, i.e., brain endothelial cells (b.END3), immortalized microglia cells (IMGs), primary astrocytes, and primary neurons. Similarly, the permeation of CBD through the dual-modified LNPs across the in vitro coculture blood-brain barrier model was significantly higher (-value <0.05) compared to free CBD or nonfunctionalized nanoparticles. The LNPs demonstrated anti-inflammatory activity against lipopolysaccharides and human amyloid beta oligomer induction as they reduced the protein and mRNA expression of pro-inflammatory cytokines TNF-α ( < 0.05) and IL-1β ( < 0.05) in IMG cells. In summary, the penetratin and mannose-functionalized LNPs encapsulating CBD and pBDNF could serve as a promising therapy in AD, requiring further validation in animal models.
炎症通过在前馈回路中与β淀粉样蛋白斑块相互作用，正成为阿尔茨海默病（AD）疾病进展中的关键因素。大脑中营养和丰富神经营养因子——脑源性神经营养因子（BDNF）也会减少。因此，通过基因传递向大脑补充BDNF，并在这种情况下递送抗炎剂大麻二酚（CBD），以减轻炎症引发的疾病级联反应，提供了一种有吸引力的治疗策略。为了实现CBD和pBDNF在大脑中的定位，使用了用甘露糖和穿膜肽功能化的脂质纳米颗粒（LNP）。CBD和pBDNF成功封装在LNP中（超过80%），粒径小于180nm，多分散指数小于0.25，ζ电位为23mV。CBD在一周的时间内从制剂中释放出来。在四种脑细胞系，即脑内皮细胞（b.END3）、永生化小胶质细胞（IMG）、原代星形胶质细胞和原代神经元中，双功能化的LNP显示出对CBD的更高细胞摄取率，并且在转染后表达的BDNF量显著更高（P值<0.05），高于其未修饰的对应物。同样，与游离CBD或未功能化的纳米颗粒相比，双修饰的LNP使CBD穿过体外共培养血脑屏障模型的渗透率显著更高（P值<0.05）。LNP对脂多糖和人β淀粉样寡聚体诱导表现出抗炎活性，因为它们降低了IMG细胞中促炎细胞因子TNF-α（P<0.05）和IL-1β（P<0.05）的蛋白质和mRNA表达。总之，封装CBD和pBDNF的穿膜肽和甘露糖功能化的LNP有望成为AD的一种治疗方法，需要在动物模型中进一步验证。
