Penetratin and Mannose-Functionalized Cannabidiol Lipid Nanoparticles Encapsulating the BDNF Gene Reduce Amyloid-Induced Inflammation

炎症 大麻酚 化学 甘露糖 神经保护 淀粉样蛋白(真菌学) 药理学 淀粉样纤维 生物化学 医学 淀粉样β 免疫学 内科学 大麻 无机化学 疾病 精神科
作者
Bivek Chaulagain,Jagdish Singh
出处
期刊:Molecular Pharmaceutics [American Chemical Society]
标识
DOI:10.1021/acs.molpharmaceut.4c00811
摘要

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 (p-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 (p-value <0.05) compared to free CBD or nonfunctionalized nanoparticles. The LNPs demonstrated anti-inflammatory activity against lipopolysaccharides and human amyloid beta1–42 oligomer induction as they reduced the protein and mRNA expression of pro-inflammatory cytokines TNF-α (p < 0.05) and IL-1β (p < 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.
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