Authors: Hammed, Hammidat D, Enoma, Samuel, Donkoh, Christian J. K, Kikeh, Emric N, Agboola, Anthonia O, Benin, Sandra
Abstract: Neurodegenerative illnesses pose a significant problem, partly due to the challenge of getting therapeutic drugs across the blood-brain barrier (BBB), as well as the complex interactions between neuroinflammation and metabolic dysregulation. As a way to address these issues, we have created a lipid nanoparticle (LNP) system. It combines two different types of transporters with the intended goal of delivering omega-3 fatty acids through the use of plant lectins to help facilitate the movement of DHA and EPA across the BBB. As a special feature of this created LNP system, when utilizing the GLUT1 and LAT1 transporters located on the endothelium of the BBB in order to move the LNPs across the BBB from the circulation to the brain, both GLUT1 and LAT1 are used simultaneously, allowing a more efficient means of delivering the LNP system across the BBB without being limited by saturation kinetics when both GLUT1 and LAT1 are engaged. Within the LNP, both DHA and EPA are contained in an optimized ratio for both optimal delivery and maximal effect, supporting the activation of neuroprotective pathways (NF-κB suppression) and the promotion of mitochondrial biogenesis. The use of lectin (a binding agent derived from plant sources) as a means by which to reduce inflammation and provide a pathway to help the LNP system penetrate the BBB and provide an inflammatory reduction via helping to change microglial polarity towards an anti-inflammatory phenotype was also demonstrated. The experimental validations done with this LNP system, using human induced pluripotent stem cell (iPSC) derived human BBB models, clearly showed significantly greater levels of transcytosis flow than what is typically expected. As well, in transgenic Alzheimer's mouse models, the oxidative stress levels were significantly decreased and the synaptic structure was maintained. The novel nature of this work is due to the ability of each of the transporters, GLUT1 and LAT1, to target neurodegenerative disorders while also utilizing immunomodulatory and metabolic pathways in tandem. The strategy applied here provides an innovative and effective platform to enhance neuronal resiliency through the combination of neuroprotection and directional/neural specific drug delivery with applicability across a broad range of neurodegenerative diseases.
DOI: http://doi.org/10.5281/zenodo.21357715
