Abstract
The efficacy of brain therapeutics is largely hampered by the presence of the blood–brain barrier (BBB), mainly due to the failure of most (bio) pharmaceuticals to cross it. Accordingly, this study aims to develop nanocarriers for targeted delivery of recombinant precursor microRNA (pre-miR-29b), foreseeing a decrease in the expression of the BACE1 protein, with potential implications in Alzheimer’s disease (AD) treatment. Stearic acid (SA) and lactoferrin (Lf) were successfully exploited as brain-targeting ligands to modify cationic polymers (chitosan (CS) or polyethyleneimine (PEI)), and its BBB penetration behavior was evaluated. The intracellular uptake of the dual-targeting drug delivery systems by neuronal cell models, as well as the gene silencing efficiency of recombinant pre-miR-29b, was analyzed in vitro. Labeled pre-miR-29b-CS/PEI-SA-Lf systems showed very strong fluorescence in the cytoplasm and nucleus of RBE4 cells, being verified the delivery of pre-miR-29b to neuronal cells after 1 h transfection. The experiment of transport across the BBB showed that CS-SA-Lf delivered 65% of recombinant pre-miR-29b in a period of 4 h, a significantly higher transport ratio than the 42% found for PEI-SA-Lf in the same time frame. Overall, a novel procedure for the dual targeting of DDS is disclosed, opening new perspectives in nanomedicines delivery, whereby a novel drug delivery system harvests the merits and properties of the different immobilized ligands.
Highlights
Alzheimer’s disease (AD) is the most prevalent (45–60%) and devastating form of dementia in the elderly and can lead to death within 3 to 9 years after the appearance of symptoms [1]
The following chemical shifts were observed in the 1H nuclear magnetic resonance (NMR) spectrum of the PEI-Stearic acid (SA) conjugate (Figure S2 of Supplementary Material): a sharp peak at δ = 1.26 ppm corresponding to 28 methylene protons of stearate group, two peaks between δ = 2.17 ppm and δ = 1.93 ppm corresponding to two CH2 adjacent to the amide group and one peak at δ = 0.85 ppm attributed to the methyl group
The results showed that the zeta potential values of the chitosan–stearic acid (CS-SA) and polyethyleneimine–stearic acid (PEI-SA) polymers with the conjugation of Lf on the surface were decreased, what could be explained by the modification of the surface of the polymers with Lf causing a decrease in the number of protonated amino groups on polymers, leading to the drop of zeta potential
Summary
Alzheimer’s disease (AD) is the most prevalent (45–60%) and devastating form of dementia in the elderly and can lead to death within 3 to 9 years after the appearance of symptoms [1]. Several research groups demonstrated that the levels and activity of the BACE1 protein are increased in sporadic AD patients’ brains, suggesting that BACE1 dysregulation is directly implicated in AD pathogenesis For these reasons, BACE1 has been recognized as a promising drug target for the therapy of this disease, once BACE1 inhibition may decrease the formation of all forms of Aβ peptides and, reduce cell death [10,11,12]. The receptors existing on the BBB have been explored to target drugs to the brain facilitating the ability of a drug containing a specific ligand to interact with its specific receptor expressed on the luminal side of BBB endothelial cells
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