Biomimetic ApoE-Reconstituted High Density Lipoprotein Nanocarrier for Blood–Brain Barrier Penetration and Amyloid Beta-Targeting Drug Delivery

Abstract

Amyloid beta (Aβ) and its aggregation forms in the brain have been suggested as key targets for the therapy of Alzheimer's disease (AD). Therefore, the development of nanocarriers that possess both blood-brain barrier permeability and Aβ-targeting ability is of great importance for the intervention of AD. Here we constructed a biomimetic nanocarrier named apolipoprotein E (ApoE)-reconstituted high density lipoprotein nanocarrier (ANC) from recombinant ApoE and synthetic lipids to achieve the above goals. α-Mangostin (α-M), a polyphenolic agent that can inhibit the formation of Aβ oligomers and fibrils and accelerate Aβ cellular degradation, was used as the model drug. Compared with the control liposome, ANC demonstrated about 54-fold higher cellular uptake in brain endothelial cell line in vitro in an ApoE-dependent manner and much higher brain delivery efficiency in vivo. Confocal microscopy analysis witnessed the penetration of ANC across the brain vessels and its accumulation at the surrounding of Aβ aggregates. Following the loading of α-M, the Aβ-binding affinity of the nanoformulation (ANC-α-M) was not reduced but even enhanced. The effect of ANC-α-M on facilitating the microglia-mediated uptake and degradation of Aβ was enhanced by 336% and 29-fold when compared with that of the nontreated control and also much higher than that of ANC. Following intravenous administration for 2 to 4 weeks, ANC-α-M exhibited the most efficient efficacy in decreasing amyloid deposition, attenuating microgliosis, and rescuing memory defect in SAMP8 mice, an AD mouse model. Taken together, the findings of this work provided strong evidence that the ApoE-based biomimetic nanocarrier could provide a promising platform for brain drug delivery toward the treatment of AD.

ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice

“…APP/PS1 mice lacking apoA-I (apoA-I KO ) have more CAA [34] with no significant change in total amyloid burden [35,36] or neuroinflammation [34]. Conversely, increasing HDL levels in Aβ overexpressing mice, either through transgenic overexpression or upon treatment with an apoA-I mimetic, resulted in reduced CAA [37], lower amyloid plaque load [38][39][40][41], and attenuated neuroinflammation [37][38][39]41]. Others have administrated reconstituted HDL, recombinant apoA-I, and apoA-I mimetics to APP/PS1 or other AD model mice and similarly observed improvements in memory, neuroinflammation, and CAA, and some also observed reduced total soluble Aβ levels and Aβ deposition [39,[41][42][43].…”

Cationic polymethacrylate-copolymer acts as an agonist for β-amyloid and antagonist for amylin fibrillation

“…But the poor solubility and bioavailability affect their therapeutic nature and recently have been shown to be overcome using nanocarriers. [13][14][15] Although, their mechanism of action remains unknown, hydrogen bonding, hydrophobic interactions and π-π stacking are thought to be the major driving forces for their inhibitory mechanism of action. 16,17 Despite substantial efforts, no significant new drugs have been discovered against these most tenacious and unnerving medical disorders.…”

Targeting epigenetic mechanisms for chronic visceral pain: A valid approach for the development of novel therapeutics

“…In order to modulate epigenetic pathways in the central nervous system, these drugs will need to be able to cross the blood‐brain or blood‐spinal cord barrier. Certain viral vectors, nanoparticles, exosomes, and various other techniques are being used to deliver drugs directly across the blood‐brain and blood‐spinal cord barrier or prolong their time at these barriers to facilitate their uptake in the central nervous system through other uptake methods, for instance receptor‐mediated uptake or passive diffusion . Just like other drugs, epigenetic drugs could be packaged in lipophilic substances or hydrophilic agents and potentially cross the blood‐brain/blood‐spinal cord barrier.…”

“…Certain viral vectors, nanoparticles, exosomes, and various other techniques are being used to deliver drugs directly across the blood-brain and blood-spinal cord barrier or prolong their time at these barriers to facilitate their uptake in the central nervous system through other uptake methods, for instance receptor-mediated uptake or passive diffusion. [154][155][156][157][158][159][160] Just like other drugs, epigenetic drugs could be packaged in lipophilic substances or hydrophilic agents and potentially cross the blood-brain/blood-spinal cord barrier. Despite these improvements in delivery methods, high doses and/or long-term administration of the drug will be required for the drug to reach the central nervous system and exert its effects.…”