B6 Peptide-Modified PEG-PLA Nanoparticles for Enhanced Brain Delivery of Neuroprotective Peptide

Abstract

The blood-brain barrier (BBB), which is formed by the brain capillary wall, greatly hinders the development of new drugs for the brain. Over the past decades, among the various receptor-mediated endogenous BBB transport systems, the strategy of using transferrin or anti-transferrin receptor antibodies to facilitate brain drug delivery system is of particular interest. However, the application of large proteins still suffers from the drawbacks including synthesis procedure, stability, and immunological response. Here, we explored a B6 peptide discovered by phase display as a substitute for transferrin, and conjugated it to PEG-PLA nanoparticles (NP) with the aim of enhancing the delivery of neuroprotective drug across the BBB for the treatment of Alzheimer's disease. B6-modified NP (B6-NP) exhibited significantly higher accumulation in brain capillary endothelial cells via lipid raft-mediated and clathrin-mediated endocytosis. In vivo, fluorescently labeled B6-NP exhibited much higher brain accumulation when compared with NP. Administration of B6-NP encapsulated neuroprotective peptide-NAPVSIPQ (NAP)-to Alzheimer's disease mouse models showed excellent amelioration in learning impairments, cholinergic disruption, and loss of hippocampal neurons even at lower dose. These findings together suggested that B6-NP might serve as a promising DDS for facilitating the brain delivery of neuropeptides.

Sialic acid (SA)-modified selenium nanoparticles coated with a high blood–brain barrier permeability peptide-B6 peptide for potential use in Alzheimer’s disease

“…The peptide is regarded as a promising candidate with a potential to improve drug transport across the BBB [11,12].…”

Nanoparticles in relation to peptide and protein aggregation

“…One example of this type of peptide was reported by Todorova et al; 32 this peptide, cyc (60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70), is derived from human apolipoprotein CII, which acts against amyloid formation by the fibrillogenic peptide, apoC-II (60-70). Liu et al 33 explored a B6 peptide in conjugation with polyethylene glycol-polylactic acid nanoparticles to enhance the delivery of neuroprotective drugs across the blood-brain barrier for the treatment of Alzheimer's disease. These modified conjugates show higher accumulation in brain capillary endothelial cells via lipid raft-mediated and clathrin-mediated endocytosis.…”

“…These modified conjugates show higher accumulation in brain capillary endothelial cells via lipid raft-mediated and clathrin-mediated endocytosis. 33 …”

Poly(lactic acid) for delivery of bioactive macromolecules

“…Researchers have aggressively tackled many of the issues in- 91 volved in controlled release and delivery of biomolecules by innovating 92 techniques to protect the biomolecule from degradation mechanisms, 93 metered release of therapeutic concentrations to ensure high serum 94 bioavailability, and by incorporating targeting approaches to minimize 95 systemic toxicity. 96 Biodegradable polymers are significantly advantageous to non- 97 degradable polymers which require a secondary procedure for removal. 98 Poly(lactic acid) is among the most widely used biodegradable polymer 99 and combined with properties of low immunogenicity and toxicity, it is 100 highly biocompatible and can be reproducibly fabricated as compared 101 to polymers derived from natural sources.…”

“…Targeted DNA delivery can localize treatment to a specific tissue 596 leading to enhanced efficacy and reduced side effects, and antibodies 597 and peptides have been used clinically for targeting [95,96]. Peptides .…”