Cyclic β-hairpin peptide loaded PLGA nanoparticles: A potential anti-amyloid therapeutic

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by β-amyloid peptide (Aβ1–42) deposits, with no definitive therapies. Recently, cyclic peptides have been considered potential therapeutics because of proteolytic stability and tight and precise binding to Aβ1–42. We modified the classic cyclic peptide viz., PPLeu, via a directed approach to arrive at a new β-hairpin cyclic peptide BSBP8 (Mw 1450 Da), a potent anti-amyloidogenic agent. BSBP8 also disassembled pre-formed Aβ1–42 fibrils and rescued neuronal cells from Aβ1–42 induced cytotoxicity. In the Thioflavin T assay, BSBP8 showed ∼82 % aggregation reduction when co-incubated with Aβ1–42. Biophysical techniques, viz. Circular Dichroism, Fourier Transform Infrared Spectroscopy, and Atomic Force Microscopy substantiated these results. To achieve permeation of BSBP8 across the blood-brain barrier, the peptide was loaded onto poly D,L-lactide-co-glycolide nanoparticles (PLGA NPs). Compared to BSBP8 alone, the negatively charged (−8.96 ± 1.22 mV) spherical particles with a mean diameter of 223.2 ± 3.52 nm, loaded with BSBP8 (2.86 % w/w) permeated across the BBB formed by the Madin-Darby canine kidney cells. In vivo biodistribution profile indicated ∼9 %, 52 % and 20 % particle accumulation in the brain, liver, and kidney. Tissue retention of BSBP8-PLGA NPs was observed for at least seven days. It can be anticipated that this study will significantly promote the development of therapeutics for AD.