Biodegradable delivery system containing a peptide inhibitor of polyglutamine aggregation: a step toward therapeutic development in Huntington's disease

Abstract

Huntington's and eight other neurodegenerative diseases occur because of CAG repeat expansion mutation culminating into an expanded polyglutamine tract in respective protein. In Huntington's disease (HD), a number of CAG repeats beyond normal repeat length (>36) lead to the formation of mutant protein, the proteolytic cleavage of which induces aggregation in polyglutamine length-dependent manner. The neurodegeneration in this disease is linked to aggregation, and its inhibition is a potential approach for therapeutic development. Although peptides and other molecules have been developed for inhibiting aggregation, peptides in general are susceptible to degradation in vivo conditions. To understand their clinical significance, they also need to be delivered through blood-brain barrier. Here, for the first time, we have synthesized poly-d,l-lactide-co-glycolide nanoparticles containing a polyglutamine aggregation inhibitor peptide PGQ9 [P(2) ], by nanoprecipitation method. This process yielded less than 200 nm spherical nanoparticles with uniform distribution. Characterization studies by infrared spectroscopy-based and HPLC-based assays show the presence of PGQ9 [P(2) ] in nanoparticles. In vitro release kinetics demonstrates that nanoparticles release PGQ9 [P(2) ] by erosion and diffusion processes. When the PGQ9 [P(2) ]-loaded nanoparticles are incubated with aggregation-prone Q35 P10 peptide, representing N-terminal part of Huntingtin protein, it arrests the elongation phase of Q35 P10 aggregation. These findings propose the first step toward delivery of a peptide inhibitor against polyglutamine aggregation in HD.

Inhibition of polyglutamine aggregation by SIMILAR huntingtin N‐terminal sequences: Prospective molecules for preclinical evaluation in Huntington's disease

“…These inhibitors can be tested now in cell and animal models for their potential to prevent huntingtin aggregation. Furthermore, they can be evaluated for their therapeutic potential in HD animal models by nanoparticle‐based delivery approaches to brain . They can also be utilized as chemical tools for deciphering aggregation pathways in animal and cell models of HD.…”

“…Furthermore, they can be evaluated for their therapeutic potential in HD animal models by nanoparticle-based delivery approaches to brain. [80,81] They can also be utilized as chemical tools for deciphering aggregation pathways in animal and cell models of HD.…”

Deciphering the mechanism and structural features of polysorbate 80 during adsorption on PLGA nanoparticles by attenuated total reflectance – Fourier transform infrared spectroscopy

“…The results obtained from dynamic light scattering shows uniform size distribution and comply with our previously reported data. 34…”

“…The hydrophobic PLGA polymer is soluble in various organic solvents like acetone, acetonitrile, dimethylformamide in which PVA remains insoluble. 34,51,52 Taking advantage of differential solubility of two polymeric phases, PVA and PLGA were separated in subsequent steps as described in Scheme 1. At the end, the surfactant present in aqueous solution was analyzed with FTIR.…”

Biocompatible Inhibitor Based on Chitosan and Amphiphilic Peptide against Mutant Huntingtin Toxicity

“…On the other hand, others developed a preventive strategy by using an inhibitor or presymptomatic intervention. Along this line, peptides such as QBP1, PGQ 9 [P 2 ], β‐hairpin structure peptide, and chaperone‐like N ‐methyl peptide have been reported . In addition, small molecules such as Hum ‐NT 1 variant or analogue, DNA aptamer, isomerase, phosphorodiamidate morpholino oligomers, small heat shock protein, HSP40 gene, and chaperone‐mediated autophagy have also been utilized.…”