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[P2], 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[P2] in nanoparticles. In vitro release kinetics demonstrates that nanoparticles release PGQ9[P2] by erosion and diffusion processes. When the PGQ9[P2]-loaded nanoparticles are incubated with aggregation-prone Q35P10 peptide, representing N-terminal part of Huntingtin protein, it arrests the elongation phase of Q35P10 aggregation. These findings propose the first step toward delivery of a peptide inhibitor against polyglutamine aggregation in HD. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.
The nanoparticulate drug-delivery system was developed for a novel peptide inhibitor ‘PGQ9[P2]’. The in vitro characterization confirmed uniform and narrow distribution of particles below 200 nm with high entrapment of peptide. When PGQ9[P2]-loaded nanoparticles were incubated with aggregating peptide Q35P10 that represents N-terminus of Huntingtin, the released PGQ9[P2] suppressed its aggregation. These results indicate a progressive step toward the delivery of peptide inhibitor for therapeutic development in Huntington's disease.