Codelivery of peptide therapeutics for polyglutamine diseases via polymeric nanoparticles

Abstract

Polyglutamine diseases refer to a group of neurodegenerative diseases caused by abnormal expansion of CAG trinucleotides. Peptide therapeutics named P3V8 and QBP1 have been developed to suppress the toxicity of the expanded CAG repeats, but face challenge in clinical administration due to their susceptibility to enzymatic degradation. By using polymeric nanoparticles as drug carriers, peptide therapeutics can be protected and stabilized, elongating the systemic circulation. Polymeric nanoparticles can also be functionalized with cell penetrating peptides or other ligands to assist cell membrane penetration. In this thesis, we report our results of developing and optimizing polymeric nanoparticles to co-encapsulate P3V8 and QBP1. By using different particle synthesis methods, we have developed nanoparticles of different size distribution, drug encapsulation efficiency, and drug release profile. In general, nanoparticles synthesized by double emulsion method created particles of around 150nm in diameter, with drug encapsulation efficiency of around 40% for both P3V8 and QBP1 and drug release profile in 0.1M acetate buffer of pH5.5 that evens out at around 20% after 48 hours. Nanoparticles synthesized with the lipid POPG by nanoprecipitation method created particles of around 300nm in diameter, with drug encapsulation efficiency close to 100% and drug release profile in 0.1M acetate buffer of pH5.5 that exceeds 40% after 48 hours. The nanoparticles were functionalized with octa-arginine and a combination of ligands (denoted “mix ligands”) to enable cell uptake. Using this functionalized nanoparticle, we observed cellular uptake using STED microscope. We also studied the in vitro therapeutic effect of our co-encapsulated nanoparticles and demonstrated significant cell rescue using mix ligands nanoparticles made by double emulsion or with POPG at pH3 and pH5.

Date of Award	2017
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology