RPG Student List

 

Teng FENG

Doctor Candidate in Chemical and Biomolecular Engineering

Supervisor: Prof. Ying CHAU

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Research Topic

Polymeric Nanoparticles for Co-delivery of Peptidyl Inhibitors into the Central Nervous System

Abstract

The treatment of certain central nervous system (CNS) diseases is limited by inadequate delivery efficiency and non-specific tissue distribution of the therapeutic drugs. Before entering the targeted brain regions, therapeutics targeting the brain need to first cross the biological barriers separating the blood and the brain parenchyma, in particular the blood-brain barrier (BBB) composed of endothelial cells with tight junctions. One of the approaches is to use drug-loaded polymeric nanoparticles with covalently modified peptide ligands that can be recognized by receptors and transporters on BBB and certain brain compartments. Therapeutic drugs will be physically encapsulated inside the nanoparticles, which serves as a shell that can protect the encapsulated therapeutics from rapid clearance by kidneys and enzymatic degradation in blood circulation; this can increase the circulation half-life of the therapeutic drug inside the body. Poly(ethylene glycol)-block-poly(caprolactone) (PEG-b-PCL) and poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-b-PEG) are chosen as the block copolymers used in this project, since PEG, PCL, and PLGA are FDA-approved, have good biocompatibility, and are biodegradable. PCL exhibits faster degradation rate in acidic environment than in physiological pH, therefore once entering the cell, release of therapeutic drugs from PEG-b-PCL nanoparticles will be accelerated. PLGA can have tunable degradation and release rate by varying the ratio of hydrophobic PLA to hydrophilic PGA blocks. Peptide ligands modified to the nanoparticles are selected based on three categories: peptides that can enhance BBB crossing, peptides that can target specific receptors and transporters on certain brain tissues to increase regional uptake, and cell-penetrating peptides that can transport cargos across the cell membrane to achieve intracellular delivery. The polymeric nanoparticles will be prepared via double emulsion. After encapsulating the peptidyl inhibitors in the polymeric nanoparticles modified with peptide ligands, they can be co-delivered into the CNS and to specific brain regions. Release of the peptidyl inhibitors will be examined both in vitro and in vivo. It is expected that tunable release of the peptidyl inhibitors can also be manipulated by varying polymer composition as well as certain processing parameters and conditions. The mechanism and effect of peptide ligands to enhance BBB crossing and uptake at cellular and tissue levels will also be evaluated both in vitro and in vivo.