Functional Protein Delivery Using Polymeric Nanoparticles: A Novel Therapeutic Approach to Alpha-Synuclein Aggregation and Parkinson's Disease

An efficient route for delivering specific proteins and peptides into neurons could greatly accelerate the development of therapies for various diseases, especially those involving intracellular defects such as Parkinson's disease (PD). Synthetic nanoparticles made from polybutylcyanoacrylate (PBCA) have been previously shown to deliver otherwise impermeable drugs to therapeutic levels in vivo across the blood-brain barrier (BBB). It was not yet known, however, whether such particles could also be taken up by neurons and other brain cells. Here we report the novel use of polybutylcyanoacrylate nanoparticles (NPs) for delivery of intact, functional proteins into neurons and neurogenic cell lines. Uptake of these particles is primarily dependent on endocytosis via the low-density lipoprotein receptor. The nanoparticles are rapidly turned over and display minimal toxicity to cultured neurons. Delivery of three different functional cargo proteins is demonstrated. When primary neuronal cultures are treated with recombinant E. coli beta-galactosidase as nanoparticle cargo, persistent enzyme activity is measured beyond the period of nanoparticle degradation. Delivery of the small GTPase rhoG induces neurite outgrowth and differentiation in PC12 cells. In addition, a monoclonal antibody (H3C) directed against the C-terminus of synuclein is capable of interacting with endogenous alpha-synuclein (alpha-syn) in neurons following transport via polybutylcyanoacrylate NPs.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Cell and Developmental Biology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2014

Author dc:creator

• Hasadsri, Linda

Contributors dc:contributor

• Clayton, David F.
• George, Julia M.

• Biology, Neuroscience
• Biology, Cell
• Engineering, Biomedical

Identifier

(UMI)AAI3337786

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/72484