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Delivery of Targeted Nanoparticles Across the Blood-Brain Barrier Using a Detachable Targeting Ligand

Citation

Clark, Andrew James (2016) Delivery of Targeted Nanoparticles Across the Blood-Brain Barrier Using a Detachable Targeting Ligand. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9WH2MZ6. http://resolver.caltech.edu/CaltechTHESIS:04282016-162609209

Abstract

Chronic diseases of the central nervous system are poorly treated due to the inability of most therapeutics to cross the blood-brain barrier. The blood-brain barrier is an anatomical and physiological barrier that severely restricts solute influx, including most drugs, from the blood to the brain. One promising method to overcome this obstacle is to use endogenous solute influx systems at the blood-brain barrier to transport drugs. Therapeutics designed to enter the brain through transcytosis by binding the transferrin receptor, however, are restricted within endothelial cells. The focus of this work was to develop a method to increase uptake of transferrin-containing nanoparticles into the brain by overcoming these restrictive processes.

To accomplish this goal, nanoparticles were prepared with surface transferrin molecules bound through various liable chemical bonds. These nanoparticles were designed to shed the targeting molecule during transcytosis to allow increased accumulation of nanoparticles within the brain.

Transferrin was added to the surface of nanoparticles through either redox or pH sensitive chemistry. First, nanoparticles with transferrin bound through disulfide bonds were prepared. These nanoparticles showed decreased avidity for the transferrin receptor after exposure to reducing agents and increased ability to enter the brain in vivo compared to those lacking the disulfide link.

Next, transferrin was attached through a chemical bond that cleaves at mildly acidic pH. Nanoparticles containing a cleavable link between transferrin and gold nanoparticle cores were found to both cross an in vitro model of the blood-brain barrier and accumulate within the brain in significantly higher numbers than similar nanoparticles lacking the cleavable bond. Also, this increased accumulation was not seen when using this same strategy with an antibody to transferrin receptor, indicating that behavior of nanoparticles at the blood-brain barrier varies depending on what type of targeting ligand is used.

Finally, polymeric nanoparticles loaded with dopamine and utilizing a superior acid-cleavable targeting chemistry were investigated as a potential treatment for Parkinson’s disease. These nanoparticles were capable of increasing dopamine quantities in the brains of healthy mice, highlighting the therapeutic potential of this design. Overall, this work describes a novel method to increase targeted nanoparticle accumulation in the brain.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Nanoparticle, therapeutic delivery, blood-brain barrier, systemic administration, in vivo
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Davis, Mark E.
Thesis Committee:
  • Heath, James R. (chair)
  • Beauchamp, Jesse L.
  • Shapiro, Mikhail G.
  • Davis, Mark E.
Defense Date:26 April 2016
Funders:
Funding AgencyGrant Number
National Institutes of HealthR01 NS0711121
National Cancer InstituteCA 151819
Record Number:CaltechTHESIS:04282016-162609209
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:04282016-162609209
DOI:10.7907/Z9WH2MZ6
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1517048112DOIArticle adapted for ch. 3
http://dx.doi.org/10.1073/pnas.1603018113DOIArticle adapted for Appendix A
ORCID:
AuthorORCID
Clark, Andrew James0000-0003-4240-7119
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:9689
Collection:CaltechTHESIS
Deposited By: Andrew Clark
Deposited On:05 May 2016 00:03
Last Modified:05 May 2016 00:03

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