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Design of Nanoparticles that Cross the Blood-Brain Barrier by Receptor Mediated Transcytosis


Wiley, Devin Thomas (2013) Design of Nanoparticles that Cross the Blood-Brain Barrier by Receptor Mediated Transcytosis. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/DKRM-S631.


The primary objective of my thesis work is to establish a set of design criteria for nanoparticles whose purpose is to safely and efficiently access the brain after systemic injection. Nanoparticles that can access the brain may be able to deliver therapeutic molecules to the brain that otherwise would be excluded by the blood-brain barrier.

E. coli glycoprotein 96 (Ecgp96) is explored as a candidate receptor on the blood-brain barrier that could potentially facilitate nanoparticle-receptor mediated transcytosis into the brain. Results from studies utilizing PET/CT, SPECT/CT, MRI, Xenogen fluorescence imaging, and confocal microscopy conclude that Ecgp96 is observed in the blood-brain barrier endothelial cells, but is not accessible from the blood of adult or neonatal mice under normal, non-pathological conditions.

Transferrin receptor is a well-characterized receptor on the blood-brain barrier that is accessible from the blood and known to transcytose transferrin. I focused on this receptor and on synthesizing and characterizing a well-defined set of transferrin containing gold nanoparticles of various sizes and transferrin compositions that would be investigated during in-vivo studies. Nanoparticle sizes were measured by DLS and nanoparticle tracking analysis. Zeta potentials were also measured. Nanoparticle transferrin content was directly measured by labeling transferrin with 64Cu and measuring the nanoparticle associated gamma activity. The nanoparticle binding avidities to mouse transferrin receptors were ranked by a silver enhancement fluorescence-based method using the mouse Neruo2A cell line.

Each nanoparticle formulation was systemically injected into mice, and localization in the mouse brain was observed by silver enhancement light microscopy, and TEM. The quantitation of the gold was determined by ICP-MS. Nanoparticles with large amounts of transferrin remain strongly attached to brain endothelial cells, while nanoparticles with less transferrin are capable of both interacting with transferrin receptor on the luminal side of the blood-brain barrier and detaching from transferrin receptor on the brain side of the blood-brain barrier. These results highlight the fact that the nanoparticle avidity must be tuned to maximize the number of nanoparticles exiting the endothelial cells and entering the brain tissue. Lanthanum nitrate perfusion-fixation studies demonstrate that the nanoparticle formulations investigated do not degrade the blood-brain barrier integrity and enter the brain by transferrin receptor-mediated transcytosis. The results from these studies provide initial design criteria for creating nanoparticle therapeutics for delivery to the brain from systemic administrations.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Nanoparticle Transferrin Blood Brain Barrier Receptor Mediated Transcytosis
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemical Engineering
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Davis, Mark E.
Thesis Committee:
  • Davis, Mark E. (chair)
  • Flagan, Richard C.
  • Tirrell, David A.
  • Webster, Paul
Defense Date:1 May 2013
Non-Caltech Author Email:devinwiley (AT)
Funding AgencyGrant Number
NIHR01 NS071112
Record Number:CaltechTHESIS:03062013-145838327
Persistent URL:
Related URLs:
URLURL TypeDescription adapted for ch. 3
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:7498
Deposited By: Devin Wiley
Deposited On:15 May 2014 16:27
Last Modified:03 Oct 2019 23:59

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