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Pharmacological behavior of systemically administered nanoparticles of defined properties : mechanistic investigations at the organ, tissue, and cellular levels

Citation

Choi, Chung Hang Jonathan (2011) Pharmacological behavior of systemically administered nanoparticles of defined properties : mechanistic investigations at the organ, tissue, and cellular levels. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:02162011-153857988

Abstract

The objective of this thesis is to establish design rules for nanoparticle properties that enable their in vivo transport to target destinations. Gold nanoparticles containing surface-engrafted polyethylene glycol (PEG) chains are prepared with controlled physicochemical properties (hydrodynamic size, surface charge, targeting ligand density). Upon systemic injection into mice, the transport of nanoparticles is monitored by blood pharmacokinetics as well as distribution at the organ, tissue, and subcellular levels from the same injection in an individual animal. At a constant, slightly negative surface charge (ca. -10 mV), most PEGylated gold nanoparticles (PEG-AuNPs) deposit in the liver, spleen, and kidney of normal mice 24 hours after injection. Increasing retention in the liver (Kupffer cells) and spleen correlate positively with increasing nanoparticle diameter over the range of 25-165 nm, largely due to phagocytic uptake. Accumulation in the kidney is size-dependent, but shows a maximum uptake at ca. 75 ± 25 nm that also gives the highest deposition in the mesangium (uptake by mesangial cells). Tumor-bearing mice received injections of PEG-AuNPs of near-constant size (ca. 75 nm) and surface charge (ca. -10 mV) but with variable amounts of ligands that target cancer cells (0-144 ligands per nanoparticle). Independent of ligand content, nanoparticles accumulate in the tumor by the enhanced permeation and retention effect to the same magnitude, and adjacent to leukocytes. Nanoparticles only enter cancer cells in significant amounts when they contain targeting ligands above a threshold amount (between 18 and 144 ligands per nanoparticle). Mechanistic studies from model nanoparticles provide insights for the delivery of therapeutic nanoparticles. Systemic administrations of targeted, cyclodextrin-based, siRNA-containing nanoparticles are investigated in animals and humans (Phase I clinical trial). A fluorescent chemical stain with exposed adamantane molecules for binding into the cyclodextrin cups of the targeted nanoparticles is created, allowing for the examination of tumor tissue sections from animals and patient biopsies. Results from both animal and human tissues reveal intracellular, dose-dependent accumulation of targeted nanoparticles in cancer cells of the tumor.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:drug delivery; gold nanoparticles; cancer; imaging
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemical Engineering
Awards:Constantin G. Economou Memorial Prize, 2008 ; AIChE Bionanotechnology Graduate Student Award (2nd Prize), 2010
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Davis, Mark E.
Thesis Committee:
  • Brady, John F.
  • Wang, Zhen-Gang
  • Webster, Paul
  • Davis, Mark E. (chair)
Defense Date:26 April 2011
Funders:
Funding AgencyGrant Number
National Cancer InstituteCA 119347
National Institute of HealthR01 EB004657
National Institute of Health2P30DC006272-06
Record Number:CaltechTHESIS:02162011-153857988
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:02162011-153857988
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:6245
Collection:CaltechTHESIS
Deposited By: Chung Hang Choi
Deposited On:17 May 2011 23:08
Last Modified:12 Dec 2014 18:22

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