Affordable Access

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

Authors
Publication Date
Disciplines
  • Chemistry
  • Design
  • Medicine
  • Pharmacology

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.

There are no comments yet on this publication. Be the first to share your thoughts.