Cellular Uptake and Toxicity of Dendritic Nanomaterials: An Integrated Physicochemical and Toxicogenomics StudyEPA Grant Number: R832525
Title: Cellular Uptake and Toxicity of Dendritic Nanomaterials: An Integrated Physicochemical and Toxicogenomics Study
Investigators: Diallo, Mamadou S. , Goddard, William A. , Riechmann, Jose Luis
Institution: California Institute of Technology , Howard University
EPA Project Officer: Carleton, James N
Project Period: November 1, 2005 through November 30, 2008
Project Amount: $375,000
RFA: Exploratory Research: Nanotechnology Research Grants Investigating Environmental and Human Health Effects of Manufactured Nanomaterials: A Joint Research Solicitation - EPA, NSF, NIOSH (2005) RFA Text | Recipients Lists
Research Category: Health Effects , Nanotechnology , Health , Safer Chemicals
Dendrimers are relatively monodisperse and highly branched nanoparticles that can be designed to (i) chelate metal ions, (ii) encapsulate metal clusters, (iii) bind organic solutes or bioactive compounds and (iv) become soluble in appropriate media or bind onto appropriate surfaces. Because of these unique properties, dendrimers are providing unprecedented opportunities to develop functional nanomaterials for a variety of applications including chemical separations and catalysis, chemical sensing, medical imaging, DNA/drug delivery and water purification. As the U.S. Environmental Protection Agency (EPA) begins its assessment of the impact of Nanotechnology on human health and the environment, there is a critical need of data and quantitative tools for assessing the environmental fate and toxicity of nanomaterials such as dendrimers. The overall objective of this project is to advance our fundamental understanding of the relationships between the affinity of ethylene diamine (EDA) core poly(amidoamine) PAMAM dendrimers to cell membranes and their vascular and ingestion toxicity using (i) n-octanol and solid-supported phosphatidylcholine lipid bilayers as model cell membranes and (ii) endothelial and kidney cells as model human cells.
To achieve this overall objective, we propose to implement an integrated physical-chemical and toxicogenomics study that combines: 1) dendrimer synthesis and characterization; 2) measurements of the octanol-water and liposomes-water partition coefficients of EDA core PAMAM dendrimers at physiological pH; 3) AFM imaging of dendrimer interactions with liposomes at physiological pH; 4) molecular dynamics (MD) simulations to determine the physical-chemical properties (e.g., size, shape, internal structure and extent of hydration, etc.) of EDA core PAMAM dendrimers in aqueous solutions at physiological pH; and 5) experimental characterization of the vascular and ingestion toxicity of dendrimers through in vitro measurements of cell viability and toxicogenomics studies of human endothelial and kidney cells exposed to aqueous solutions of dendrimers at physiological pH.
The successful completion of this project is expected to provide industry with critical data and predictive tools needed to assess the health and environmental impact of dendritic nanomaterials such as EDA core PAMAM dendrimers.