This project will focus on proof-of-concept research applying Accelerator Mass Spectrometry (AMS) for low-level detection of complex nanomaterials in biological media. A successful project will enable major improvements in mechanistic studies of the fate and transport of complex engineered nanomaterials (ENMs as nanoparticles) in environmental, health and safety studies. AMS can separate rare isotopes with high selectivity and high sensitivity. In this proposal, complex ENMs are defined as nanoparticles with one material as their core and different surface-bound molecules (hereafter referred to as coatings) to assist their performance in applications. Complex ENM nanoparticles often agglomerate during environmental and biological testing, both the core and coating may be transformed by such exposures, and material balances need to be performed on both the core and coatings materials in order to properly interpret their transport and transformations over the product life cycles.

The research team has recently synthesized complex ENMs containing different rare isotopes in the core and the coating. Two pathways are proposed: 1) the synthesis and testing of a complex ENM system, an 26Al-labeled alumina core (Al2O3) with 14C-labeled coatings (citric acid), which will be tested at low dose levels in a rat model and 2) the synthesis and biodegradation evaluation of both a core material, 32Si-labeled mesoporous silica, and a coating material, 14C-labeled PLGA. Pathway 1 work will attempt to demonstrate the lower limits of detection of the AMS method, which is expected to be 103 to 109 times more sensitive that radioactivity detection. Pathway 2 work will provide an experimental system for explicit testing of degradable cores and coatings. As these rare isotopes (RI) can be detected near attomole levels using AMS, it should be possible to identify any changes in the molar ratios (coating RI/ENM RI) during dosing, cell uptake, coating by environmental chemicals, transformations in cell, or in the environment. Transformational testing will be done in another, follow-on, project.

Intellectual Merit: A successful study will develop rare isotope AMS, a method with high sensitivity and high selectivity, as a platform technology for measurement of complex ENM transformations in relevant media. AMS should be particularly valuable in determining the long-term fate of complex ENMs in biological and environmental media, especially if the ENMs are aggregated or agglomerated. These test systems will address ENM measurement infrastructure needs specified in the NNI 2011 EHS Research Strategy Needs report.

Broader Impact: A successful proposal will stimulate and support the development and dissemination of next-generation instrumentation and multiuser facilities, specifically, the application of AMS methods to EHS studies of nanomaterial toxicology. The investigators will continue their current activities in education and training, and will include the new methodology in EGR 780, Characterization of nanomaterials for medical applications, is a new course supporting our Cancer Nanotechnology Training Center, an 26Al-labeled NIH-funded program.

Project Report

Report Type: Project Outcomes PI: Eric Grulke Awardee: University of Kentucky Research Foundation Program Officer Name: Barbara Karn Program Officer Email: bkarn@nsf.gov Background Complex engineered nanoparticles (CENPs)[1], which have different core and surface components, are being developed for medicinal, pharmaceutical and industrial applications. Central to the understanding of the potential toxicological or beneficial effects of complex ENMs is where they go (distribution), how long they stay there (residence time/persistence), and are they transformed during these processes. Complex ENM nanoparticles often agglomerate during environmental and biological testing, both the core and coating may be transformed by such exposures, and material balances need to be performed on both the core and coating materials in order to properly interpret their transport and transformations over the product life cycles. Accelerator mass spectroscopy (AMS) can separate rare isotopes with high selectivity and high sensitivity, detecting such species at levels 103 to 109 times lower than other methods. AMS studies to measure coating and core components in biological and environmental milieu should permit us to answer such questions. This project intended to demonstrate the potential for tracking of both the core ENM and its surface coating (or a second component of a multi-component ENM) AMS, which is an exquisitely sensitive, highly selective, and precise analytical technique. Results This study reports the effects of in vivo exposure on citrate-coated nanoalumina with different rare isotope labels on each component. Dual-labeled CENPs were dosed to the rat and accelerator mass spectrometry (AMS) was used to quantify 26Al, 14C, and their ratio in the dosing material and tissue samples. For CENPs detected in the liver, the rare isotope ratio, 14C/26Al, was 88% of the dosing material’s ratio. The citrate coating on the nanoalumina in the liver was stable or, if it degraded, its metabolites were incorporated with nearby tissue. However, in brain and bone where little alumina was detected, this ratio greatly exceeded that of the dosing material (Figure 1). Therefore, in some biological environment(s), citrate dissociated from CENPs and redistributed to brain and bone. The methodology presents a new approach for characterizing transformations of complex engineered nanoparticle components in biological milieu or environments. Figure 1. % of 26Al dose and % of 14C/26Al (compared to dose) in three tissues. Intellectual Merit Our study has shown proof-of-concept for using rare isotope AMS, a method with high sensitivity and high selectivity, as a platform technology for measurement of complex ENM transformations in relevant media. AMS will be particularly valuable in determining the long-term fate for components of complex ENMs in biological and environmental media, even if the dose is aggregated or agglomerated. This measurement technology can help answer specific ENM measurement infrastructure needs as identified by NSTC[2]: · What are the effects of surface functionalization on ENM agglomeration? · What are the effects of surface functionalization on the long-term stability of agglomerates? · What surface functionalizations lead to reduced persistence via agglomeration? · What is the rate of agglomerate formation, long-term stability of agglomerates? The following manuscript, based on this EAGER research project, has been submitted: Broader Impact Reports of this project should stimulate and support the development and dissemination of next-generation instrumentation and multiuser facilities, specifically, the application of AMS methods to EHS studies of nanomaterial toxicology. Specific broader impacts include: 1) a chapter in the Ph.D. dissertation of Dr. Binghui Wang, successfully defended on November 22, 2013; 2) the synthesis of mesoporous silica with a visiting graduate student from Iraq (Muntadher Abdulabbas Hasan Al-Hilo, Dept. of Medical Biochemistry, Kufa University, Najafi, Iraq; chapter in his M.S. thesis under the direction of Prof. Hussein Kadhem Al-Hakeim), and 3) experiential training in nanoparticle characterization for Mr. Will Troske, a senior at Lafayette High School who started chemical engineering at the University of Michigan in the fall of 2013. [1] We define complex ENMs as nanoparticles with one material as their core and with different surface-bound molecules (hereafter referred to as coatings) to assist their performance in applications. [2] NSTC, National Nanotechnology Initiative. Environmental, Health, and Safety Research Strategy, E. Subcommittee on Nanoscale Science, and Technology, Editor. 2011, National Science and Technology Council. Committee on Technology Washington, DC. p. 138.

Project Start
Project End
Budget Start
2012-10-01
Budget End
2013-09-30
Support Year
Fiscal Year
2012
Total Cost
$49,894
Indirect Cost
Name
University of Kentucky
Department
Type
DUNS #
City
Lexington
State
KY
Country
United States
Zip Code
40526