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Chemical Characterization of Nanomaterial Formulations for Cancer Treatment in Support of the NCI Nanotechnology Characterization Laboratory

Summary:


New generations of nanoparticles are being developed to provide early-stage detection and treatment of cancer. Much of the evaluative work on these systems is being conducted by the Nanotechnology Characterization Laboratory (NCL) of the National Cancer Institute (NCI). In a cooperative effort with NCL, NIST is supporting this program by providing research tools and analytical methodology for the measurement of some of the critical species of interest. The NIST program with NCI NCL is coordinated by the Ceramics Division in MML.

Description:


Recent technological advances in the manufacture of nanoparticles containing specialized drug delivery and imaging pharmaceuticals has opened up new areas for the effective management of disease. Among these are medical products that offer promise for better diagnosis and treatment of tumors. One such product is Aurimune, a drug delivery system which consists of recombinant human tumor necrosis factor (TNF) surface bound along with PEG-Thiol to colloidal gold nanoparticles. This permits the delivery of TNF without immune system interference at much higher systemic clinical concentrations than previously attainable. Another area of clinical research interest is the early-stage detection of tumors using imaging pharmaceuticals. Gadolinium is one of the more successful metal ions that have been used in contrast agents, since it has a large number of unpaired electrons that show up well in magnetic resonance imaging (MRI) systems. However, free gadolinium is toxic, so gadolinium-based contrast agents generally consist of a gadolinium-ligand complex to improve acute tolerance. Several gadolinium chelates have been approved by the Food and Drug Administration (FDA) and are commercially available. 

The Nanotechnology Characterization Laboratory (NCL) is a technological center of the National Cancer Institute (NCI), a federally funded research and development organization within the National Institutes of Health (NIH). The NCL has responsibility for providing many critical infrastructure and characterization services with the objective of accelerating the development and application of in-vitro nano-devices for the diagnosis and treatment of cancer. This includes pre-clinical toxicology studies together with in-vivo and in-vitro characterization, pharmacokinetics, and dose-response relationships. A critical component of these studies is the accurate chemical characterization of some of the significant bioactive agents, especially in view of their potential toxicity. To support this program, a joint collaborative program has been initiated between NCL, NIST, and the FDA, which is intended to facilitate a rapid deployment of effective drug systems.

Additional Technical Details:


Research is being conducted to develop new analytical methods for the accurate determination of target analytes in pharmaceutical preparations, and samples derived from in-vivo formulation testing studies. This requires the effective combination of a wide array of different analytical techniques and expertise. At present the main focus areas of research are the development of methods for gadolinium speciation in complexed contrast agents, and the determination of gold, TNF, and PEG-Thiol in drug formulations. Two methods have been developed for the simultaneous, quantitative determination of free and complexed gadolinium in the presence of emulsifiers, surfactants, biomarkers, and oils in a nano-emulsion-based MRI contrast agent formulation. In this formulation, diethylenetriamine penta-acetic acid-phosophatidylethanolamine (DTPA-PE) is used as the chelating agent for gadolinium. The first analytical method utilizes coupled reversed-phase chromatography and fluorescence detection, where the chelator, ethylenediaminetetracetic acid (EDTA), is added to the aqueous mobile phase to bind any free gadolinium. A second method uses size exclusion chromatography coupled to online isotope dilution inductively coupled plasma mass spectrometry (ID-ICP-MS) to quantify free gadolinium. While the quantification of gold in nanomaterial formulations and clinical samples is relatively straightforward by quadrupole ICP-MS, the measurement of PEG-Thiol and TNF is much more challenging. Research is presently underway to develop suitable methods for these species. One approach being explored is the quantitative measurement of PEG-Thiol by means of the sulfur group using high-resolution sector field ICP-MS. 

Major Accomplishments:

  • Development of high-accuracy analytical methods for the determination of total and speciated gadolinium in nanomaterial formulations.
  • Development of analytical methods for determination of gold nanoparticle distribution in blood and tissue samples.
  • Preparation of two analytical protocols for gold nanoparticle measurements.

Start Date:

February 1, 2007

End Date:

Ongoing

Lead Organizational Unit:

mml

Customers/Contributors/Collaborators:

Staff:

Lee L. Yu
Karen W. Phinney
Michael R. Winchester
Karen E. Murphy
Danielle Cleveland
Laura J. Wood

Contact

Stephen E. Long
Phone 301-975-4101
stephen.long@nist.gov

Lane C. Sander
Phone 301-975-3117
lane.sander@nist.gov

Gregory C. Turk
Phone 301-975-4118
gregory.turk@nist.gov

Stephen A. Wise
Phone 301-975-3112
stephen.wise@nist.gov