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Superior Method of Preparing Dendrimers for Use as Magnetic Resonance Imaging (MRI) Contrast Agents

Posted Aug 10 2009 5:00pm

Description of Invention:
There is a need to develop more efficient gadolinium-containing (Gd) contrast agents for magnetic resonance imaging (MRI) as the small molecules presently used clinically have the disadvantage of being rapidly cleared from circulation and excreted by the kidneys.

Dendrimer-based macromolecular MRI contrast agents in which numerous chelated Gd ions are covalently attached to a multivalent dendritic architecture are a promising class of diagnostic agents for medical imaging applications. Clinical development of the dendrimer-based agents has been limited as the current methods for synthesizing them result in a complex mixture that produces inconsistent imaging results.

The present technology describes the development of a new method of pre-forming the metal-ligand chelate in alcohol prior to conjugation to the dendrimer. Specifically, for example, a 1B4M-DTPA-Gd chelate is preformed in methanol and purified prior to conjugation to a PAMAM dendrimer molecule. This results in a dendrimer-based MRI contrast agent with greatly improved homogeneity and stability, and possessing an unexpectedly greater molar relaxivity that allows the use of much less of the agent than previously required to obtain comparable images. The use of a DOTA-Gd chelate is equally possible.

Applications:
An improved method for synthesis of dendrimer-based MRI contrast agents that is greatly suited for clinical development.

Advantages:
  • Efficient preparation of stable dendrimer-based contrast agents suitable for medical imaging
  • Higher molar relaxivity translates into a lower dosage needed for imaging
  • Ability to control dendrimer size conducive for development of compartment-specific imaging agents


Inventors:
Kido Nwe (NCI)
Martin W Brechbiel (NCI)


Relevant Publication:
  1. K Nwe, H Xu, CA Regino, M Bernardo, L Ileva, L Riffle, KJ Wong, MW Brechbiel. A new approach in the preparation of dendrimer-based bifunctional diethylenetriaminepentaacetic acid MR contrast agent derivatives. Bioconjugate Chem. 2009 Jul;20(7):1412-1418. [ PubMed abs ]
  2. OA Gansow, MW Brechbiel, MA Magerstadt. Complexes of functionalized tetraazacyclododecane chelates with bismuth, lead, yttrium, actinium, or lanthanide metal ions. U.S. Patent 5,428,154 issued 27 Jun 1995.


Licensing Status:
Available for licensing.

Collaborative Research Opportunity:
The Inorganic & Radioimmune Chemistry Section, ROB, CCR, NCI is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize macromolecular (dendrimer-based) MR contrast agents as well as multi-modality analogs. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.


Portfolios:
Devices/Instrumentation
Devices/Instrumentation - Diagnostics
Cancer
Cancer - Diagnostics
Internal Medicine
Internal Medicine - Diagnostics
Nanotechnology



For Additional Information Please Contact:
Surekha Vathyam Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Email: vathyams@mail.nih.gov
Phone: 301-435-4076
Fax: 301-402-0220


Ref No: 2001

Updated: 08/2009

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