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Dendrimer Conjugates Targeting Adenosine Receptors, P2Y Receptors and Other Receptors of the GPCR Superfamily, for Use in the Tr

Posted Mar 22 2009 5:00pm

Description of Invention:
Available for licensing and commercial development are conjugate compositions useful in the treatment of a variety of diseases, comprising a dendrimer and a ligand. The ligand is a functionalized congener of an agonist or antagonist of a receptor of the G-protein coupled receptor (GPCR) superfamily. More specifically, the invention focuses on several agonists and antagonists of A1, A2A, A2B, and A3 adenosine receptors and P2Y receptors, all members of the GPCR superfamily. For example, an agonist of the A1 adenosine receptor is useful for treating a number of diseases including neurodegeneration, stroke, epilepsy, and pain. Antithrombotic treatment is another example of the use of this dendrimer technology. Dendrimers are polymers made from branched monomers through the iterative organic synthesis by adding one layer at each step to provide a symmetrical structure. Certain drugs, such as taxol, cisplatin, methotrexate, and ibuprofen, have been covalently linked to dendrimers in a reversible fashion. However, dendrimer conjugates in this application are biologically active without cleavage of the drug or cellular uptake. The conjugate of the invention can include any suitable dendrimer, particularly a poly(amidoamine) (PAMAM) dendrimer. The invention further provides pharmaceutical compositions and methods of treating various diseases and diagnostic methods employing such conjugates.

  • Treatment of a number of diseases involving receptors of the GPCR superfamily.
  • Determination of a potential treatment of a patient with an agonist or antagonist or receptors of the GPCR superfamily.

The dendrimer conjugates described in this invention have one or more advantages over corresponding monomeric drugs, including altered pharmacokinetics, decreased toxicity, increased solubility, enhanced potency or selectivity due to the multivalency.

Development Status:
The development is still in the early stages.

Kenneth A Jacobson (NIDDK)

Patent Status:
HHS, Reference No. E-219-2007/0
US, Application No. 60/947,121 filed 29 Jun 2007
US, Application No. 12/143,451 filed 20 Jun 2008 , which published as US 20090012035 on 08 Jan 2009

Relevant Publication:
  1. Y Kim, B Hechler, A Klutz, C Gachet, KA Jacobson. Toward multivalent signaling across G protein-coupled receptors from poly(amidoamine) dendrimers. Bioconjug Chem. 2008 Feb;19(2):406-411. [ PubMed abs ]
  2. Y Kim, AM Klutz, KA Jacobson. Systematic investigation of polyamidoamine dendrimers surface-modified with poly(ethylene glycol) for drug delivery applications: Synthesis, characterization, and evaluation of cytotoxicity. Bioconjug Chem. 2008 Aug;19(8):1660-1672. [ PubMed abs ]
  3. Y Kim, AM Klutz, B Hechler, ZG Gao, C Gachet, KA Jacobson. Application of the functionalized congener approach to dendrimer-based signaling agents acting through A2A adenosine receptors. Purinergic Signal. 2009 Mar;5(1):39-50.
  4. AA Ivanov and KA Jacobson. Molecular modeling of a PAMAM-CGS21680 dendrimer bound to an A2A adenosine receptor homodimer. Bioorg Med Chem Lett. 2008 Aug 1;18(15):4312-4315. [ PubMed abs ]
  5. AM Klutz, ZG Gao, J Lloyd, A Shainberg, KA Jacobson. Enhanced A3 adenosine receptor selectivity of multivalent nucleoside-dendrimer conjugates. J Nanobiotechnol. 2008 Oct 23;6:12. [ PubMed abs ]

Licensing Status:
Available for licensing.

Collaborative Research Opportunity:
The Laboratory of Bioorganic Chemistry of the National Institute of Diabetes & Digestive & Kidney Diseases is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize dendrimer conjugates of suitably functionalized small molecule ligands of adenosine receptors and P2Y nucleotide receptors. Please contact Dr. Kenneth A. Jacobson at 301-496-9024, or email , for more information.

Internal Medicine
Internal Medicine - Diagnostics
Internal Medicine - Therapeutics

For Additional Information Please Contact:
Cristina Thalhammer-Reyero Ph.D., M.B.A.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325 Room 33,
Rockville, MD 20852
United States
Phone: 301-435-4507
Fax: 301-402-0220

Ref No: 1903

Updated: 03/2009

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