New Ligands for Radioimmunotherapy and MRI of Cancer

Summary

Principal Investigator: Hyun Soon Chong
Abstract: The development of the adequate ligands to effectively hold metals is a critical step for enhancing the efficacy of radioimmunotherapy (RIT) and magnetic resonance imaging (MRI). The long-term objective of the proposed research is to develop clinically viable ligands that have direct applications in two cancer research fields, RIT and MRI. In the current proposal we will focus our effort on two specific aims regarding the design of macrocyclic ligands that may address the pressing needs for active clinical exploration of RIT and MRI. The first specific aim is to explore a bimodal binding approach to generate better bifunctional ligands to efficiently bind promising radionuclides for use in RIT. This aim is based on the hypothesis that the cooperative binding using both a macrocyclic cavity and an acyclic pendant binding group may provide enhanced kinetics in metal complexation while maintaining a high level of complex stability. Our preliminary data indicate that one of the new ligands, NOETA binds Y-86, an important radioactive metal for RIT for the first time, with excellent kinetics and in vivo stability. We will further test the bimodal binding approach by preparing bifunctional ligands for RIT applications, and by evaluating complexation kinetics and thermodynamics of the bifunctional ligands with a variety of radioactive metals for RIT such as Y-90, Bi-213 and Ac-225. The second specific aim is to investigate how incorporation of naturally occurring steroid(s) into the conventional contrast agent affects criteria of tumor-specific MR contrast agents, i.e., high and extended signal intensity, in vivo stability, good cell permeation, complete clearance, and high target specificity. This aim is based on the hypothesis that a steroid moiety incorporated into the conventional MR contrast agent promotes non-covalent interactions between the steroid transporters and the conjugated contrast construct. The new ligand NOETA also has shown MR signal intensity, and in vivo stability comparable to the clinically approved non-specific MRI agents. Using this ligand as a scaffold, we will investigate the potential of the attached steroid as a tumor targeting vector of tumor-specific MR contrast agents. The results of the proposed research will contribute to the development of better drugs for both MRI and RIT, which will greatly enhance clinical exploration of both modalities, and directly benefit cancer patients.
Funding Period: 2004-09-23 - 2008-08-31
more information: NIH RePORT

Top Publications

  1. pmc Rational design and generation of a bimodal bifunctional ligand for antibody-targeted radiation cancer therapy
    Hyun Soon Chong
    Chemistry Division, Biological, Chemical, and Physical Sciences Department, Illinois Institute of Technology, Chicago, Illinois 60616, USA
    J Med Chem 51:118-25. 2008
  2. pmc Synthesis and evaluation of a bifunctional chelate for development of Bi(III)-labeled radioimmunoconjugates
    Mamta Dadwal
    Chemistry Division, Biological, Chemical, and Physical Sciences Department, Illinois Institute of Technology, 3101 S Dearborn St, LS 182, Chicago, IL 60616, USA
    Bioorg Med Chem Lett 21:7513-5. 2011
  3. ncbi A novel cholic acid-based contrast enhancement agent for targeted MRI
    Hyun Soon Chong
    Chemistry Division, Biological, Chemical, and Physical Sciences Department, Illinois Institute of Technology, 3101 S Dearborn St, LS 182, Chicago, IL 60616, USA
    Bioorg Med Chem Lett 18:2505-8. 2008
  4. ncbi Efficient synthesis and evaluation of bimodal ligand NETA
    Hyun Soon Chong
    Chemistry Division, Biological, Chemical, and Physical Sciences Department, Illinois Institute of Technology, 3101 S Dearborn Street, LS 182, Chicago, IL 60616, USA
    Bioorg Med Chem Lett 18:3436-9. 2008
  5. pmc Novel bimodal bifunctional ligands for radioimmunotherapy and targeted MRI
    Hyun Soon Chong
    Chemistry Division, Biological, Chemical, and Physical Sciences Department, Illinois Institute of Technology, Chicago, Illinois 60616, USA
    Bioconjug Chem 19:1439-47. 2008

Scientific Experts

  • Hyun Soon Chong
  • Mamta Dadwal
  • Chi Soo Kang
  • Martin W Brechbiel
  • Hyun A Song
  • Xiang Sun
  • Kwamena E Baidoo
  • Anzhi Dai

Detail Information

Publications5

  1. pmc Rational design and generation of a bimodal bifunctional ligand for antibody-targeted radiation cancer therapy
    Hyun Soon Chong
    Chemistry Division, Biological, Chemical, and Physical Sciences Department, Illinois Institute of Technology, Chicago, Illinois 60616, USA
    J Med Chem 51:118-25. 2008
    ..C-NETA rapidly binds both Lu(III) and Bi(III), and the respective metal complexes remain extremely stable in serum for 14 days. (177)Lu -C-NETA and (205/6)Bi -C-NETA possess an excellent or acceptable in vivo biodistribution profile...
  2. pmc Synthesis and evaluation of a bifunctional chelate for development of Bi(III)-labeled radioimmunoconjugates
    Mamta Dadwal
    Chemistry Division, Biological, Chemical, and Physical Sciences Department, Illinois Institute of Technology, 3101 S Dearborn St, LS 182, Chicago, IL 60616, USA
    Bioorg Med Chem Lett 21:7513-5. 2011
    ..The in vitro radiolabeling kinetics and serum stability data suggest that C-DEPA is a potential chelate for preclinical RIT applications using (212)Bi and (213)Bi...
  3. ncbi A novel cholic acid-based contrast enhancement agent for targeted MRI
    Hyun Soon Chong
    Chemistry Division, Biological, Chemical, and Physical Sciences Department, Illinois Institute of Technology, 3101 S Dearborn St, LS 182, Chicago, IL 60616, USA
    Bioorg Med Chem Lett 18:2505-8. 2008
    ..The new cholic acid-conjugated nanoparticle MR contrast enhancement agent, Gd(CA-NE3TA) possesses great promise for use in targeted MRI...
  4. ncbi Efficient synthesis and evaluation of bimodal ligand NETA
    Hyun Soon Chong
    Chemistry Division, Biological, Chemical, and Physical Sciences Department, Illinois Institute of Technology, 3101 S Dearborn Street, LS 182, Chicago, IL 60616, USA
    Bioorg Med Chem Lett 18:3436-9. 2008
    ..The structure of NETA was determined by X-ray crystallography. The arsenazo-based UV spectroscopic complexation kinetics data suggest that NETA is a promising chelator for use in RIT applications of (212)Bi, (213)Bi, and (177)Lu...
  5. pmc Novel bimodal bifunctional ligands for radioimmunotherapy and targeted MRI
    Hyun Soon Chong
    Chemistry Division, Biological, Chemical, and Physical Sciences Department, Illinois Institute of Technology, Chicago, Illinois 60616, USA
    Bioconjug Chem 19:1439-47. 2008
    ..C-NETA and C-NE3TA were further modified for conjugation to the monoclonal antibody Trastuzumab...