Abstract
One of the major design considerations for a drug is its pharmacokinetics in the blood. A drug with short half-life in the blood is less available at a target organ. Such a limitation dictates treatment with either high doses or more frequent doses, both of which may increase the likelihood of undesirable side effects. To address the need for additional methods to improve the blood half-life of drugs and molecular imaging agents, we developed an “add-on” molecule that contains three groups: (i) truncated Evans Blue (EB) dye molecule that binds to albumin with low micromolar affinity and provides prolonged half-life in the blood; (ii) a metal chelate that allows radiolabeling for imaging and radiotherapy; and (iii) a maleimide for easy conjugation to drug molecules. Methods: The truncated EB was conjugated with 1,4,7-triazacyclononane-triacetic acid (NOTA) or 1,4,7,10-tetraazacyclododecane-tetraacetic acid (DOTA) chelator and were denoted as NMEB and DMEB, respectively. As a proof-of-concept, we coupled NMEB and DMEB to c(RGDfK), which is a small cyclic arginine-glycine-aspartic acid (RGD) peptide for targeting integrin αvβ3. NMEB and DMEB were radiolabeled with 64Cu and 90Y, respectively, and tested in xenograft models. Results: The resulting radiolabeled conjugates showed prolonged circulation half-life and enhanced tumor accumulation in αvβ3-expressing tumors. Tumor uptake was markedly improved compared to NOTA or DOTA conjugated c(RGDfK). Tumor radiotherapy experiments in mice using 90Y-DMEB-RGD showed promising results and eliminated existing tumors. Conclusion: Conjugation of our novel “add-on” molecules, NMEB or DMEB, to potential tracers and/or therapeutic agents improves blood half-life and tumor uptake, and can transform such agents into theranostic entities.
- Animal Imaging
- Molecular Imaging
- Peptides
- Radionuclide Therapy
- Radiopharmaceuticals
- 90Y
- Evans blue
- RGD peptide
- integrin
- theranostics
- Copyright © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.