title: Novel "Add-On" Molecule Based on Evans Blue Confers Superior Pharmacokinetics and Transforms Drugs to Theranostic Agents.
abstract: One of the major design considerations for a drug is its pharmacokinetics in the blood. A drug with a 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 3 groups: a truncated Evans blue dye molecule that binds to albumin with a low micromolar affinity and provides a prolonged half-life in the blood; a metal chelate that allows radiolabeling for imaging and radiotherapy; and maleimide for easy conjugation to drug molecules.Methods:The truncated Evans blue molecule was conjugated with the chelator NOTA or DOTA, and the resulting conjugate was denoted as NMEB or 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 αvβ3NMEB and DMEB were radiolabeled with64Cu and90Y, respectively, and tested in xenograft models.Results:The resulting radiolabeled conjugates showed a prolonged circulation half-life and enhanced tumor accumulation in integrin αvβ3-expressing tumors. Tumor uptake was markedly improved over that with NOTA- or DOTA-conjugated c(RGDfK). Tumor radiotherapy experiments in mice with90Y-DMEB-RGD showed promising results; existing tumors were eliminated.Conclusion:Conjugation of our novel add-on molecule, NMEB or DMEB, to potential tracers or therapeutic agents improved blood half-life and tumor uptake and could transform such agents into theranostic entities.
authors.affiliation: Department of Nuclear Medicine, Xiamen Cancer Hospital of the First Affiliated Hospital of Xiamen University, Xiamen, China.|Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Haojun
authors.initials: H
authors.lastname: Chen
authors.affiliation: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Orit
authors.initials: O
authors.lastname: Jacobson
authors.affiliation: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Gang
authors.initials: G
authors.lastname: Niu
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Ido D
authors.initials: ID
authors.lastname: Weiss
authors.affiliation: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Dale O
authors.initials: DO
authors.lastname: Kiesewetter
authors.affiliation: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Nuclear Medicine, Xiamen Cancer Hospital of the First Affiliated Hospital of Xiamen University, Xiamen, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wu
authors.affiliation: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland; and shawn.chen@nih.gov.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes; D005070:Evans Blue / Q000737:chemistry*; D015972:Gene Expression Regulation, Neoplastic; D006571:Heterocyclic Compounds / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000627:therapeutic use
chemical_list: D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D005070:Evans Blue; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid; C047981:arginyl-glycyl-aspartic acid
keywords: 90Y; Evans blue; RGD peptide; albumin binding; integrin; theranostics