title: Heterobivalent agents targeting PSMA and integrin-αvβ3.
abstract: Differential expression of surface proteins on normal vs malignant cells provides the rationale for the development of receptor-, antigen-, and transporter-based, cancer-selective imaging and therapeutic agents. However, tumors are heterogeneous, and do not always express what can be considered reliable, tumor-selective markers. That suggests development of more flexible targeting platforms that incorporate multiple moieties enabling concurrent targeting to a variety of putative markers. We report the synthesis, biochemical, in vitro, and preliminary in vivo evaluation of a new heterobivalent (HtBv) imaging agent targeting both the prostate-specific membrane antigen (PSMA) and integrin-αvβ3 surface markers, each of which can be overexpressed in certain tumor epithelium and/or neovasculature. The HtBv agent was functionalized with either 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or the commercially available IRDye800CW. DOTA-conjugated HtBv probe 9 bound to PSMA or αvβ3 with affinities similar to those of monovalent (Mnv) compounds designed to bind to their targets independently. In situ energy minimization experiments support a model describing the conformations adapted by 9 that enable it to bind both targets. IRDye800-conjugated HtBv probe 10 demonstrated target-specific binding to either PSMA or integrin-αvβ3 overexpressing xenografts. HtBv agents 9 and 10 may enable dual-targeted imaging of malignant cells and tissues in an effort to address heterogeneity that confounds many cancer-targeted imaging agents.
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions , Baltimore, Maryland 21287, United States.
authors.forename: Hassan M
authors.initials: HM
authors.lastname: Shallal
authors.forename: Il
authors.initials: I
authors.lastname: Minn
authors.forename: Sangeeta R
authors.initials: SR
authors.lastname: Banerjee
authors.forename: Ala
authors.initials: A
authors.lastname: Lisok
authors.forename: Ronnie C
authors.initials: RC
authors.lastname: Mease
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
mesh_terms: D000954:Antigens, Surface / Q000737:chemistry*; D043425:Glutamate Carboxypeptidase II / Q000737:chemistry*; D039302:Integrin alphaVbeta3 / Q000737:chemistry*
chemical_list: D000954:Antigens, Surface; D039302:Integrin alphaVbeta3; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II