Heterobivalent agents targeting PSMA and integrin- αvβ3

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)393-405
Number of pages13
JournalBioconjugate Chemistry
Volume25
Issue number2
DOIs
StatePublished - Feb 19 2014

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

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