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Molecular Imaging of bcl-2 Expression in Small Lymphocytic Lymphoma Using ¹¹¹In-Labeled PNA–Peptide Conjugates

¹ Department of Veterinary Medicine and Surgery, University of Missouri-Columbia, Columbia, Missouri; ² Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri; ³ Molecular Biology Program, University of Missouri-Columbia, Columbia, Missouri; ⁴ Department of Biochemistry, University of Missouri-Columbia, Columbia, Missouri; ⁵ Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri; ⁶ Department of Internal Medicine, University of Missouri-Columbia, Columbia, Missouri; ⁷ Department of Radiology, University of Missouri-Columbia, Columbia, Missouri; and ⁸ Nuclear Science and Engineering Institute, University of Missouri-Columbia, Columbia, Missouri

Correspondence: For correspondence or reprints contact: Michael R. Lewis, PhD, Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, 900 E. Campus Dr., University of Missouri-Columbia, Columbia, MO 65211. E-mail: LewisMic{at}missouri.edu

The bcl-2 gene is overexpressed in non-Hodgkin's lymphoma (NHL), such as small lymphocytic lymphoma (SLL), and many other cancers. Noninvasive imaging of bcl-2 expression has the potential to identify patients at risk for relapse or treatment failure. The purpose of this study was to synthesize and evaluate radiolabeled peptide nucleic acid (PNA)-peptide conjugates targeting bcl-2 gene expression. An ¹¹¹In-labeled PNA complementary to the translational start site of bcl-2 messenger RNA was attached to Tyr³-octreotate for somatostatin receptor-mediated intracellular delivery. Methods: DOTA-anti-bcl-2-PNA-Tyr³-octreotate (1) and 3 control conjugates (DOTA-nonsense-PNA-Tyr³-octreotate (2), DOTA-anti-bcl-2-PNA-Ala[3,4,5,6]-substituted congener (3), and DOTA-Tyr³-octreotate (4) [DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid]) were synthesized by standard solid-phase 9-fluorenylmethoxycarbonyl (Fmoc) chemistry. In vitro studies were performed in Mec-1 SLL cells, which express both bcl-2 messenger RNA and somatostatin receptors. Biodistributions and microSPECT/CT studies were performed in Mec-1–bearing SCID (severe combined immunodeficiency) mice, a new animal model of human SLL. Results: ¹¹¹In-Labeled conjugate 1 was taken up by Mec-1 cells through a somatostatin receptor-mediated mechanism. Biodistribution studies showed specific tumor uptake of conjugate 1, the somatostatin analog 4, and the PNA nonsense conjugate 2, but not of the mutant peptide conjugate 3. Mec-1 tumors could be detected by microSPECT/CT using ¹¹¹In-labeled DOTA-Tyr³-octreotate (4) and the targeted anti-bcl-2 conjugate (1), but not using the 2 negative control conjugates 2 and 3. Conclusion: A new ¹¹¹In-labeled antisense PNA–peptide conjugate demonstrated proof of principle for molecular imaging of bcl-2 expression in a new mouse model of human SLL. This imaging agent may be useful for identifying NHL patients at risk for relapse and conventional treatment failure.

Key Words: bcl-2 • peptide nucleic acid • somatostatin receptor • microSPECT/CT • non-Hodgkin's lymphoma

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