4.7 Article

Ex Vivo and In Vivo Evaluation of Overexpressed VLA-4 in Multiple Myeloma Using LLP2A Imaging Agents

期刊

JOURNAL OF NUCLEAR MEDICINE
卷 57, 期 4, 页码 640-645

出版社

SOC NUCLEAR MEDICINE INC
DOI: 10.2967/jnumed.115.164624

关键词

animal imaging; molecular imaging; radiobiology/dosimetry; dosimetry; LLP2A; multiple myeloma; VLA-4 specificity

资金

  1. NIH NCI [R01CA176221, U54CA199092, 1R21CA180211]

向作者/读者索取更多资源

Very-late-antigen-4 (VLA-4, alpha(4)beta(1) integrin, CD49d/CD29) is a transmembrane adhesion receptor that plays an important role in cancer and immune responses. Enhanced VLA-4 expression has been observed in multiple myeloma (MM) cells and surrounding stroma. VLA-4 conformational activation has been associated with MM pathogenesis. VLA-4 is a promising MM imaging and therapeutic biomarker. Methods: Specificity of Cu-64-LLP2A (Cu-64-CB-TE1A1P-PEG(4)-LLP2A), a high-affinity VLA-4 peptidomimetic-based radiopharmaceutical, was evaluated in alpha(4) knock-out mice and by competitive blocking in wild-type tumor-bearing mice. Cu-64-LLP2A PET/CT (static and dynamic) imaging was conducted in C57BL6/KaLwRij mice bearing murine 5TGM1-GFP syngeneic tumors generated after intravenous injection via the tail. Blood samples were collected for serum protein electrophoresis. Bone marrow and splenic cells extracted from tumor-bearing and control mice (n = 3/group) were coincubated with the optical analog LLP2A-Cy5 and mouse B220, CD4, Gr1, and Mac1 antibodies and analyzed by fluorescence-activated cell sorting. Human radiation dose estimates for Cu-64-LLP2A were extrapolated from mouse biodistribution data (6 time points, 0.78 MBq/animal, n = 4/group). Ten formalin-fixed paraffin-embedded bone marrow samples from deceased MM patients were stained with LLP2A-Cy5. Results: Cu-64-LLP2A and LLP2A-Cy5 demonstrated high specificity for VLA-4-positive mouse 5TGM1-GFP myeloma and nonmalignant inflammatory host cells such as T cells and myeloid/monocytic cells. Ex vivo flow cytometric analysis supported a direct effect of myeloma on increased VLA-4 expression in host hematopoietic microenvironmental elements. SUVs and the number of medullar lesions detected by Cu-64-LLP2A PET corresponded with increased monoclonal (M) protein (g/dL) in tumor-bearing mice over time (3.29 +/- 0.58 at week 0 and 9.97 +/- 1.52 at week 3). Dynamic PET with Cu-64-LLP2A and F-18-FDG demonstrated comparable SUV in the prominent lesions in the femur. Human radiation dose estimates indicated urinary bladder wall as the dose-limiting organ (0.200 mGy/MBq), whereas the dose to the red marrow was 0.006 mGy/MBq. The effective dose was estimated to be 0.017 mSv/MBq. Seven of the ten human samples displayed a high proportion of cells intensely labeled with LLP2A-Cy5 probe. Conclusion: Cu-64-LLP2A and LLP2A-Cy5 demonstrated binding specificity for VLA-4 in an immune-competent murine MM model. Cu-64-LLP2A displayed favorable dosimetry for human studies and is a potential imaging candidate for overexpressed VLA-4.

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