15 research outputs found
RAG-mediated DNA breaks attenuate PU.1 activity in early B cells through activation of a SPIC-BCLAF1 complex
Very Late Antigen-4 (α<inf>4</inf>β<inf>1</inf> Integrin) Targeted PET Imaging of Multiple Myeloma
Biomedical imaging techniques such as skeletal survey and 18F-fluorodeoxyglucose (FDG)/Positron Emission Tomography (PET) are frequently used to diagnose and stage multiple myeloma (MM) patients. However, skeletal survey has limited sensitivity as it can detect osteolytic lesions only after 30-50% cortical bone destruction, and FDG is a marker of cell metabolism that has limited sensitivity for intramedullary lesions in MM. Targeted, and non-invasive novel probes are needed to sensitively and selectively image the unique molecular signatures and cellular processes associated with MM. Very late antigen-4 (VLA-4; also called α4β1 integrin) is over-expressed on MM cells, and is one of the key mediators of myeloma cell adhesion to the bone marrow (BM) that promotes MM cell trafficking and drug resistance. Here we describe a proof-of-principle, novel molecular imaging strategy for MM tumors using a VLA-4 targeted PET radiopharmaceutical, 64Cu-CB-TE1A1P-LLP2A. Cell uptake studies in a VLA-4-positive murine MM cell line, 5TGM1, demonstrated receptor specific uptake (P<0.0001, block vs. non-block). Tissue biodistribution at 2 h of 64Cu-CB-TE1A1P-LLP2A in 5TGM1 tumor bearing syngeneic KaLwRij mice demonstrated high radiotracer uptake in the tumor (12±4.5%ID/g), and in the VLA-4 rich organs, spleen (8.8±1.0%ID/g) and marrow (11.6±2.0%ID/g). Small animal PET/CT imaging with 64Cu-CB-TE1A1P-LLP2A demonstrated high uptake in the 5TGM1 tumors (SUV 6.6±1.1). There was a 3-fold reduction in the in vivo tumor uptake in the presence of blocking agent (2.3±0.4). Additionally, 64Cu-CB-TE1A1P-LLP2A demonstrated high binding to the human MM cell line RPMI-8226 that was significantly reduced in the presence of the cold targeting agent. These results provide pre-clinical evidence that VLA-4-targeted imaging using 64Cu-CB-TE1A1P-LLP2A is a novel approach to imaging MM tumors. © 2013 Soodgupta et al
Correction: Very Late Antigen-4 (α4β1 Integrin) Targeted PET Imaging of Multiple Myeloma
Correction: Very Late Antigen-4 (α4β1 Integrin) Targeted PET Imaging of Multiple Myeloma.
Graph representing <i>in vivo</i> blocking of <sup>64</sup>Cu-CB-TE1A1P-LLP2A.
<p>Averaged tumor MIP SUV’s (N = 4) calculated from small animal PET images in the presence and absence of the blocking agent, LLP2A. <b>Inset</b>-Representative MIP image showing mice with similar tumors in the nape of the neck imaged in the absence <b>(L)</b> and presence <b>(R)</b> of the blocking agent (LLP2A). Mice were imaged with small animal PET and <sup>64</sup>Cu-CB-TE1A1P-LLP2A at 2 h post-injection (0.9 MBq, 0.05 µg, 27 pmol, (SA: 37 MBq/µg). Blocking dose: ∼200 fold excess than the tracer amount. P<0.05.</p
Schematic diagram depicting the interaction of multiple myeloma (MM) and stromal cells.
<p>A. Very late antigen-4 (VLA-4, also known as integrin α<sub>4</sub>β<sub>1</sub>) is over expressed on MM cells. VLA-4 mediates myeloma cell adhesion to the bone marrow (BM) stroma through interactions with fibronectin, a glycoprotein of extracellular matrix (ECM) protein and vascular cell adhesion molecule-1 (VCAM-1) protein expressed on bone marrow (BM) stromal cells. B. Structure of CB-TE1A1P-LLP2A.</p
Cellular uptake of <sup>64</sup>Cu-CB-TE1A1P-LLP2A in human myeloma RPMI-8226 cells.
<p>Cell uptake of <sup>64</sup>Cu-CB-TE1A1P-LLP2A (0.1 nM), in human RPMI-8226 cells at 37°C in the absence (red bar) and presence (blue bar) of excess LLP2A (P<0.0001).</p
Small Molecule MYC Inhibitor Conjugated to Integrin-Targeted Nanoparticles Extends Survival in a Mouse Model of Disseminated Multiple Myeloma
Graph representing tumor to muscle and blood respectively at early and late time-points.
<p>The Tumor/Muscle and Tumor/Blood ratios at 2 h and 24 h respectively calculated from the MIP images (SUVs). The ratios were higher at 24 h indicating improved contrast after clearance of the radioactive probe from the background tissues over time.</p