Abstract
BackgroundMultiple myeloma (MM) is a disease of cancerous plasma cells in the bone marrow. Imaging-based timely determination of therapeutic response is critical for improving outcomes in MM patients. Very late antigen-4 (VLA4, CD49d/CD29) is overexpressed in MM cells. Here, we evaluated [18F]FDG and VLA4 targeted [64Cu]Cu-LLP2A for quantitative PET imaging in disseminated MM models of variable VLA4 expression, following bortezomib therapy.MethodsIn vitro and ex vivo VLA4 expression was evaluated by flow cytometry. Human MM cells, MM.1S-CG and U266-CG (C: luciferase and G: green fluorescent protein), were injected intravenously in NOD-SCID gamma mice. Tumor progression was monitored by bioluminescence imaging (BLI). Treatment group received bortezomib (1 mg/kg, twice/week) intraperitoneally. All cohorts (treated, untreated and no tumor) were longitudinally imaged with [18F]FDG (7.4–8.0 MBq) and [64Cu]Cu-LLP2A (2–3 MBq; Molar Activity: 44.14 ± 1.40 MBq/nmol) PET, respectively.ResultsFlow cytometry confirmed high expression of CD49d in U266 cells (> 99%) and moderate expression in MM.1S cells (~ 52%). BLI showed decrease in total body flux in treated mice. In MM.1S-CG untreated versus treated mice, [64Cu]Cu-LLP2A localized with a significantly higher SUVmean in spine (0.58 versus 0.31, p < 0.01) and femur (0.72 versus 0.39, p < 0.05) at week 4 post-tumor inoculation. There was a four-fold higher uptake of [64Cu]Cu-LLP2A (SUVmean) in untreated U266-CG mice compared to treated mice at 3 weeks post-treatment. Compared to [64Cu]Cu-LLP2A, [18F]FDG PET detected treatment-related changes at later time points.Conclusion[64Cu]Cu-LLP2A is a promising tracer for timely in vivo assessment of therapeutic response in disseminated models of MM.
Highlights
Multiple myeloma (MM) is a disease of cancerous plasma cells in the bone marrow
LLP2A-CB-TE1A1P (LLP2A) peptide was purchased from Auspep (Tullamarine Victoria, Australia), and all other chemicals used in radiolabeling were purchased from Sigma-Aldrich unless otherwise noted
Radiochemical purity of the labeled peptide was evaluated by analytical reversed-phase high-performance liquid chromatography (HPLC), that was performed on 1200 Infinity series chromatography system, purchased from Agilent Technologies (Santa Clara, CA)
Summary
Multiple myeloma (MM) is a disease of cancerous plasma cells in the bone marrow. Multiple myeloma (MM) is a cancer of abnormal plasma cells in the bone marrow It is a complex disease characterized by intratumoral heterogeneity, inflammatory tumor microenvironment, and genetic instability [1, 2]. The International Myeloma Working Group (IMWG) has proposed the evaluation of minimal residual disease (MRD) as one of the key criteria for defining response [11]. Techniques such as whole-body imaging that can improve the accuracy of MRD detection are critical for comprehensive assessment of complete response [12]
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