Intratherapeutic Biokinetic Measurements, Dosimetry Parameter Estimates, and Monitoring of Treatment Efficacy Using Cerenkov Luminescence Imaging in Preclinical Radionuclide Therapy

摘要

In recent years, there has been increasing interest in noninvasive Cerenkov luminescence imaging (CLI) of in vivo radionuclide distribution in small animals, a method proven to be a high-throughput modality for confirmation of tracer uptake. 11B6 is an IgG(1) monoclonal antibody that is specific to free human kallikrein-related peptidase 2, an antigen abundant in malignant prostatic tissue. Free human kallikrein-related peptidase 2 was targeted in prostate cancer xenografts using Lu-177-labeled 11B6 in either murine or humanized forms for radionuclide therapy. In this setting, CLI was investigated as a tool for providing parameters of dosimetric importance during radionuclide therapy. First, longitudinal imaging of biokinetics using CLI and SPECT was compared. Second, the CLI signal was correlated to quantitative ex vivo tumor activity measurements. Finally, CLI was used to monitor the radionuclide treatment, and the integrated CLI radiance was found to correlate well with subject-specific tumor volume reduction. Methods: 11B6 was radiolabeled with Lu-177 through the CHX-A.-DTPA chelator. In vivo CLI and SPECT imaging of Lu-177-DTPA-11B6 uptake was performed on NMRI and BALB/c nude mice with subcutaneous LNCaP xenografts up to 14 d after injection. Tumor size was measured to assess response to radionuclide therapy. Results: CLI correlated well with SPECT imaging and could be applied up to 14 d after injection of 20 MBq with the specific tracer used. Through integration of the CLI radiance as a function of time, a dose metric for the tumors could be formed that correlated exponentially with tumor volume reduction. Conclusion: CLI provided valuable intratherapeutic biokinetic measurements for treatment monitoring and could be used as a tool for subject-specific absorbed dose estimation. Key Words: Cerenkov luminescence imaging; radionuclide therapy; prostate cancer; human kallikrein related peptidase 2; human kallikrein gene family; Lu-177-DTPA-11B6; molecular imaging; dosimetry; optical imaging