Whole-Body and Microenvironmental Localization of Radium-223 in Naïve and Mouse Models of Prostate Cancer Metastasis.

Bone-metastatic, castration-resistant prostate cancer (bmCRPC) represents a lethal stage of the most common noncutaneous cancer in men. The recent introduction of Radium-223 dichloride, a bone-seeking alpha particle (α)-emitting radiopharmaceutical, demonstrates statistically significant survival benefit and palliative effect for bmCRPC patients.

Clinical results have established safety and efficacy, yet questions remain regarding pharmacodynamics and dosing for optimized patient benefit.

We elucidated the biodistribution of (223)Ra as well as interaction with the bone and tumor compartments in skeletally mature mice (C57Bl/6 and CD-1, n = 3-6) and metastasis models (LNCaP and PC3, n = 4). Differences in uptake were evaluated by µCT and histological investigation. Novel techniques were leveraged on whole-mount undecalcified cryosections to determine microdistribution of Radium-223. All statistical tests were two-sided.

(223)Ra uptake in the bones (>30% injected activity per gram) at 24 hours was also accompanied by non-negligible remnant activity in the kidney (2. 33% ± 0. 36%), intestines (5. 73% ± 2. 04%), and spleen (10. 5% ± 5. 9%) Skeletal accumulation across strains did not correspond with bone volume or surface area but instead to local blood vessel density (P = . 04). Microdistribution analysis by autoradiography and α camera revealed targeting of the ossifying surfaces adjacent to the epiphyseal growth plate. In models of PCa metastasis, radioactivity does not localize directly within tumors but instead at the apposite bone surface. Osteoblastic and lytic lesions display similar intensity, which is comparable with uptake at sites of normal bone remodeling.

Profiling the macro- and microdistribution of (223)Ra in healthy and diseased models has important implications to guide precision application of this emerging α-therapy approach for bmCRPC and other bone metastastic diseases.

Journal of the National Cancer Institute. 2015 Dec 18*** epublish ***

Diane S Abou, David Ulmert, Michele Doucet, Robert F Hobbs, Ryan C Riddle, Daniel L J Thorek

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Radiological Science (DSA, DLJT), Department of Orthopaedic Surgery (MD, RCR), Department of Radiation Oncology (RFH), and Cancer Molecular and Functional Imaging Program, Department of Oncology (RFH, DLJT), Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University (JHU) School of Medicine, Baltimore, MD; Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY (DU); Department of Clinical Sciences (Urology), Lund University, Skåne University Hospital, Malmö, Sweden (DU). , Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Radiological Science (DSA, DLJT), Department of Orthopaedic Surgery (MD, RCR), Department of Radiation Oncology (RFH), and Cancer Molecular and Functional Imaging Program, Department of Oncology (RFH, DLJT), Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University (JHU) School of Medicine, Baltimore, MD; Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY (DU); Department of Clinical Sciences (Urology), Lund University, Skåne University Hospital, Malmö, Sweden (DU). , Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Radiological Science (DSA, DLJT), Department of Orthopaedic Surgery (MD, RCR), Department of Radiation Oncology (RFH), and Cancer Molecular and Functional Imaging Program, Department of Oncology (RFH, DLJT), Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University (JHU) School of Medicine, Baltimore, MD; Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY (DU); Department of Clinical Sciences (Urology), Lund University, Skåne University Hospital, Malmö, Sweden (DU). , Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Radiological Science (DSA, DLJT), Department of Orthopaedic Surgery (MD, RCR), Department of Radiation Oncology (RFH), and Cancer Molecular and Functional Imaging Program, Department of Oncology (RFH, DLJT), Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University (JHU) School of Medicine, Baltimore, MD; Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY (DU); Department of Clinical Sciences (Urology), Lund University, Skåne University Hospital, Malmö, Sweden (DU). , Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Radiological Science (DSA, DLJT), Department of Orthopaedic Surgery (MD, RCR), Department of Radiation Oncology (RFH), and Cancer Molecular and Functional Imaging Program, Department of Oncology (RFH, DLJT), Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University (JHU) School of Medicine, Baltimore, MD; Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY (DU); Department of Clinical Sciences (Urology), Lund University, Skåne University Hospital, Malmö, Sweden (DU). , Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Radiological Science (DSA, DLJT), Department of Orthopaedic Surgery (MD, RCR), Department of Radiation Oncology (RFH), and Cancer Molecular and Functional Imaging Program, Department of Oncology (RFH, DLJT), Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University (JHU) School of Medicine, Baltimore, MD; Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY (DU); Department of Clinical Sciences (Urology), Lund University, Skåne University Hospital, Malmö, Sweden (DU). 

PubMed