Tumor Dosimetry Using [124I]m-iodobenzylguanidine MicroPET/CT for [131I]m-iodobenzylguanidine Treatment of Neuroblastoma in a Murine Xenograft Model
ABSTRACT PURPOSE: [(124)I]m-iodobenzylguanidine ((124)I-mIBG) provides a quantitative tool for pretherapy tumor imaging and dosimetry when performed before [(131)I]m-iodobenzylguanidine ((131)I-mIBG) targeted radionuclide therapy of neuroblastoma. (124)I (T (1/2) = 4.2 days) has a comparable half-life to that of (131)I (T (1/2) = 8.02 days) and can be imaged by positron emission tomography (PET) for accurate quantification of the radiotracer distribution. We estimated expected radiation dose in tumors from (131)I-mIBG therapy using (124)I-mIBG microPET/CT imaging data in a murine xenograft model of neuroblastoma transduced to express high levels of the human norepinephrine transporter (hNET). PROCEDURES: In order to enhance mIBG uptake for in vivo imaging and therapy, NB 1691-luciferase (NB1691) human neuroblastoma cells were engineered to express high levels of hNET protein by lentiviral transduction (NB1691-hNET). Both NB1691 and NB1691-hNET cells were implanted subcutaneously and into renal capsules in athymic mice. (124)I-mIBG (4.2-6.5 MBq) was administered intravenously for microPET/CT imaging at 5 time points over 95 h (0.5, 3-5, 24, 48, and 93-95 h median time points). In vivo biodistribution data in normal organs, tumors, and whole-body were collected from reconstructed PET images corrected for photon attenuation using the CT-based attenuation map. Organ and tumor dosimetry were determined for (124)I-mIBG. Dose estimates for (131)I-mIBG were made, assuming the same in vivo biodistribution as (124)I-mIBG. RESULTS: All NB1691-hNET tumors had significant uptake and retention of (124)I-mIBG, whereas unmodified NB1691 tumors did not demonstrate quantifiable mIBG uptake in vivo, despite in vitro uptake. (124)I-mIBG with microPET/CT provided an accurate three-dimensional tool for estimating the radiation dose that would be delivered with (131)I-mIBG therapy. For example, in our model system, we estimated that the administration of (131)I-mIBG in the range of 52.8-206 MBq would deliver 20 Gy to tumors. CONCLUSIONS: The overexpression of hNET was found to be critical for (124)I-mIBG uptake and retention in vivo. The quantitative (124)I-mIBG PET/CT is a promising new tool to predict tumor radiation doses with (131)I-mIBG therapy of neuroblastoma. This methodology may be applied to tumor dosimetry of (131)I-mIBG therapy in human subjects using (124)I-mIBG pretherapy PET/CT data.
Chapter: Medical Radiology[Show abstract] [Hide abstract]
ABSTRACT: At present, standard of care for targeted therapy with radionuclides include; 131I for therapy of well-differentiated thyroid cancer; 89Sr chloride, and 153Sm-EDTMP for bone pain; radionuclide microembolization with either resin or glass microspheres; radiolabeled antibodies in lymphoma; metaiodobenzylguanidine for pheochromocytoma; radio peptide therapy for carcinoid, and other endocrine tumors. Growth in this sector of nuclear medicine has been modest. Recent advances in targeted radiotherapy are predicted to set the stage for a phase of rapid growth of the therapeutic aspects of nuclear medicine, as the most unique and potentially most distinctive utilitarian feature of our specialty. A plethora of targeting agents, ranging from small molecules to large nanoparticles offers many alternatives for pharmaceutical carrier of the radioactivity. In particular, major improvement in efficient production of a range of biologicals such as peptides, nanobodies, affibodies, and antibodies has occurred in the recent past and this has led to serious consideration of these agents as carriers of radioactivity after parenteral injection. In this brief overview, we highlight selected advances that have occurred in quantitative imaging, cancer biology, and radiobiology/radiochemistry which are likely to have significant short-term impact on radionuclide therapy. In regard to imaging improvements, there is now widespread availability of the potential for truly quantitative images, especially fusion images based on PET-CT, PET MRI, and SPECT-CT that have the ability to permit internal dosimetry as a guide to optimize therapeutic radionuclide dosing for better management of individual patients. Such imaging improvements, are leading to opportunities for use of theranostic radiotracers, whereby the same drug with minor changes is used for both diagnosis at tracer levels and therapy at tumoricidal levels. From a cancer biology point of view, targeted therapy of specific oncoproteins can restore some cancer cells to a more, nearly normal or differentiated state and this may have special relevance to thyroid cancers and other cancers (Pacak et al. 2012). Thus, non-iodine avid thyroid cancers can be differentiated to concentrate therapeutic levels of radioactive iodine or MIBG, by treatment with a short course of drugs that overcome the effects of specific oncogenic proteins. In regard to radiobiology/radiochemistry improvements, practical methods for accessing alpha emitters as therapeutic radionuclides have been developed.Therapeutic Nuclear Medicine, 01/2013: pages 3-9;
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ABSTRACT: Iodine-131‑labeled monoiodohypericin (131I‑Hyp) is a necrosis avid compound used as a complementary anticancer agent. Herein, the biodistribution in rats with re-perfused partial liver infarction (RPLI) was used to estimate its human internal radiation dosimetry. Iodine-123‑labeled monoiodohypericin (123I-Hyp) as a safer surrogate for 131I-Hyp was prepared with iodogen as oxidant. Determination of radiochemical yield and purification was performed by high performance liquid chromatography (HPLC). To control aggregation, the formulation was macroscopically and microscopically examined. Biodistribution of 123I-Hyp was studied in RPLI rats (n=18) at 4, 24 and 48 h post-injection. Tissue gamma counting (TGC), autoradiography and histology were performed. Dosimetry of 131I-Hyp in hepatic necrosis and in normal human organs was estimated using biodistribution data of 123I-Hyp, the Organ Level Internal Dose Assessment/Exponential Modeling (OLINDA/EXM®), a sphere model and male and female phantoms. A radiochemical yield of 95% was achieved in labeling of 123I-Hyp with a radiochemical purity of 99% after HPLC purification. In the Hyp added formulation, no macroscopic but minimal microscopic aggregation was observed. By TGC, selective accumulation in hepatic infarction and low uptake in viable liver of 123I‑Hyp/Hyp were detected, as confirmed by autoradiography and histology. Significantly higher doses of 131I-Hyp were delivered to necrotic (276‑93,600 mGy/MBq) than to viable (4.2 mGy/MBq) liver (P<0.05). In normal organs, 123I‑Hyp was eliminated within 24 h except for relatively high levels in the lungs and thyroid. Hepatobiliary elimination was a major pathway of 123I-Hyp causing high activity in the intestines. For both genders, dosimetry showed the longest residence time of 131I-Hyp in the remainder, followed by the lungs, intestines and thyroid. The highest absorbed radiation dose was seen in necrotic tissues and the shortest residence times and lowest absorbed radiation dose were found in the brain. 131I-Hyp selectively delivers higher radiation dose to necrosis compared with the rest of the body. Among normal organs, thyroids, lungs and intestines receive considerable radiation dose, which deserves cautious attention in developing this anticancer approach.International Journal of Oncology 12/2013; 44(3). DOI:10.3892/ijo.2013.2217 · 3.03 Impact Factor
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ABSTRACT: Translational medicine pursues the conversion of scientific discovery into human health improvement. It aims to establish strategies for diagnosis and treatment of diseases. Cancer treatment is difficult. Radio-pharmaceutical research has played an important role in multiple disciplines, particularly in translational oncology. Based on the natural phenomenon of necrosis avidity, OncoCiDia has emerged as a novel generic approach for treating solid malignancies. Under this systemic dual targeting strategy, a vascular disrupting agent first selectively causes massive tumor necrosis that is followed by iodine-131 labeled-hypericin ((123)I-Hyp), a necrosis-avid compound that kills the residual cancer cells by crossfire effect of beta radiation. In this review, by emphasizing the potential clinical applicability of OncoCiDia, we summarize our research activities including optimization of radioiodinated hypericin Hyp preparations and recent studies on the biodistribution, dosimetry, pharmacokinetic and, chemical and radiochemical toxicities of the preparations. Myocardial infarction is a global health problem. Although cardiac scintigraphy using radioactive perfusion tracers is used in the assessment of myocardial viability, searching for diagnostic imaging agents with authentic necrosis avidity is pursued. Therefore, a comparative study on the biological profiles of the necrosis avid (123)I-Hyp and the commercially available (99m)Tc-Sestamibi was conducted and the results are demonstrated. Cholelithiasis or gallstone disease may cause gallbladder inflammation, infection and other severe complications. While studying the mechanisms underlying the necrosis avidity of Hyp and derivatives, their naturally occurring fluorophore property was exploited for targeting cholesterol as a main component of gallstones. The usefulness of Hyp as an optical imaging agent for cholelithiasis was studied and the results are presented. Multiple uses of automatic contrast injectors may reduce costs and save resources. However, cross-contaminations with blood-borne pathogens of infectious diseases may occur. We developed a radioactive method for safety evaluation of a new replaceable patient-delivery system. By mimicking pathogens with a radiotracer, we assessed the feasibility of using the system repeatedly without septic risks. This overview is deemed to be interesting to those involved in the related fields for translational research.12/2013; 3(4):45-64. DOI:10.5662/wjm.v3.i4.45