Using Indium-111 labeled radiopharmaceuticals to target the BB2 receptor on human prostate cancer cells [abstract]

Abstract only availableThe BB2 receptor, belonging to the Bombesin receptor family, has been shown to be highly over expressed in a variety of cancer cell lines, including human prostate cancer. Our laboratory have been involved, for over a decade, in synthesizing Bombesin analogues that target the BB2 receptor for the purpose of developing radiopharmaceuticals for diagnostic and/or therapeutic treatment of cancer. Radiopharmaceuticals based on Bombesin are typically composed of a chelator, isotope, linking group and targeting vector [See Bifunctional Conjugate Design [figure below]. Previous studies by our group and others have shown that variations in linking groups affect the retention time of the bifunctional conjugate in prostate cancer (PC-3) cells. Higher retention time allows for more efficacious therapeutic benefits and enhanced diagnostic imaging capabilities. In this study, we seek to determine the pharmacokinetic benefits achieved in altering the linking group using aliphatic and aromatic linking groups. In-vitro analysis of the radiopharmaceuticals studied found that the Bombesin derivative with the aliphatic linking group demonstrated a slightly higher affinity for the BB2 receptor compared to the Bombesin analogs containing aromatic linking groups. In vivo pharmacokinetic and imaging studies were performed using pre-clinical models of prostate cancer. The tumor uptake of the Bombesin derivatives with the aromatic linking groups were found to be significantly higher compared to that of the Bombesin derivative with the aliphatic linking group. In contrast, the aromatic Bombesin analogs also exhibited higher amounts of undesirable accumulation in the kidneys and other non-target tissues. In conclusion, we found that the aliphatic compounds were more appropriate for diagnostic imaging of prostate cancer due to the reduced non-target retention. The Bombesin analogs with aromatic linking groups showed potential for use as therapeutic agents for prostate cancer treatment.National Institutes of Health Molecular Imaging Progra

Targeting the BB2 receptor on human prostate cancer cells using Indium-111 labeled radiopharmaceutical [abstract]

Abstract only availableFaculty Mentor: Dr. Timothy Hoffman, Internal MedicineThe BB2 receptor, belonging to the Bombesin receptor family, has been shown to be highly over expressed in a variety of cancer cell lines, including human prostate cancer. Over expression of the BB2 receptor offers an appealing target for the design of targeted radiopharmaceuticals.  The Hoffman laboratory and others have been involved, for over a decade, in synthesizing Bombesin analogues that target the BB2 receptor for the purpose of developing a viable radiopharmaceutical for diagnostic or therapeutic treatment of cancer. Radiopharmaceuticals based on Bombesin analogues are typically composed of a targeting vector, radioisotope, chelator and linking group [See Bifunctional Conjugate Design figure below]. Previous studies have shown that variations in linking groups may affect the retention time of the bifunctional conjugate in prostate cancer (PC-3) cells.  Higher retention time allows for more efficacious therapeutic benefits and enhanced diagnostic imaging capabilities.  In the work presented, we designed and synthesized a 111In-Bombesin analogue with a phenyl linker group in order to determine if the phenyl linker group would provide higher retention times in prostate cancer.  In-vitro analysis of the radiopharmaceutical was performed using PC-3 cells to determine the affinity of the new compound for the BB2 receptor to be 1.09 nM. In-vivo studies of the radiopharmaceutical were also conducted by injection of the radiopharmaceutical into CF-1 (“normal”) mice, as well as SCID (Severe Combined Immunodeficient) mice bearing 2-3 week old PC-3 tumors. Experimental results on SCID mice revealed uptakes of 6.36, 3.34, 2.42 and 1.69 % Injected Dose of radiopharmaceutical per gram of tumor tissue at 0.25, 1, 4 and 24 hours, respectively. Imaging using Micro-SPECT (Single-Photon Emission Computed Tomography) was performed to track the dispersion of the radiopharmaceutical throughout the mouse model and confirmed the targeted uptake of the radiopharmaceutical

Discrete NaI(TI) crystal detector optimization for small animal SPECT molecular imaging

The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.Title from title screen of research.pdf file viewed on (November 15, 2006)Includes bibliographical references.Vita.Thesis (Ph.D.) University of Missouri-Columbia 2005.Dissertations, Academic -- University of Missouri--Columbia -- Nuclear engineering.[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Dual-modality imaging instrumentation has allowed the noninvasive analysis of preclinical models of human disease. A combined microSPECT/CT unit (Siemens) equipped with dual discrete crystal SPECT detectors was under performance evaluation in our laboratory for SPECT molecular imaging. The CT component consists of a CCD x-ray detector and a micro-focus x-ray source (40 [mu] m focal spot). MicroSPECT performance was assessed thru characteristics measurements and high resolution phantoms. Gamma camera SPECT properties investigated using Tc-99m included system photon sensitivity, detection efficiencies, detector uniformity, spectral energy resolution, spatial resolution (FWHM), count rate, and tomograhic pre-clinical performance employing a 3D-OSEM algorithm with geometrical misalignment corrections. Camera gamma-ray sensitivity was calculated to be 3.5, 37 and 73 cps/[mu] Ci for the 0.5, 2 and 3 mm pinhole apertures, respectively. Intrinsic uniformity for the central field of view was 1.42% differential and 2.99% integral. Energy spectral resolution (FWHM) at 140 keVwas 14.3% [plus or minus]1.5 %. Volumetric spatial resolution of 1.2 mm was achieved with a hot-rod Tc-99m SPECT micro-phantom. Camera count rate linearity was achieved up to 1 mCi. In-vivo osteoblastic bone lesions 0.6 mm in diameter measured by CT were also detectable with SPECT Tc-99m-HDP imaging. Spatial resolution (FWHM) results suggest that the microCAT II® SPECT unit is capable of sub-millimeter resolution, however, photon sensitivity improvements either by employing multi-pinhole collimation and/or larger crystal elements will significantly enhance the SPECT pre-clinical performance of the unit

Performancee evaluation of a dual Micro-SPECT detector system [abstract]

Abstract only availableFaculty Mentor: Dr. Timothy Hoffman, Internal MedicineThe ability to conduct radiopharmaceutical research in vivo is largely dependent on nuclear imaging hardware and is subject to its limitations. The inability of clinical instrumentation to conduct non-invasive tracer bio-kinetics has spurred the development of dedicated pre-clinical imaging systems such as Micro-SPECT. Pixelated NaI(Tl) detectors are a relatively new attempt to further increase Micro-SPECT viability in conducting longitudinal research. The goal of this experiment is to evaluate a dual pixelated NaI(Tl) gamma-ray Micro-SPECT system and its ability to conduct routine preclinical studies. The SPECT detectors each have an area of 150 mm x 150 mm composed of 4624 (2 mm x 2 mm x 10 mm) NaI(Tl) scintillators coupled to position sensitive photomultiplier tubes. Various tungsten pinhole collimators are used depending on the amount of radioactivity in the SPECT field of view. The Micro-SPECT images are reconstructed using an OSEM routine with sub-voxel capabilities. The sensitivities and efficiencies of the SPECT detectors were determined for Tc-99m and In-111. The practical and optimum SPECT system resolutions were determined using commercial phantoms and evaluated in a Tc-99m-MDP SPECT/CT scan. Longitudinal SPECT/CT studies were performed on tumor bearing models using a receptor targeted radiopharmaceutical at 1, 4, 24, 48 and 72 hours post injection. System sensitivities of 340 cps/MBq and efficiencies of 0.03% were achieved at 25 mm from the 2 mm pinhole aperture. The spatial resolution of the SPECT was determined to optimally be 1.6 mm and practically 2.4 mm using a hot-rod reconstructed Tc-99m phantom scanned for 16 hours and 30 minutes respectively. Bone and tumor SPECT studies revealed excellent target tissue/organ visualization. Longitudinal Micro-SPECT/CT studies were conducted successfully over a 72 hour period post injection. These findings suggest that pixelated NaI(Tl) detector technology is capable of repeated imaging in the same subject.The ability to conduct radiopharmaceutical research in vivo is largely dependent on nuclear imaging hardware and is subject to its limitations.  The inability of clinical instrumentation to conduct non-invasive tracer bio-kinetics has spurred the development of dedicated pre-clinical imaging systems such as Micro-SPECT.  Pixelated NaI(Tl) detectors are a relatively new attempt to further increase Micro-SPECT viability in conducting longitudinal research.  The goal of this experiment is to evaluate a dual pixelated NaI(Tl) gamma-ray Micro-SPECT system and its ability to conduct routine preclinical studies.  The SPECT detectors each have an area of 150 mm x 150 mm composed of 4624 (2 mm x 2 mm x 10 mm) NaI(Tl) scintillators coupled to position sensitive photomultiplier tubes.  Various tungsten pinhole collimators are used depending on the amount of radioactivity in the SPECT field of view.  The Micro-SPECT images are reconstructed using an OSEM routine with sub-voxel capabilities.  The sensitivities and efficiencies of the SPECT detectors were determined for Tc-99m and In-111.  The practical and optimum SPECT system resolutions were determined using commercial phantoms and evaluated in a Tc-99m-MDP SPECT/CT scan.  Longitudinal SPECT/CT studies were performed on tumor bearing models using a receptor targeted radiopharmaceutical at 1, 4, 24, 48 and 72 hours post injection.  System sensitivities of 340 cps/MBq and efficiencies of 0.03% were achieved at 25 mm from the 2 mm pinhole aperture.  The spatial resolution of the SPECT was determined to optimally be 1.6 mm and practically 2.4 mm using a hot-rod reconstructed Tc-99m phantom scanned for 16 hours and 30 minutes respectively.  Bone and tumor SPECT studies revealed excellent target tissue/organ visualization.  Longitudinal Micro-SPECT/CT studies were conducted successfully over a 72 hour period post injection.  These findings suggest that pixelated NaI(Tl) detector technology is capable of repeated imaging in the same subject

Evaluation of [99MTc]glucarate as a breast cancer imaging agent : bench to bedside [abstract]

The use of [99mTc]glucarate has been reported as an infarct-avid agent with the potential for very early detection of myocardial infarction. [99mTc]glucarate has also been postulated as an agent for non-invasive detection of tumors. The aim of the study was to develop a glucarate kit and evaluate [99mTc]glucarate as a potential cancer imaging agent in female SCID mice bearing human MDA-MB-435 breast tumors and in preliminary patient studies

Microimaging Characterization of a B16-F10 Melanoma Metastasis Mouse Model

Metastatic mouse models of melanoma have been characterized by gross necropsy examination, histopathology, and optical imaging. To determine if the time progression, extent, and metabolism of melanoma metastases could be monitored noninvasively, serial micro-CT and small-animal PET imaging studies were performed by using a mouse model of melanoma. Juvenile female C57BL/6 mice were injected intravenously with syngenic B16-F10 melanoma cells. Serial micro-CT imaging studies were performed on anesthetized mice. Mice were necropsied at the development of adverse clinical signs or at postinjection Day 30, and tissues were collected for histopathology. In a separate study of four mice, tumor viability was assessed with 2-deoxy-2-[ 18 F]fluoro- d -glucose ([ 18 F]FDG) and studied by using small-animal PET imaging. A total of 59% of the mice developed metastatic tumors. Micro-CT image analysis was able to identify and follow up to 36% of metastatic lesions. Examples of metastatic lesions identified and followed up by micro-CT imaging included a lung metastasis, mandibular metastasis, subcutaneous metastasis, and tibial/femoral metastasis. Micro-CT and small-animal PET fusion imaging successfully correlated anatomic localization of glucose metabolism of the metastatic tumors. Micro-CT and small-animal PET imaging were found to be highly effective in detection and characterization of lesions produced by this metastatic melanoma model

TLD assessment of mouse dosimetry during microCT imaging

Advances in laboratory animal imaging have provided new resources for noninvasive biomedical research. Among these technologies is microcomputed tomography (microCT) which is widely used to obtain high resolution anatomic images of small animals. Because microCT utilizes ionizing radiation for image formation, radiation exposure during imaging is a concern. The objective of this study was to quantify the radiation dose delivered during a standard microCT scan. Radiation dose was measured using thermoluminescent dosimeters (TLDs), which were irradiated employing an 80 kVp x-ray source, with 0.5 mm Al filtration and a total of 54 mA s for a full 360 deg rotation of the unit. The TLD data were validated using a 3.2 cm3 CT ion chamber probe. TLD results showed a single microCT scan air kerma of 78.0±5.0 mGy when using a poly(methylmethacrylate) (PMMA) anesthesia support module and an air kerma of 92.0±6.0 mGy without the use of the anesthesia module. The validation CT ion chamber study provided a measured radiation air kerma of 81.0±4.0 mGy and 97.0±5.0 mGy with and without the PMMA anesthesia module, respectively. Internal TLD analysis demonstrated an average mouse organ radiation absorbed dose of 76.0±5.0 mGy. The author’s results have defined x-ray exposure for a routine microCT study which must be taken into consideration when performing serial molecular imaging studies involving the microCT imaging modality