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Hydrophobic adsorbents such as C18 and C30 were coated with PEG and subsequently used for the separation of Mo/Tc. The most effective resin for adsorbing PEG was the C18-U resin, which demonstrated a coating capacity of 97.6±2.8mg PEG per g of resin. The ability to adsorb pertechnetate was proportional to the amount of PEG coated on the hydrophobic resin. The [(99m)Tc]pertechnetate recovery during the separation of cyclotron produced (99m)Tc from (100)Mo was 91.8±0.3% (n=2). The resultant product met relevant USP monograph specifications.

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The physical properties of I-131 may be suboptimal for the delivery of therapeutic radiation to bone marrow metastases, which are common in the natural history of neuroblastoma. In vitro and preliminary clinical studies have implied improved efficacy of I-125 relative to I-131 in certain clinical situations, although areas of uncertainty remain regarding intratumoral dosimetry. This prompted our study using human neuroblastoma multicellular spheroids as a model of metastasis. 3D dose calculations were made using voxel-based Medical Internal Radiation Dosimetry (MIRD) and dose-point-kernel (DPK) techniques. Dose distributions for I-131 and I-125 labeled mIBG were calculated for spheroids (metastases) of various sizes from 0.01 cm to 3 cm diameter, and the relative dose delivered to the tumors was compared for the same limiting dose to the bone marrow. Based on the same data, arguments were advanced based upon the principles of tumor control probability (TCP) to emphasize the potential theoretical utility of I-125 over I-131 in specific clinical situations. I-125-mIBG can deliver a higher and more uniform dose to tumors compared to I-131 mIBG without increasing the dose to the bone marrow. Depending on the tumor size and biological half-life, the relative dose to tumors of less than 1 mm diameter can increase several-fold. TCP calculations indicate that tumor control increases with increasing administered activity, and that I-125 is more effective than I-131 for tumor diameters of 0.01 cm or less. This study suggests that I-125-mIBG is dosimetrically superior to I-131-mIBG therapy for small bone marrow metastases from neuroblastoma. It is logical to consider adding I-125-mIBG to I-131-mIBG in multi-modality therapy as these two isotopes could be complementary in terms of their cumulative dosimetry.

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There is growing interest in the large scale cyclotron production of (99m)Tc via the (100)Mo(p,2n)(99m)Tc reaction. While the use and recycling of cyclotron-irradiated enriched molybdenum targets has been reported previously in the context of (94m)Tc production, to the best of our knowledge, previous recycling studies have been limited to the use of oxide targets. To facilitate reuse of high-power enriched (100)Mo targets, this work presents and evaluates a strategy for recycling of enriched metallic molybdenum. For the irradiated (100)Mo targets in this study, an overall metal to metal recovery of 87% is reported. Evaluation of "new" and "recycled" (100)Mo revealed no changes in the molybdenum isotopic composition (as measured via ICP-MS). For similar irradiation conditions of "new" and "recycled" (100)Mo, (i.e. target thicknesses, irradiation time, and energy), comparable levels of (94g)Tc, (95g)Tc, and (96g)Tc contaminants were observed. Comparable QC specifications (i.e. aluminum ion concentration, pH, and radiochemical purity) were also reported. We finally note that [(99m)Tc]-MDP images obtained by comparing MDP labelled with generator-based (99m)Tc vs. (99m)Tc obtained following the irradiation of recycled (100)Mo demonstrated comparable biodistribution. With the goal of producing large quantities of (99m)Tc, the proposed methodology demonstrates that efficient recycling of enriched metallic (100)Mo targets is feasible and effective.

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As water-soluble ionic contaminants, which arise following proton irradiation of [18O]H2O have been associated with decreased [18F]FDG yields, the minimization of these contaminants is an asset in improving the [18F]F reactivity. To this end, we have previously demonstrated that the use of Nb-sputtered Havar foils results in decreased radionuclidic and chemical impurities in proton irradiated [18O]H2O, improved [18F]FDG yields, and improved [18F]FDG yield consistency when compared with non-sputtered Havar. Resulting from the highly reactive chemical microenvironment within the target however, this niobium layer is observed to degrade over time. To find a material that displays increased longevity with regards to maintaining high [18F]F reactivity, this project extensively investigated and compared Havar foils sputtered with Nb, Pt, Ta, Ti, Zr and ZrO2. Of the materials investigated, the results of this study suggest that Ta-sputtered Havar foil is the preferred choice. For similar integrated currents (~1,000,000 µA min), when comparing the Ta-sputtered Havar with Nb-sputtered Havar we observed: (i) greater than an order of magnitude decrease in radionuclidic impurities, (ii) a 6.4 percent increase (p=0.0025) in the average TracerLab MX [18F]FDG yield, and (iii) an overall improvement in the FDG yield consistency. Excellent performance of the Ta-sputtered foil was maintained throughout its ~1,500,000 µA min lifetime.

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The use of radiochromic films as a simple and inexpensive tool to accurately measure and analyze the beam profile of charged particle accelerators is described. In this study, metallic foils of different materials and thicknesses were irradiated with 17.8MeV protons and autoradiographic images of the beam strike were acquired by exposing pieces of RCF in direct contact with the irradiated foils. The films were digitalized using a conventional scanner and images were analyzed using DoseLab. Beam intensity distributions, isodose curves and linear beam profiles of the digitalized images were acquired.

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Pharmacokinetic models play a crucial role in analyzing and assessing the results of in vitro and in vivo studies. In this review, comparative analysis of pharmacokinetic models under homogeneous and heterogeneous conditions is performed, placing special focus on the role of fractal theory. The concept of fractals provides a new perspective from which processes occurring in heterogeneous, confined, or poorly mixed environments can be modeled. Following a brief theoretical overview, the applicability of fractals in characterizing anatomical structures and physiological processes as well as the transport and reaction of drugs within the body is discussed. There is significant evidence that drug absorption, distribution, metabolism, and excretion are often anomalous, that is to say their behavior deviates from classical theory, and possible reasons and appropriate models are considered.

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Niobium sputtered Havar entrance foils were used for the production of reactive [(18)F]fluoride by proton irradiation of [(18)O]H(2)O targets under pressurized conditions. The synthesis yield in the routine production of 2-[(18)F]fluoro-2-deoxy-glucose (FDG) was used as an indicative parameter of the reactivity of (18)F. The yield of FDG obtained with (18)F produced in a target with Havar foil was used as a baseline. No statistically significant difference was found in the saturated yields of (18)F when using Havar or Havar-Nb sputtered entrance foils. However, the amount of long-lived radionuclidic impurities decreased more than 10-fold using the Havar-Nb entrance foil. The average decay corrected synthesis yield of FDG, evaluated over a period of more than 2 years, was found to be approximately 5% higher when using a Havar-Nb entrance foil and a marked improvement on the FDG yield consistency was noted. In addition, the frequency of target rebuilding was greatly diminished when using the Nb sputtered entrance foil.

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BACKGROUND: We have previously reported the polyamine uptake kinetics in various prostate and non-prostate cancer cell lines, concluding that the prostate cancer cell lines took up and accumulated polyamines at higher levels than non-prostate cell lines, with a view to their use as PET agents. The objective of the present study was to assess their in vivo accumulation in a rat prostate tumor model. MATERIALS AND METHODS: A comparative biodistribution study of the polyamines was conducted in AT3B-1 prostate tumors in male Copenhagen rats to determine which of the polyamines show preferential accumulation in the tumor. Tissue samples were collected one hour post administration of the polyamines (i.v.), and the radioactivity of the samples was measured by first combusting the tissue samples in a biological oxidizer and then assaying the trapped 14CO2 in a liquid scintillation counter. RESULTS: Putrescine exhibited the highest tumor accumulation followed by ornithine (4.1% and 1.8% of injected dose/g of the tumor respectively). The tumor-to-blood ratio was highest with putrescine followed by spermidine (18.7 and 12.9 respectively) and the order of tumor-to-normal prostate accumulation ratio was putrescine>ornithine>spermine>spermidine. CONCLUSION: The results indicated preferential accumulation of putrescine and ornithine in the prostate tumor.

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Cross-sections for the production of (181)Re, (182m)Re, (182g)Re, (183)Re, (184)Re, and (186)Re from proton bombardment of natural tungsten have been measured using the stacked foil technique for proton energies up to 17.6 MeV. Results are compared with the theoretical excitation functions as calculated by the EMPIRE II code (version 2.19) and experimental literature values. Results are in strong agreement with some of the previously reported literature as well at theoretical calculations for multiple reactions providing for more reliable estimates for the (186)W(p,n)(186)Re reaction.

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Single event spectra for five beta-emitting radionuclides (Lu-177, Cu-67, Re-186, Re-188, Y-90) were calculated for single cells from two source geometries. The first was a surface-bound isotropically emitting point source and the second was a bath of free radioactivity in which the cell was submerged. Together these represent a targeted intraperitoneal radionuclide therapy. Monoenergetic single event spectra were calculated over an energy range of 11 keV to 2500 keV using the EGSnrc Monte Carlo system. Radionuclide single event spectra were constructed by weighting monoenergetic single event spectra according to radionuclide spectra appropriate for each source geometry. In the case of surface-bound radioactivity, these were radionuclide beta decay spectra. For the free radioactivity, a continuous slowing down approximation spectrum was used that was calculated based on the radionuclide decay spectra. The frequency mean specific energy per event increased as the energy of the beta emitter decreased. This is because, at these energies, the stopping power of the electrons decreases with increasing energy. The free radioactivity produced a higher frequency mean specific energy per event than the corresponding surface-bound value. This was primarily due to the longer mean path length through the target for this geometry. This information differentiates the radionuclides in terms of the physical process of energy deposition and could be of use in the radionuclide selection procedure for this type of therapy.

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A simple model has been developed to investigate the dosimetry of micrometastases in the peritoneal cavity during intraperitoneal targeted liposomal radioimmunotherapy. The model is applied to free-floating tumours with radii between 0.005 cm and 0.1 cm. Tumour dose is assumed to come from two sources: free liposomes in solution in the peritoneal cavity and liposomes bound to the surface of the micrometastases. It is assumed that liposomes do not penetrate beyond the surface of the tumours and that the total amount of surface antigen does not change over the course of treatment. Integrated tumour doses are expressed as a function of biological parameters that describe the rates at which liposomes bind to and unbind from the tumour surface, the rate at which liposomes escape from the peritoneal cavity and the tumour surface antigen density. Integrated doses are translated into time-dependent tumour control probabilities (TCPs). The results of the work are illustrated in the context of a therapy in which liposomes labelled with Re-188 are targeted at ovarian cancer cells that express the surface antigen CA-125. The time required to produce a TCP of 95% is used to investigate the importance of the various parameters. The relative contributions of surface-bound radioactivity and unbound radioactivity are used to assess the conditions required for a targeted approach to provide an improvement over a non-targeted approach during intraperitoneal radiation therapy. Using Re-188 as the radionuclide, the model suggests that, for microscopic tumours, the relative importance of the surface-bound radioactivity increases with tumour size. This is evidenced by the requirement for larger antigen densities on smaller tumours to affect an improvement in the time required to produce a TCP of 95%. This is because for the smallest tumours considered, the unbound radioactivity is often capable of exerting a tumouricidal effect before the targeting agent has time to accumulate significantly on the tumour surface.

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The Km and Vmax of [14C]-radiolabeled polyamines were determined for PC-3 and AT3B-1 cell lines. With PC-3 Km values are in the following order: ornithine> spermidine> spermine> putrescine, while with AT3B-1 it was spermidine> ornithine> spermine> putrescine. To determine which of these polyamines exhibit higher accumulation, the relative uptake of all the four amines was studied with prostate (PC-3, AT3B-1, LNCaP) and non-prostate (MCF-7, KLN-205, OVCAR) cell lines at 10 and 20 microM after 1 hour. Spermine and spermidine accumulated at higher levels in prostate (AT3B-1 and LNCaP) over non-prostate cell lines (p < 0.01). Putrescine accumulated more in PC-3 and LNCaP than the non-prostate cancer cells.

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To improve tumor-to-tissue ratios of anticancer agents in radioimmunotherapy, a three-step targeting approach was used to deliver biotinylated liposomes to human ovarian cancer cells (NIH:OVCAR-3, SK-OV-3) in vitro. Targeting was based upon the use of two antibodies specific for the CA-125 antigen that is highly expressed on NIH:OVCAR-3 cells but not expressed on SK-OV-3 cells. Briefly, the approach consists of prelabeling target cells with biotinylated anti-CA-125 antibody and FITC-labeled streptavidin (SAv) prior to administration of biotinylated liposomes containing a marker dye for visualization by confocal laser scanning microscopy (CLSM). In addition, the two anti-CA-125 antibodies (B27.1 and B43.13) were labeled with FITC and incubated with ovarian cancer cells at 37 degrees C from 30 min to 24 h to study binding and uptake kinetics. Shedding kinetics of bound antibody from tumor cells was performed using radiolabeled B27.1. Results demonstrated that both B27.1 and B43.13 specifically bound to the cell surface of OVCAR-3 cells but not to SK-OV-3 cells. Biotinylation, FITC-labeling and radiolabeling of the antibodies did not compromise immunoreactivity. Less than 6% of the bound B27.1 was shed from tumor cells by 4 h following incubation, and the antibody-antigen complex resided predominantly on the cell surface by 4 h at 37 degrees C with slow internalization by 12-24 h. Biotinylated, conventional liposomes were specifically and effectively delivered to OVCAR-3 cells prelabeled with biotinylated B27.1 and SAv. The slow internalization and shedding properties of these antibodies are useful for multistep pretargeting methods. Thus, a modified targeting strategy, utilizing a bispecific antibody and liposomes, may be feasible for radioimmunoliposomal therapy of ovarian cancer.

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UNLABELLED: 123I-Labeled iodoazomycin arabinoside (IAZA) is a marker of hypoxia in vivo. It has been used clinically to image hypoxic tissue in solid tumors, peripheral vascular disease of diabetic origin, blunt brain trauma, and rheumatoid joints and in an animal model of cerebrovascular disease. The radiation dose biodistribution for 123I-IAZA was studied to assess and characterize its suitability as a clinical radiopharmaceutical. METHODS: Six healthy volunteers each received a nominal 185-MBq (5 mCi) dose of 123I-IAZA administered as a slow (1-3 min) intravenous injection in the arm. Anterior and posterior whole-body planar images were acquired for each volunteer beginning immediately after injection and at 1-2, 3-4, 6-8, and 20-24 h after injection. Venous blood samples (0 h predose through 28 h after dosing) and 28-h cumulative urine samples were taken from each volunteer for pharmacokinetic analysis. Radiation dose estimates were performed for all volunteers, with "reference adult" (for men) and "adult female" (for women) phantoms, and both the International Commission on Radiological Protection 30 gastrointestinal tract model and the dynamic bladder model, using the MIRDOSE3 program. Two sets of estimates, 1 using a pharmacokinetic analysis of total serum radioactivity and 1 based on scintigraphic image data, were obtained for each volunteer after 123I-IAZA administration. RESULTS: Two compartments were discernible by pharmacokinetic analysis, and 4 compartments were discernible by image analysis. The urinary bladder wall received the greatest radiation dose (6.3E-02 +/- 8.7E-03 mGy/MBq), followed by the upper large intestinal wall (5.6E-02 +/- 1.2E-02 mGy/MBq), the lower large intestinal wall (5.0E-02 +/- 1.2E-02 mGy/MBq), and the thyroid (4.4E-02 +/- 1.4E-02 mGy/MBq). Approximately 90% of physiologically eliminated radioactivity was excreted through the kidneys. Radioactivity entering the intestinal tract from the gallbladder constituted <10% of biologically eliminated activity. CONCLUSION: The dosimetric analysis of 123I-IAZA in 6 healthy volunteers indicated that both disposition kinetics and radiation dosimetry support its clinical use for imaging tissue hypoxia.

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A review of published data on some of the problems associated in treating cancer using radioimmunotherapy is presented. Potential improvements for this type of therapy using pretargeting strategies are discussed and preliminary results on a novel multistep regimen to treat human ovarian cancer are presented. A pretargeting strategy using a biotinylated, anti-CA125 monoclonal antibody (MAb) to attract biotinylated long-circulating liposomes to the surface of CA125-expressing ovarian cancer cells, was employed. Confocal laser scanning microscopy and fluorescent labels were used to establish the biodistribution patterns in NIH:OVCAR-3 (CA-125 positive) and SK-OV-3 (CA-125 negative) human ovarian cancer cells. Shedding kinetics of the pretargeted stage were measured using 125I labeled MAbs. No significant internalization of the MAb used in the pretargeting step was observed by 4 hrs. The antibody was gradually internalized starting at 6 hrs, and most of the labelled MAb was detected in cytoplasm by 24 hrs. Shedding and exocytosis of the antigen-MAb complex was not significant for up to 6-hours following administration of the iodinated MAb. Biotinylated liposomes were shown to specifically target the biotinylated MAb/streptavidin complex on the cell surface. We have demonstrated that by a three-step pretargeting approach, biotinylated liposomes can be specifically delivered to cells pretargeted with biotinylated MAb/SAv complex. The slow internalization and shedding properties of the two MAbs are ideal for multistep pretargeting methods. A successful multistep linkage was established with the biotinylated MAb B27.1, streptavidin and biotinylated liposomes to OVCAR-3 cells, but not to SK-OV-3 cells.

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The radionuclide 41Ar has many ideal properties as a gas flow tracer. However, the modest cross-section of 40Ar for thermal neutron activation makes preparation of suitable activities of 41Ar technically difficult particularly for low flux reactors. Argon can however be trapped in a molecular complex called a clathrate that can then be irradiated. We prepared argon clathrate and explored its irradiation and stability characteristics. Argon clathrate can be used to provide gigabecquerel quantities of 41Ar even with low power reactors.

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PURPOSE: Iodine-125 induces cell death by a mechanism similar to that of high linear energy transfer (high-LET) radiation. This study investigates the cytotoxicity of high-specific-activity [125I]meta-iodobenzylguanidine (125I-mIBG) in human SK-N-MC neuroblastoma cells grown as three-dimensional multicellular spheroids. MATERIALS AND METHODS: Spheroids were incubated with high-specific-activity 125I-mIBG (6 mCi/microg, 1000 times that of the conventional specific activity used for autoradiography). Cytotoxicity was assessed by fluorescence viability markers and confocal microscopy for intact spheroids, fluorescence-activated cell sorting and clonogenic assay, and clonogenic assays for dispersed whole spheroids. Distribution of radioactive mIBG was determined by quantitative light-microscope autoradiography of spheroid cryostat sections. Dose estimation was based on temporal knowledge of the retained radioactivity inside spheroids, and of the radiolabel's emission characteristics. Findings were compared with those of spheroids treated under the same conditions with 131I-mIBG, cold mIBG, and free iodine-125. RESULTS: 125I-mIBG exerted significant cell killing. Complete spheroids were eradicated when they were treated with 500 microCi of 125I-mIBG, while those treated with 500 microCi or 1000 microCi of 131I-mIBG were not. The observed difference in cytotoxicity between treatments with 125I- and 131I-mIBG could not be accounted for by the absorbed dose of spheroid alone. The peripheral, proliferating cell layer of the spheroids remained viable at the moderate radioactivity of 100 microCi for both isotopes. Cytotoxicity induced by 125I-mIBG was quantitatively comparable by the peripheral rim thickness to that of 131I-mIBG at the dose of 100 microCi. The peripheral rim thickness decreased most significantly in the first 17 hours after initial treatment. There was no statistical decrease in the rim thickness identified afterwards for the second, third, and fourth days of incubation. CONCLUSION: The cytotoxic effect of high-specific-activity 125I-mIBG appears to be comparable to, if not more efficient than that of conventionally used 131I-mIBG at the same level of total radioactivity. 125I-mIBG may improve the therapeutic index over that of 131I-mIBG in the clinical management of metastatic neuroblastoma due to the short range of Auger electrons.

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UNLABELLED: PURPOSE. This article reports the pharmacokinetics, radiation dosimetry and radioimmunoscintigraphy (RIS) of two (99m)Tc-labelled monoclonal antibodies (MAb) used to detect cancer. METHODS: The effects of circulating antigen in female cancer patients are explored and their effects on the ability of these MAbs to effectively perform as RIS agents noted. To illustrate the effects of circulating antigen, data using MAb B43.13 (OVAREX, AltaRex Corp., Waltham, MA, USA) from a Pilot study in ovarian cancer patients are presented. The results from a Phase II study of MAb 170H.82 (Tru-Scint AD, BIOMIRA INC., Edmonton, Alberta, Canada) in patients with primary and locally recurrent breast cancer were used to portray the biodistribution patterns when no circulating antigen is present. Data from planar gamma camera images were obtained for both groups and used for pharmacokinetic and radiation dosimetry analyses. RESULTS: A pharmacokinetic analysis indicated a shorter residence time and higher clearance of (99m)Tc-MAb-B43.13 that was ascribed in part to the circulating CA 125 antigen in this group of ovarian cancer patients. CONCLUSION: These clearance patterns resulted in acceptable, though higher radiation doses to the spleen and urinary bladder wall for these patients when compared to the MAb-170H.82 group. Both MAbs were found to produce acceptable radioimmunoscintigraphic images

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OVAREX MAb B43.13 is a new radiopharmaceutical based on a monoclonal antibody (MAb-B43.13) known to recognize CA 125, a tumour antigen associated with epithelial ovarian cancer. This MAb is capable of facile radiolabelling with 99Tcm and has been shown previously to localize in the tumours of ovarian cancer patients. The present study was initiated to measure the pharmacokinetics of this MAb in the serum of 10 patients with primary or metastatic ovarian cancer. A two-compartment model was found to be best at representing the biodistribution of the 99Tcm-labelled MAb, yielding a 2.6 h distribution phase half-life and a 31.3 h elimination phase half-life. The serum and renal clearances for 99Tcm-MAb-B43.13 were 121 and 53 ml h-1 respectively. These parameters were compared with a similar model developed from the serum values of the MAb itself (determined using an ELISA detection method). Based on the serum pharmacokinetics of 99Tcm-MAb-B43.13 and whole-body planar gamma camera images, an estimate of the radiation dose from 99Tcm was calculated using standard MIRD schema. The organs demonstrating significant 99Tcm uptake included the liver, kidneys, heart and spleen. The whole-body dose was similar to other 99Tcm-labelled MAbs.

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