Radiation Dosimetry of Theragnostic Pairs for Isotopes of Iodine in IAZA.

Theragnostic pairs of isotopes are used to infer radiation dosimetry for a therapeutic radiopharmaceutical from a diagnostic imaging study with the same tracer molecule labelled with an isotope better suited for the imaging task. We describe the transfer of radiation dosimetry from the diagnostic radioiodine isotope 123I, labelled for the hypoxia tracer molecule iodoazomycin arabinoside ([123I]IAZA), to isotopes 131I (therapeutic) and 124I (PET imaging). Uncertainties introduced by the dissimilar isotope half-lives are discussed in detail. Radioisotope dosimetries for [123I]IAZA were obtained previously. These data are used here to calculate residence times for 131I and 124I and their uncertainties. We distinguish two cases when extrapolating to infinity: purely physical decay (case A) and physical decay plus biological washout (case B). Organ doses were calculated using the MIRD schema with the OLIDNA/EXM code. Significant increases in some organ doses (in mSv per injected activity) were found for 131I and 124I. The most affected organs were the intestinal walls, thyroid, and urinary bladder wall. Uncertainty remained similar to 123I for case A but considerably greater for case B, especially for long biological half-lives (GI tract). Normal tissue dosimetries for IAZA must be considered carefully when substituting isotope species. A long biological half-life can significantly increase dosimetric uncertainties. These findings are relevant when considering PET imaging studies with [124I]IAZA or therapeutic administration of [131I]IAZA.

Pharmacokinetics and Scintigraphic Imaging of the Hypoxia-Imaging Agent [123I]IAZA in Healthy Adults Following Exercise-Based Cardiac Stress †.

The objective of this work is to evaluate the potential effect of cardiac stress exercise on the accumulation of [123I]IAZA, a radiopharmaceutical used to image focal tissue hypoxia, in otherwise normal myocardium in healthy volunteers, and to determine the impact of exercise on [123I]IAZA pharmacokinetics. The underlying goal is to establish a rational basis and a baseline for studies of focal myocardial hypoxia in cardiac patients using [123I]IAZA. Three healthy male volunteers ran the 'Bruce' treadmill protocol, a clinically-accepted protocol designed to expose myocardial ischemia in patients. The 'Bruce' criterion heart rate is 85% of [220-age]. Approximately one minute before reaching this level, [123I]IAZA (5.0 mCi/0.85 mg) was administered as a slow (1-3 min) single intravenous (i.v.) injection via an indwelling venous catheter. The volunteer continued running for an additional 1 min before being transferred to a gamma camera. Serum samples were collected from the arm contralateral to the administration site at pre-determined intervals from 1 min to 45 h post injection and were analyzed by radio HPLC. Pharmacokinetic (PK) parameters were derived for [123I]IAZA and total radioactivity (total[123I]) using compartmental and noncompartmental analyses. Whole-body planar scintigraphic images were acquired from 0.75 to 24 h after dosing. PK data and scintigraphic images were compared to previously published [123I]IAZA data from healthy volunteers rest. Following exercise stress, both [123I]IAZA and total[123I] exhibited bi-exponential decline profiles, with rapid distribution phases [half-lives (t1/2α) of 1.2 and 1.4 min, respectively], followed by slower elimination phases [t1/2ß of 195 and 290 min, respectively]. Total body clearance (CLTB) and the steady state volume of distribution (Vss) were 0.647 L/kg and 185 mL/min, respectively, for [123I]IAZA and 0.785 L/kg and 135 mL/min, respectively, for total[123I]. The t1/2ß, CLTB and Vss values were comparable to those reported previously for rested volunteers. The t1/2α was approximately 4-fold shorter for [123I]IAZA and approximately 3-fold shorter for total[123I] under exercise relative to rested subjects. The heart region was visualized in early whole body scintigraphic images, but later images showed no accumulated radioactivity in this region, and no differences from images reported for rested volunteers were apparent. Minimal uptake of radiotracer in myocardium and skeletal muscle was consistent with uptake in non-stressed myocardium. Whole-body scintigrams for [123I]IAZA in exercise-stressed healthy volunteers were indistinguishable from images of non-exercised volunteers. There was no evidence of hypoxia-dependent binding in exercised but otherwise healthy myocardium, supporting the conclusion that exercise stress at Bruce protocol intensity does not induce measurable myocardial hypoxia. Effects of exercise on PK parameters were minimal; specifically, the t1/2α was shortened, reflecting increased cardiac output associated with exercise. It is concluded that because [123I]IAZA was not metabolically bound in exercise-stressed myocardium, a stress test will not create elevated myocardial background that would mask regions of myocardial perfusion deficiency. [123I]IAZA would therefore be suitable for the detection of viable, hypoxic myocardium in patients undergoing stress-test-based diagnosis.

An automated module for the separation and purification of cyclotron-produced 99mTcO4-.

INTRODUCTION: The shortage of reactor-produced molybdenum-99 ((99)Mo, t(½)=66 h) has renewed interest in alternative production methods of its daughter isotope, technetium-99m ((99m)Tc, t(½)=6.02 h). While adsorption chromatography serves as a mechanism for selective elution of sodium pertechnetate from technetium generators, this method of purification is not sufficient for many alternative production methods. Several ion-separation/solid phase extraction chromatography methods are known, yet none have been demonstrated on cyclotron-produced [(99m)Tc]TcO(4)(-). Herein we describe the design, manufacture and optimization of a remotely operated module for the purification of sodium pertechnetate from a bulk solution of molybdate. METHODS: The automated purification module was designed to separate [(99m)Tc]TcO(4)(-) using either Dowex 1x8 or an Aqueous Biphasic Extraction Chromatography (ABEC) resin. (100)Mo composite targets were irradiated with 18.5 MeV protons for 10 µA·h using an ASCI TR19 cyclotron. Once purified, the radiopharmaceutical quality of (99m)TcO(4)(-) isolated from each process (Dowex and/or ABEC) was established by assaying for molybdate breakthrough, alumina levels and, in the case of the Dowex approach, residual organics. RESULTS: The separation processes are efficient (75% for Dowex, 90% for ABEC) and complete in less than 30 min. Overall, up to 2.1 GBq of (99m)Tc was produced using the (100)Mo(p,2n)(99m)Tc transformation, processed using the separation module and subjected to a detailed chemical and radionuclidic analysis. Due to its expense and limited availability, (100)MoO(4)(2-) was recovered in >90% yield using a precipitation/filtration/lyophilization approach. CONCLUSIONS: Na[(99m)Tc]TcO(4) was produced using a medical cyclotron, recovered using an automated purification module and found to exceed all established quality control parameters.

Design of a bifunctional fusion protein for ovarian cancer drug delivery: single-chain anti-CA125 core-streptavidin fusion protein.

We have developed a universal ovarian cancer cell targeting vehicle that can deliver biotinylated therapeutic drugs. A single-chain antibody variable domain (scFv) that recognizes the CA125 antigen of ovarian cancer cells was fused with a core-streptavidin domain (core-streptavidin-VL-VH and VL-VH-core-streptavidin orientations) using recombinant DNA technology and then expressed in Escherichia coli using the T7 expression system. The bifunctional fusion protein (bfFp) was expressed in a shaker flask culture, extracted from the periplasmic soluble protein, and affinity purified using an IMAC column. The two distinct activities (biotin binding and anti-CA125) of the bfFp were demonstrated using ELISA, Western blot and confocal laser-scanning microscopy (CLSM). The ELISA method utilized human NIH OVCAR-3 cells along with biotinylated bovine serum albumin (B-BSA) or biotinylated liposomes, whereas, the Western blot involved probing with B-BSA. The CLSM study has shown specificity in binding to the OVCAR-3 cell-line. ELISA and Western blot studies have confirmed the bifunctional activity and specificity. In the presence of bfFp, there was enhanced binding of biotinylated antigen and liposome to OVCAR-3 cells. In contrast, the control EMT6 cells, which do not express the CA125 antigen, showed minimal binding of the bfFp. Consequently, bfFp based targeting of biotinylated therapeutic drugs, proteins, liposomes, or nanoparticles could be an alternative, convenient method to deliver effective therapy to ovarian cancer patients. Peritoneal infusion of the bfFp-therapeutic complex could also be effective in locally targeting the most common site of metastatic spread.