Preparation of Rhenium-188-Lipiodol Using Freeze-Dried Kits for Transarterial Radioembolization: An Overview and Experience in a Hospital Radiopharmacy.

Background: Rhenium-188(188Re)-lipiodol is a clinically effective, economically viable radiopharmaceutical for Selective Internal Radiation Therapy of liver cancer. Present study evaluates the performance of three freeze-dried kits with respect to the radiochemistry, quality control, and overall "ease of preparation" aspects in a hospital radiopharmacy. Materials and Methods: Freeze-dried kits of acetylated 4-hexadecyl-4,7-diaza-1,10-decanedithiol (AHDD), super six sulfur (SSS), and diethyl dithiocarbamate (DEDC), obtained commercially or received as gift, were used for the preparation of 188Re-lipiodol using freshly eluted 188Re-sodium perrhenate from commercial Tungsten-188/188Re generator following recommended procedures. Results: The overall yield of 188Re-lipiodol prepared using AHDD Kit, SSS Kit, and DEDC Kit was 74.82% ± 3.3%, 87.55% ± 4.8%, and 76.38% ± 4.6%, respectively. Observed radiochemical purity (RCP) of 188Re-lipiodol prepared using these kits was 88.65% ± 2.8%, 92.92% ± 3.0%, and 91.38% ± 3.0%, respectively. Using a modified version of the DEDC Kits, overall yield of 87.17% ± 2.7% and RCP of 95.43% ± 2.3% could be achieved. Conclusions: While all three freeze-dried kits can be used for the preparation of 188Re-lipiodol in >70% overall yield, the modified version of DEDC Kits has some advantages in terms of preparation time and volume of Rhenium-188 activity that can be added to the kit vial. The latter feature of the DEDC Kit is particularly useful for patient dose preparation with 188Re activity of low radioactive concentration.

Improved freeze-dried kit for the preparation of 188ReN-DEDC/lipiodol for the therapy of unresectable hepatocellular carcinoma.

Rhenium-188-N-(DEDC)2/lipiodol (abbreviated as 188ReN-DEDC, where DEDC = monoanionic diethyldithiocarbamate) is a clinically proven radiopharmaceutical for the therapy of unresectable hepatocellular carcinoma (HCC) through trans arterial radioembolization (TARE). A two-vial freeze-dried kit for the preparation of [188ReN(DEDC)2] complex using sodium perrhenate (Na188ReO4) obtained from a commercial Tungsten-188/Rhenium-188 generator had been reported earlier. This method required addition of stipulated volume of glacial acetic acid into vial 1 by the user for efficient preparation of [188ReN]2+ intermediate. An error in this step can result in low radiochemical yield of [188ReN]2+ intermediate as well as sub-optimal pH of the reaction mixture for the second step, leading to poor radiochemical purity of 188ReN-DEDC complex. In the present work, a solution to this problem was found by including an oxalate buffer of pH = 3 in vial 1, eliminating the need for the addition of glacial acetic acid by the user. This modification not only made the kits more user-friendly, it resulted in significant improvement in the kinetics of formation of [188ReN]2+ intermediate, wherein > 95% radiochemical purity could be achieved within 5 min incubation at ambient temperature. Moreover, the novel route for the preparation of [188ReN]2+ intermediate may be applied to any radiopharmaceutical based on 188ReN-core.

Preclinical testing of radiopharmaceuticals for novel applications in HIV, bacterial and fungal infectious diseases.

Antibiotics, antifungal and antiviral medications have traditionally been used in the management of infections. Due to widespread emergence of resistance to antimicrobial medications, and their side effects, there is a growing need for alternative approaches for management of such conditions. Antibiotic resistant bacterial pathogens are on the rise. A cure has not been achieved for viral infections like AIDS, while fungal and parasitic infections are constant threats to the health of general public. The incidence of opportunistic infections in immunocompromised individuals like HIV patients, patients receiving high dose steroids, chemotherapy patients, and organ transplant recipients is on the rise. Radioimmunotherapy (RIT) has the potential to be a suitable and viable therapeutic modality in the arena of infection management. Provided the target-associated antigen is expressed by the target cells and minimally or not expressed by other tissues, selective targeting of radiation to target sites can be theoretically accomplished with relative sparing normal tissues from radiation exposure. In our laboratory we successfully demonstrated the effectiveness of RIT for treating infectious diseases. We targeted murine cryptococcosis with a mAb to the Cryptococcus neoformans capsular glucuronoxylomannan labeled with Bismuth-213 ((213)Bi) or Rhenium-188 ((188)Re). We subsequently extended the applicability of RIT for treating bacterial and viral infections. One of the advantages of using RIT to treat infections as opposed to cancer is that, in contrast to tumor cells, cells expressing microbial antigens are antigenically very different from host tissues and thus provide the potential for exquisite specificity and low cross-reactivity. Ever increasing incidence of infectious pathologies, exhaustion of antimicrobial possibilities and rising drug resistance calls for use of alternative and novel therapeutic options and we believe RIT is the need of the hour to combat these infections.

Antitumor activity of a rhenium (I)-diselenoether complex in experimental models of human breast cancer.

Rhenium (I)-diselenother (Re-diselenoether) is a water soluble metal-based compound, combining one atom of rhenium and two atoms of selenium. This compound has been reported to exhibit marked activities against several solid tumor cell lines. We now disclose an improved synthesis of this complex. The Re-diselenoether showed a potent inhibitory effect on MDA-MB231 cell division in vitro, which lasted when the complex was no longer present in the culture. Re-diselenoether induced a remarkable reduction of the volume of the primitive breast tumors and of the pulmonary metastases without clinical signs of toxicity, in mice-bearing a MDA-MB231 Luc+ tumor, orthotopically transplanted, after a daily oral administration at the dose of 10 mg/kg/d. Interestingly, an antagonism was observed when cisplatin was administered as a single i.p. injection 1 week after the end of the Re-diselenoether administration. In an effort to gain insight of the mechanisms of action of Re-diselenoether complex, interaction with 9-methylguanine as a nucleic acid base model was studied. We have shown that Re-diselenoether gave both mono- and bis-guanine Re adducts, the species assumed to be responsible for the DNA intrastrand lesions.

Development of 4-hexadecyl-4,7-diaza-1,10-decanedithiol (HDD) kit for the preparation of the liver cancer therapeutic agent Re-188-HDD/lipiodol.

INTRODUCTION: A lipiodol solution of (188)Re-4-hexadecyl-2,2,9,9-tetramethyl-4,7-diaza-1,10-decanedithiol (HTDD) has been successfully developed for liver cancer therapy; however, its preparation requires a multi-step synthesis and it is characterized by a low labeling yield. METHODS: We synthesized a new compound, 4-hexadecyl-4,7-diaza-1,10-decanedithioacetate (AHDD), without gem dimethyl groups to address these issues. AHDD was formulated into a kit and was labeled with (188)Re. Biodistribution study was performed using normal BALB/c mice. RESULTS: The kit was labeled with (188)Re with a high efficiency (98.8±0.2%). After extraction with lipiodol, the overall yield of (188)Re-HDD/lipiodol was as high as 90.2±2.6%. A comparative biodistribution study of (188)Re-HTDD and (188)Re-HDD was performed in normal mice after intravenous injection. The lungs were identified as the main uptake site due to capillary-blockage. (188)Re-HDD/lipiodol showed a significantly higher lung uptake than that of (188)Re-HTDD/lipiodol (p<0.05). CONCLUSION: The newly synthesized (188)Re-HDD/lipiodol showed improved radiolabeling yield and biodistribution results compared to (188)Re-HTDD/lipiodol, and may therefore be more suitable for liver cancer therapy.

Preparation and therapeutic evaluation of (188)Re-thermogelling emulsion in rat model of hepatocellular carcinoma.

Radiolabeled Lipiodol(®) (Guerbet, Villepinte, France) is routinely used in hepatoma therapy. The temperature-sensitive hydrogel polyethylene glycol-b-poly-DL-lactic acid-co-glycolic acid-b-polyethylene glycol triblock copolymer is used as an embolic agent and sustained drug release system. This study attempted to combine the polyethylene glycol-b-poly-DL-lactic acid-co-glycolic acid-b-polyethylene glycol hydrogel and radio-labeled Lipiodol to form a new radio-thermogelling emulsion, rhenium-188-N,N'-1,2-ethanediylbis-L-cysteine diethyl-ester dihydrochloride-Lipiodol/hydrogel ((188)Re-ELH). The therapeutic potential of (188)Re-ELH was evaluated in a rodent hepatoma model. Rhenium-188 chelated with N,N'-1,2-ethanediylbis-L-cysteine diethyl-ester dihydrochloride was extracted with Lipiodol to obtain rhenium-188-N,N'-1,2-ethanediylbis-L-cysteine diethyl-ester dihydrochloride-Lipiodol ((188)Re-EL), which was blended with the hydrogel in equal volumes to develop (188)Re-ELH. The (188)Re-ELH phase stability was evaluated at different temperatures. Biodistribution patterns and micro-single-photon emission computed tomography/computed tomography images in Sprague Dawley rats implanted with the rat hepatoma cell line N1-S1 were observed after in situ tumoral injection of ~3.7 MBq (188)Re-ELH. The therapeutic potential of (188)Re-EL (48.58±3.86 MBq/0.1 mL, n=12) was evaluated in a 2-month survival study using the same animal model. The therapeutic effects of (188)Re-ELH (25.52±4.64 MBq/0.1 mL, n=12) were evaluated and compared with those of (188)Re-EL. The responses were assessed by changes in tumor size and survival rates. The (188)Re-ELH emulsion was stable in the gel form at 25°C-35°C for >52 hours. Biodistribution data and micro-single-photon emission computed tomography/computed tomography images of the (188)Re-ELH group indicated that most activity was selectively observed in hepatomas. Long-term (188)Re-ELH studies have demonstrated protracted reductions in tumor volumes and positive effects on the survival rates (75%) of N1-S1 hepatoma-bearing rats. Conversely, the 2-month survival rate was 13% in the control sham group. Therapeutic responses differed significantly between the two groups (P<0.005). Thus, the hydrogel enhanced the injection stability of (188)Re-EL in an animal hepatoma model. Given the synergistic results, direct (188)Re-ELH intratumoral injection is a potential therapeutic alternative for hepatoma treatment.

Therapeutic efficacy of 188Re-MN-16ET lipiodol in an animal model of hepatocellular carcinoma.

OBJECTIVE: In our recent study, we developed a new radiopharmaceutical (Re-188 MN-16ET lipiodol) with encouraging results for the treatment of liver malignancy. In this study, we further evaluated the therapeutic efficacy of this radiopharmaceutical by measuring tumor response and survival times in rats with liver tumors after intra-hepatic arterial injection of Re-188 MN-16ET lipiodol. METHODS: Twelve male rats bearing hepatic tumors were divided into three groups. Group 1 received an intra-hepatic arterial injection of 18.5 MBq Re-188 MN-16ET lipiodol; Group 2 received lipiodol and Group 3 received normal saline. Tumor size was measured by liver sonography before injection, at 2, 4, and 8 weeks after injection. Survival time and response rate were calculated. RESULTS: All rats showed good response and survived over 60 days in Group 1 while all rats showed poor response in Group 2 and Group 3 with only 25 % of rats in Group 2 and none (0 %) in Group 3 survived over 60 days. The p value was 0.0067 between Group 1 and Group 3; 0.04 between Group 1 and Group 2; and 0.034 between Group 2 and Group 3. CONCLUSION: Re-188 MN-16ET lipiodol has good potential for the treatment of hepatoma.

A comparison of Re-188-MN-16ET-lipiodol and transcatheter arterial chemoembolization in the treatment of hepatoma: an animal study.

INTRODUCTION: In patients with unresectable HCC, transcatheter arterial chemoembolization (TACE) is a widely used treatment. Recently, as an alternative treatment modality for HCC, transcatheter arterial embolization with radioisotopes has been investigated. In this study, we compared the therapeutic efficacy of an intra-hepatic arterial injection of Re-188-MN-16ET-lipiodol and the TACE method in rats with liver tumors. METHODS: Twelve male rats bearing hepatic tumors were divided into three groups to evaluate the efficacy of treatment (four in each group). Group 1 received an intra-hepatic arterial injection of 0.2mCi of Re-188-MN-16ET-lipiodol; group 2 received epirubicin (0.5mg/kg) and 0.1ml of lipiodol emulsion; group 3 received 0.1ml of normal saline and served as the control group. Tumor size was measured by liver sonography before injection, at two weeks, four weeks and eight weeks after injection. Survival time was calculated from the day of treatment to 56days after treatment by the life-table method. The response to treatment and the survival time in each group were evaluated and compared. RESULTS: All rats treated with Re-188 MN-16ET-lipiodol showed good response to the therapy. Their tumor size decreased and all rats survived over eight weeks. All rats treated with epirubicin plus lipiodol survived over 8weeks; however, two rats (50%) showed increased tumor size in the 8th week. As for the control group (rats treated with normal saline), all rats survived less than 37days with continuous tumor growth. CONCLUSION: Results showed that Re-188-MN-16ET-lipiodol can be a potential therapeutic pharmaceutical for the treatment of liver tumors.

Rhenium-188: availability from the (188)W/(188)Re generator and status of current applications.

Rhenium-188 is one of the most readily available generator derived and useful radionuclides for therapy emitting ß(-) particles (2.12 MeV, 71.1% and 1.965 MeV, 25.6%) and imageable gammas (155 keV, 15.1%). The (188)W/(188)Re generator is an ideal source for the long term (4-6 months) continuous availability of no carrier added (nca) (188)Re suitable for the preparation of radiopharmaceuticals for radionuclide therapy. The challenges associated with the double neutron capture route of production of the parent (188)W radionuclide have been a major impediment in the progress of application of (188)Re. Tungsten-188 of adequate specific activity can be prepared only in 2-3 of the high flux reactors operating in the World. Several useful technologies have been developed for the preparation of clinical grade (188)W/(188)Re generators. Since the specific activity of (188)W used in the generator is relatively low 185 GBq( < 5 Ci)/g], the eluted (188)ReO(4)(-) can have low radioactive concentration often insufficient for radiopharmaceutical preparation. However, several efficient post elution concentration techniques have been developed that yield clinically useful (188)ReO(4)(-) solutions. Rhenium-188 has been used for the preparation of therapeutic radiopharmaceuticals for the management of diseases such as bone metastasis, rheumatoid arthritis and primary cancers. Several early phase clinical studies using radiopharmaceuticals based on (188)Re-labeled phosphonates, antibodies, peptides, lipiodol and particulates have been reported. This article reviews the availability and use of (188)Re including a discussion of why broader use of (188)Re has not progressed as expected as a popular radionuclide for therapy.

Evaluation of S-values and dose distributions for (90)Y, (131)I, (166)Ho, and (188)Re in seven lobes of the rat liver.

PURPOSE: Rats have been widely used in radionuclide therapy research for the treatment of hepatocellular carcinoma (HCC). This has created the need to assess rat liver absorbed radiation dose. In most dose estimation studies, the rat liver is considered as a homogeneous integrated target organ with a tissue composition assumed to be similar to that of human liver tissue. However, the rat liver is composed of several lobes having different anatomical and chemical characteristics. To assess the overall impact on rat liver dose calculation, the authors use a new voxel-based rat model with identified suborgan regions of the liver. METHODS: The liver in the original cryosectional color images was manually segmented into seven individual lobes and subsequently integrated into a voxel-based computational rat model. Photon and electron particle transport was simulated using the MCNPX Monte Carlo code to calculate absorbed fractions and S-values for (90)Y, (131)I, (166)Ho, and (188)Re for the seven liver lobes. The effect of chemical composition on organ-specific absorbed dose was investigated by changing the chemical composition of the voxel filling liver material. Radionuclide-specific absorbed doses at the voxel level were further assessed for a small spherical hepatic tumor. RESULTS: The self-absorbed dose for different liver lobes varied depending on their respective masses. A maximum difference of 3.5% was observed for the liver self-absorbed fraction between rat and human tissues for photon energies below 100 keV. (166)Ho and (188)Re produce a uniformly distributed high dose in the tumor and relatively low absorbed dose for surrounding tissues. CONCLUSIONS: The authors evaluated rat liver radiation doses from various radionuclides used in HCC treatments using a realistic computational rat model. This work contributes to a better understanding of all aspects influencing radiation transport in organ-specific radiation dose evaluation for preclinical therapy studies, from tissue composition to organ morphology and activity distribution.

Synthesis and application of 188Re-MN-16ET/Lipiodol in a hepatocellular carcinoma animal model.

INTRODUCTION: Hepatocellular carcinoma is the most common form of primary hepatic carcinoma. A new N(2)S(2) tetradentate ligand, N-[2-(triphenylmethyl)thioethyl]-3-aza-19-ethyloxycarbonyl-3-[2-(triphenylmethyl)thioethyl]octadecanoate (H(3)MN-16ET), was introduced and labeled with (188)Re to create (188)Re-MN-16ET in the Lipiodol phase. The potential of (188)Re-MN-16ET/Lipiodol for hepatoma therapy was evaluated in a hepatocellular carcinoma animal model of Sprague-Dawley rats implanted with the N1S1 cell line. METHODS: Synthesis of H(3)MN-16ET was described, and characterization was identified by infrared, nuclear magnetic resonance and mass spectra. We compared the effects of transchelating agents (glucoheptonate or tartaric acid) and a reducing agent (stannous chloride) on the complexing of (188)Re-perrhenate and H(3)MN-16ET. Twenty-four rats implanted with hepatoma were injected with 3.7 MBq/0.1 ml of (188)Re-MN-16ET/Lipiodol or (188)Re-MN-16ET via transcatheter arterial embolization. Biodistribution experiments and single-photon emission computed tomography imaging were performed to investigate tumor accumulation. RESULTS: H(3)MN-16ET was proved to easily conjugate with the Re isotope and showed good solubility in Lipiodol. The radiochemical purity of (188)Re-MN-16ET/Lipiodol with 10 mg tartaric acid and stannous chloride was shown to be more than 90%. The major distribution sites of (188)Re-MN-16ET in Sprague-Dawley rats were hepatoma and the liver. However, the radioactivity at the tumor site postadministered with (188)Re-MN-16ET was quickly decreased from 9.15±0.23 (at 1 h) to 2.71%±0.18% of injected dose/g (at 48 h). The biodistribution and micro-single-photon emission computed tomography/computed tomography image data showed that (188)Re-MN-16ET/Lipiodol was selectively retained at the tumor site, with 11.55±1.44, 13.16±1.46 and 10.67%±0.95% of injected dose/g at 1, 24 and 48 h postinjection, respectively. The radioactivity in normal liver tissue was high but significantly lower than that of the tumors. CONCLUSION: H(3)MN-16ET is a suitable tetradentate ligand for (188)Re labeling. From the animal data, we suggest that (188)Re-MN-16ET/Lipiodol has the potential to be a therapeutic radiopharmaceutical for hepatoma treatment.

Preliminary evaluation of acute toxicity of (188) Re-BMEDA-liposome in rats.

Liposomes can selectively target cancer sites and carry payloads, thereby improving diagnostic and therapeutic effectiveness and reducing toxicity. To evaluate therapeutic strategies, it is essential to use animal models reflecting important safety aspects before clinical application. The objective of this study was to investigate acute radiotoxicity of ¹88Re-N,N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomes (¹88Re-BMEDA-liposome) in Sprague-Dawley rats. Rats were administered with ¹88Re-BMEDA-liposome, normal saline as blank or non-radioactive liposome as vehicle control via intravenous injection and observed for 14 days. Examinations were conducted with respect to mortality, clinical signs, food consumption, body weight and hematological and biochemical analyses. In addition, gross necropsy, histopathological examinations and cytogenetic analyses were also performed. None of the rats died and no clinical sign was observed during the 14-day study period. Rats administered with ¹88Re-BMEDA-liposome at dosage of 185 MBq displayed a significant weight loss compared with the control from study day (SD) 1 to SD 4, and the white blood cell count reduced to 5-10% of initial value (female: 18.55 ± 6.58 to 0.73 ± 0.26 x 10³ µl⁻¹; male: 14.52 ± 5.12 to 1.43 ± 0.54 x 10³ µl⁻¹) 7 days-post injection, but were found to have recovered on SD 15. There were no significant differences in biochemical parameters and histopathological assessments between the ¹88Re-BMEDA-liposome-treated and control groups. The frequencies of dicentric chromosomes were associated with dosage of ¹88Re-BMEDA-liposome. The information generated from this study on acute toxicity will serve as a safety reference for further subacute toxicity study in rats and human clinical trials.

Evaluating the potential of (188)Re-ECD/lipiodol as a therapeutic radiopharmaceutical by intratumoral injection for hepatoma treatment.

BACKGROUND/OBJECTIVES: Intratumoral injection of a radiopharmaceutical is a potential modality to treat liver tumors. Rhenium-188 ((188)Re) was used to chelate with ethyl cysteinate dimer (ECD) in lipiodol solution to form (188)Re-ECD/lipiodol, which was then evaluated for its therapeutic potential in a rodent hepatoma model. MATERIALS AND METHODS: Male Sprague-Dawley rats were implanted with N1-S1 hepatoma cells orthotopically and randomly divided into two groups. Group 1 (n = 29) and group 2 (n = 10) received (188)Re-ECD/lipiodol (30.4 +/- 21.8 MBq/0.1 mL) and 0.1 mL of normal saline by intratumoral injection, respectively. Three rats in group 1 were imaged by micro-single-photon emission computed tomography/computed tomography scan to evaluate the biodistribution pattern. All rats were monitored for change of tumor size and survival rate after 2 months. RESULTS: The in vitro stability test showed that (188)Re-ECD was well-retained in the lipiodol phase for 48 hours. The biodistribution image revealed that radioactivity was retained well in hepatomas 24 hours postinjection. Long-term studies demonstrated that rats treated with (188)Re-ECD/Lipiodol had smaller tumor volumes and a better survival rate, compared to the control group. At the end of observation, the survival rates in groups 1 and 2 were 62% and 20%, respectively (p < 0.05). CONCLUSIONS: (188)Re-ECD/lipiodol via direct intratumoral injection shows potential for treating hepatoma and warrants further clinical trials.

[Selective internal radiotherapy (radioembolization) and radiation therapy for HCC--current status and perspectives]. / Selektive interne Radiotherapie (Radioembolisation) und Strahlentherapie beim HCC--Stand und Perspektiven.

Microsphere and particle technologies for the selective transport of tumoricidal agents or radiation represent a new generation of therapeutics in interventional oncology. The intrahepatic application of radioactive microspheres via the hepatic artery, for instance, allows locoregional therapy of diffuse or multifocal liver tumours, for which to date systemic therapy was the only remaining option. Current standards for this selective internal radiotherapy or radioembolisation are 90-yttrium glass or resin microspheres. Indication, technique, and the current results are extensively discussed. In addition to 90-yttrium microspheres, other radiopharmaceuticals, such as 131-iodine or 188-rhenium lipiodol, have been successful used for SIRT. As a result of new, more selective radiation techniques, internal radiotherapy for the locoregional treatment of HCC has been recently complemented by an increasing use of percutaneous radiotherapy.

Use of the Oak Ridge National Laboratory tungsten-188/rhenium-188 generator for preparation of the rhenium-188 HDD/lipiodol complex for trans-arterial liver cancer therapy.

This work describes the installation, use, and quality control (QC) of the alumina-based tungsten-188 ((188)W)/rhenium-188 ((188)Re) generators provided by the Oak Ridge National Laboratory (ORNL). In addition, methods used for concentration of the (188)Re-perrhenate bolus and preparation of (188)Re-labeled HDD (4-hexadecyl-2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol) for trans-arterial administration for therapy of nonresectable liver cancer also are described. The (188)W/(188)Re generator has a long useful shelf-life of several months and is a convenient on-site (188)Re production system. (188)Re has excellent therapeutic and imaging properties (T(1/2) 16.9 hours; E(betamax) 2.12 MeV; 155-keV gamma ray, 15%) and is cost effectively obtained on demand by saline elution of the generator. The clinical efficacy of a variety of (188)Re-labeled agents has been demonstrated for several therapeutic applications. Because of the favorable physical properties of (188)Re, several (188)Re-labeled agents are being developed and evaluated for the treatment of nonresectable/refractory liver cancer. (188)Re-labeled HDD has been the most widely studied of these agents for this application and has been introduced into clinical trials at a number of institutions. The trans-arterial administration of (188)Re-labeled agents for treatment of inoperable liver cancer requires use of high-level (1-2 Ci) (188)W/(188)Re generators. The handling of such high levels of (188)Re imposes radiological precautions normally not encountered in a radiopharmacy and adequate care and ALARA (ie, "As Low As Reasonably Achievable") principles must be followed. The ORNL generator provides consistently high (188)Re yields (>75%) and low (188)W parent breakthrough (<10(-3)%) over an extended shelf-life of several months. However, the high elution volumes (20-40 mL for 1-2 Ci generators) can require concentration of the (188)Re bolus by postelution passage through silver cation chloride trapping columns used in the cost-effective tandem cation/anion column system. The silver column removes the high levels of chloride anion as insoluble AgCl, thus allowing subsequent specific trapping of the perrhenate anion on the small (QMA SeaPak) anion column. This method permits subsequent elution of (188)Re-perrhenate with a small volume of saline, providing a very high activity-concentration solution. Because the (188)Re-specific volume-activity concentration continually decreases with time, the tandem system is especially effective method for extending the useful generator shelf-life. Low elution flow rates (<1 mL/min) minimize any high back pressure which may be encountered during generator/tandem column elution when using tightly packed, small-particle-size commercial columns. In-house preparation of silver cation columns is recommended since the chloride trapping capacity is essentially unlimited, it is inexpensive and not limited in availability to any one supplier, and back pressure can be eliminated by the use of larger particles. Methods for the preparation of (188)Re-HDD have been optimized and this agent can be obtained in high yield (80%).

Patient-specific radiation dosimetry for radionuclide therapy of liver tumors with intrahepatic artery rhenium-188 lipiodol.

A clinically practical algorithm has been developed for the treatment of liver cancer by the administration of rhenium-188 ((188)Re)-labeled lipiodol via the hepatic artery. This algorithm is based on the "maximum tolerated-activity" paradigm for radionuclide therapy. A small "scout" activity of (188)Re-labeled lipiodol is administered to the patient before the actual therapeutic administration. At approximately 3 hours after administration, the activities in the normal liver, liver tumors, lungs, and total body are measured by gamma camera imaging using the conjugate-view method, with first-order corrections for attenuation (using a (188)Re transmission scan) and scatter (using the "dual-window" method). At the same time, peripheral blood samples are counted, and the activity concentrations in whole blood are calculated. The blood activity concentrations are then converted to red marrow activity concentrations and then total red marrow activity using anatomic data from Standard Man anthropomorphic models. Next, the cumulated activities in the normal liver, liver tumors, lungs, red marrow, and total body are calculated using the measured activities in the respective source regions and conservatively assuming elimination of activity only by physical decay in situ. The absorbed doses to the therapy-limiting normal tissues, liver, lung, and red marrow, are then calculated using the Medical Internal Radiation Dose Committee schema, adjusting the pertinent S factors for differences in total body and organ masses between the patient and the anthropomorphic model and including the dose contribution from the liver tumors. Finally, based on maximum tolerated absorbed doses of 3,000, 1,200, and 150 rad (cGy) to liver, lung, and red marrow, the respective absorbed doses per unit administered activity are used to calculate the therapy activity. Although not required for treatment planning, tumor absorbed dose may also be estimated. This algorithm has been automated using an Excel (Microsoft, Redmond, WA) spreadsheet.

A report on the implementation aspects of the International Atomic Energy Agency's first doctoral coordinated research project, "Management of liver cancer using radionuclide methods with special emphasis on trans-arterial radio-conjugate therapy and internal dosimetry".

Liver cancer is one of the most dreaded cancers, and it is highly prevalent in the developing countries, where the resources are extremely scarce to deal with this disease using the current commercially available and expensive therapeutic radiopharmaceuticals. The International Atomic Energy Agency (IAEA), in pursuit of its mandate to promote the application of nuclear technology in the health care in its Member States, has developed and clinically evaluated a new and cost-effective therapeutic radio-conjugate, rhenium-188 ((188)Re)-lipiodol for the treatment of hepatocellular carcinoma through its first Doctoral Coordinated Research Project. The ready availability of no-carrier-added (188)Re from the tungsten-188/(188)Re generator represents a potentially important source of a therapeutic radioisotope for a broad range of therapeutic applications in nuclear medicine. The alumina-based tungsten-188/(188)Re generator system comes with reasonable cost and exhibits attractive therapeutic properties, excellent performance and very long useful shelf-life. Because of the long shelf-life of several months, the use of this generator offers a unique opportunity for the cost-effective and routine availability of a versatile therapeutic radioisotope on an on-demand basis. Further, using its extensive global network and outreach, the IAEA has also transferred the technology of the in-house preparation and use of (188)Re-labeled lipiodol to many institutions around the world, which can now prepare (188)Re-labeled lipiodol in their own radiopharmacy laboratories and treat patients. This effort of the IAEA in trying to address some of the challenges of liver cancer therapy in developing countries has been and truly a global venture with involvement and contributions from several organizations, institutions and numerous individuals. This article discusses some of the implementation aspects of this very important activity of the Agency.

International Atomic Energy Agency-sponsored multination study of intra-arterial rhenium-188-labeled lipiodol in the treatment of inoperable hepatocellular carcinoma: results with special emphasis on prognostic value of dosimetric study.

A multicenter study was sponsored by the International Atomic Energy Agency (IAEA) to assess the safety and efficacy of transarterial rhenium-188 ((188)Re) HDD lipiodol (radioconjugate to lipiodol using an HDD kit) in the treatment of unresectable hepatocellular carcinoma. During 5 years, 185 patients received at least 1 treatment of radioconjugate, and 51 were retreated. The level of radioconjugate administered was based on radiation-absorbed dose to critical normal organs, calculated after a "scout" dose of radioconjugate. The total injected activity, including the scout dose during the first treatment, ranged from 21 to 364 mCi (mean, 108 mCi/4 GBq). Immediate and late side-effects were minimal. Tumor size could be evaluated in 88 patients. Among these patients, the objective response rate was 25%; stable disease was observed in 53% and tumor progression in 22%. With a median follow-up of 455 days, the estimated 12- and 24-month overall survival was 46% and 23%. This multicenter study shows that (188)Re lipiodol is a safe and cost-effective method to treat primary hepatocellular carcinoma via the transarterial route and requires further evaluation by treatment of greater numbers of patients.

Assessment of 186Re chelate-conjugated bisphosphonate for the development of new radiopharmaceuticals for bones.

INTRODUCTION: The preferable pharmacokinetics of rhenium-186 (186Re)-monoaminemonoamidedithiol-conjugated or 186Re-mercaptoacetyltriglycine-conjugated bisphosphonates (BPs) suggested that the molecular design would be applicable to other radionuclides such as 68Ga, 99mTc, 153Sm and 177Lu. In this study, a key factor affecting the pharmacokinetics of a chelate-conjugated BP was investigated to estimate the validity and the applicability of molecular design. METHODS: Chemically inert and well-characterized tricarbonyl[186Re][(cyclopentadienylcarbonyl amino)-acetic acid]rhenium ([186Re]CpTR-Gly) was conjugated with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate and purified by high-performance liquid chromatography (HPLC) to prepare [186Re](1-{3-[tricarbonyl(cyclopentadienylcarbonyl amino)-acetylamido]-1-hydroxy-1-phosphono-propyl}-phosphonic acid)rhenium ([186Re]CpTR-Gly-APD). Plasma stability, plasma protein binding, hydroxyapatite (HA) binding and the pharmacokinetics of [186Re]CpTR-Gly-APD were compared with those of 186Re 1-hydroxyethylidene-1,1-diphosphonate (HEDP). The effect of HEDP coadministration and preadministration on the pharmacokinetics of [186Re]CpTR-Gly-APD was also determined. RESULTS: The HPLC-purified [186Re]CpTR-Gly-APD showed higher plasma stability, higher HA binding, higher bone accumulation and lower plasma protein binding than did 186Re-HEDP. However, HA binding of [186Re]CpTR-Gly-APD decreased to levels slightly higher than that of 186Re-HEDP at similar HEDP concentrations. Bone accumulation of [186Re]CpTR-Gly-APD also decreased to levels similar to that of 186Re-HEDP when [186Re]CpTR-Gly-APD was coinjected with HEDP equivalent to that in 186Re-HEDP. In contrast, HEDP pretreatment did not impair bone accumulation of the two 186Re-labeled compounds. However, a delay in blood clearance and an increase in renal radioactivity levels were observed particularly with 186Re-HEDP. CONCLUSIONS: Although 186Re-HEDP possessed HA binding and bone accumulation similar to those of [186Re]CpTR-Gly-APD, the specific activity of 186Re-labeled BPs was found to play a crucial role in bone accumulation and blood clearance. Thus, the molecular design of chelate-conjugated BP would be useful for the development of bone-seeking radiopharmaceuticals with a variety of radionuclides by selecting chelating molecules that provide high specific activities.

Management of multiple intrahepatic recurrences after radiofrequency ablation of hepatocellular carcinoma with rhenium-188-HDD-lipiodol.

We tried to evaluate the role of dosimetry-guided transarterial radionuclide therapy (TART) with rhenium-188 (Re-188)-4-hexadecyl 1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol (HDD)-lipiodol in a patient with multiple intrahepatic recurrences after radiofrequency ablation of hepatocellular carcinoma (HCC). The dosimetry helped in delivering the maximum possible activity of Re-188, thus the radiation-absorbed dose, safely to the tumour without jeopardizing other organs. There was no procedure-related complication and the patient tolerated therapy well with no adverse effects. The lesions were completely ablated with a single dose of Re-188 and the patient has been disease free for the past 18 months. TART with Re-188-HDD-lipiodol appears to be a promising therapeutic option in patients with HCC who experience recurrence after percutaneous ablative therapy.