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Purpose: Despite a rise in clinical use of radiopharmaceutical therapies, the biological effects of radionuclides and their relationship with absorbed radiation dose are poorly understood. Here, we set out to define this relationship for Auger electron emitters [ 99m Tc]TcO 4 - and [ 123 I]I - and β - - particle emitter [ 188 Re]ReO 4 - . Studies were carried out using genetically modified cells that permitted direct radionuclide comparisons., Methods and Materials: Triple-negative MDA-MB-231 breast cancer cells expressing the human sodium iodide symporter (hNIS) and green fluorescent protein (GFP; MDA-MB-231.hNIS-GFP) were used. In vitro radiotoxicity of [ 99m Tc]TcO 4 - , [ 123 I]I - , and [ 188 Re]ReO 4 - was determined using clonogenic assays. Radionuclide uptake, efflux, and subcellular location were used to calculate nuclear absorbed doses using the Medical Internal Radiation Dose (MIRD) formalism. In vivo studies were performed using female NSG mice bearing orthotopic MDA-MB-231.hNIS-GFP tumors and compared with X-ray-treated (12.6-15 Gy) and untreated cohorts. Absorbed dose per unit activity in tumors and sodium iodide symporter-expressing organs was extrapolated to reference human adult models using OLINDA/EXM., Results: [ 99m Tc]TcO 4 - and [ 123 I]I - reduced the survival fraction only in hNIS-expressing cells, whereas [ 188 Re]ReO 4 - reduced survival fraction in hNIS-expressing and parental cells. [ 123 I]I - required 2.4- and 1.5-fold lower decays/cell to achieve 37% survival compared with [ 99m Tc]TcO 4 - and [ 188 Re]ReO 4 - , respectively, after 72 hours of incubation. Additionally, [ 99m Tc]TcO 4 - , [ 123 I]I - , and [ 188 Re]ReO 4 - had superior cell killing effectiveness in vitro compared with X-rays. In vivo, X-ray led to a greater median survival compared with [ 188 Re]ReO 4 - and [ 123 I]I - (54 days vs 45 and 43 days, respectively). Unlike the X-ray cohort, no metastases were visualized in the radionuclide-treated cohorts. Extrapolated human absorbed doses of [ 188 Re]ReO 4 - to a 1 g tumor were 13.8- and 11.2-fold greater than for [ 123 I]I - in female and male models, respectively., Conclusions: This work reports reference dose-effect data using cell and tumor models for [ 99m Tc]TcO 4 - , [ 123 I]I - , and [ 188 Re]ReO 4 - for the first time. We further demonstrate the tumor-controlling effects of [ 123 I]I - and [ 188 Re]ReO 4 - in comparison with external beam radiation therapy., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Nonmelanoma skin cancer and its treatment represent a significant global cancer burden for health care systems and patients. Rhenium skin cancer therapy (Rhenium SCT) is a novel noninvasive radionuclide nonmelanoma skin cancer treatment, which can be provided in a single outpatient session. The aim of this prospective, multicenter, single-arm, international, phase IV study (EPIC-Skin) is to assess clinic- and patient-reported outcomes of Rhenium SCT as a treatment for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Methods: Eligible patients had biopsy-proven stage I or stage II BCC or SCC lesions no more than 3 mm deep and no larger than 8 cm 2 in area. Rhenium SCT resin was applied to an adhesive foil affixed to the target lesion in a single session. Interim efficacy and safety analysis were planned once 50% of target patients had recorded a 6-mo follow-up visit. Primary outcome is the proportion of lesions achieving complete response using modified RECIST. Secondary and other outcome measures include patient-reported quality of life (QoL), treatment comfort, and cosmesis. Results: A total of 182 patients was enrolled and administered Rhenium SCT (50 Gy dose to deepest point of target) to at least 1 BCC or SCC. Of 81 patients who reached the 6-mo posttreatment follow-up, it was found that 97.2% (103/106) of lesions showed complete responses and 2.8% (3/106) had partial responses. Improvements in QoL were also reported, whereas no patients reported any pain or discomfort during treatment. Adverse events were reported in 15.9% (29/182) of patients and were rated grade 1 ( n = 19), grade 2 ( n = 9), or grade 3 ( n = 1). Conclusion: This preliminary analysis of the EPIC-Skin study indicates that Rhenium SCT is safe and effective for the treatment of BCC and SCC and is associated with significant QoL improvements. It will be particularly beneficial for lesions that are difficult to treat surgically because of size and location. It is also beneficial for patients with comorbidities or those unable to receive conventional fractionated radiotherapy., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Proper catheter placement for convection-enhanced delivery (CED) is required to maximize tumor coverage and minimize exposure to healthy tissue. We developed an image-based model to patient-specifically optimize the catheter placement for rhenium-186 ( 186 Re)-nanoliposomes (RNL) delivery to treat recurrent glioblastoma (rGBM)., Methods: The model consists of the 1) fluid fields generated via catheter infusion, 2) dynamic transport of RNL, and 3) transforming RNL concentration to the SPECT signal. Patient-specific tissue geometries were assigned from pre-delivery MRIs. Model parameters were personalized with either 1) individual-based calibration with longitudinal SPECT images, or 2) population-based assignment via leave-one-out cross-validation. The concordance correlation coefficient (CCC) was used to quantify the agreement between the predicted and measured SPECT signals. The model was then used to simulate RNL distributions from a range of catheter placements, resulting in a ratio of the cumulative RNL dose outside versus inside the tumor, the "off-target ratio" (OTR). Optimal catheter placement) was identified by minimizing OTR., Results: Fifteen patients with rGBM from a Phase I/II clinical trial (NCT01906385) were recruited to the study. Our model, with either individual-calibrated or population-assigned parameters, achieved high accuracy (CCC > 0.80) for predicting RNL distributions up to 24 h after delivery. The optimal catheter placements identified using this model achieved a median (range) of 34.56 % (14.70 %-61.12 %) reduction on OTR at the 24 h post-delivery in comparison to the original placements., Conclusions: Our image-guided model achieved high accuracy for predicting patient-specific RNL distributions and indicates value for optimizing catheter placement for CED of radiolabeled liposomes., Competing Interests: Declaration of competing interest William T. Phillips discloses stock ownership and board membership in NanoTx, Inc., and is consultant for Plus Therapeutics, Inc. Andrew J. Brenner discloses financial Interests and stock ownership in NanoTx, Inc., and financial Interests and advisory role in Plus Therapeutics, Inc. Ryan T. Woodall owns stake in Cairina Inc. All other authors report no conflict of interest relevant to this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The use of radiopharmaceuticals has gained a special place in the diagnosis and treatment of cancers and evaluation of the function of different organs of the body. In this study, the absorbed dose distribution of organs after injection of 188 Re-Mu-9 has been investigated using MIRD method and MCNP-4C simulation code. The 188 Re-Mu-9 labeled was injected the mouse body and the amount of 188 Re-labeled accumulation was evaluated after 1, 4 and 2 4 h. Having a map of the distribution of radiopharmaceutical activity in the animal body, it is possible to convert it into a human model to obtain the internal dose received by 188 Re-Mu-9 injection using the MIRD calculation method and the MCNP simulation code. According to the results of the study, the animal/human model can be acceptable method for dose estimation of antibody-based radiopharmaceuticals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: High-dose rate brachytherapy using a non-sealed 188 Rhenium resin ( 188 Re) is a recently approved treatment option for non-melanoma skin cancer (NMSC). The treatment goal is to deliver a personalized absorbed dose to the deepest point of neoplastic infiltration corresponding to the minimal target dose. The treatment consists of the application of a 188 Re-based resin over a plastic foil placed on the target skin surface. However, there is no treatment planning tool to assess the 188 Re activity needed for a personalized treatment., Purpose: The paper aims to present a novel Monte Carlo (MC)-based tool for 188 Re-based resin activity and dose calculation, experimentally validated using Gafchromic EBT3 films., Methods: MC simulations were carried out using FLUKA modeling density and composition of 188 Re resin. The MC-based look up table (LUT) was incorporated in an ad hoc developed tool. The proposed tool allows the personalized calculation of treatment parameters (i.e., activity to be dispensed, the treatment duration, and dose volume histograms), according to the target dimension. The proposed tool was compared using Bland-Altman analysis to the previous calculation approaches conducted using VARSKIN in a retrospective cohort of 76 patients. The tool was validated in ad hoc experimental set ups using a stack of calibrated Gafchromic EBT3 films covered by a plastic film and exposed using a homogenous activity distribution of 188 Re eluate and a heterogeneous activity distribution of 188 Re resin mimic the patient treatment., Results: The agreement between the proposed tool and VARSKIN was evaluated on the investigated cohort with median range of target area, target depth, and treatment time equal to 4.8 [1.0-60.1] cm 2 , 1.1 [0.2-3.0] mm, and 70 [21-285] min, with a median range of target dose (Gy) of 23.5 [10-54.9]. The calculated minimal target doses, ranged from 1% to 10% for intermediate target depths (1.2 ± 0.7 mm), while showing significant differences in the estimation of superficial (maximal) target doses. The agreement between MC calculation and measurements at different plans in a stack of Gafchromic EBT3 films was within 10% for both the homogenous and heterogeneous activity distribution of 188 Re. Worst agreements were observed for absorbed doses lower than 0.3 Gy., Conclusions: Our results support the implementation of our MC-based tool in the practical routine for calculating the 188 Re resin activity and treatment parameters necessary for obtaining the prescribed minimal target dose., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Rhenium (Re) is widely used in the diagnosis and treatment of cancer due to its unique physical and chemical properties. Re has more valence electrons in its outer shell, allowing it to exist in a variety of oxidation states and to form different geometric configurations with many different ligands. The luminescence properties, lipophilicity, and cytotoxicity of complexes can be adjusted by changing the ligand of Re. This article mainly reviews the development of radionuclide 188 Re in radiotherapy and some innovative applications of Re as well as the different therapeutic approaches and imaging techniques used in cancer therapy. In addition, the current application and future challenges and opportunities of Re are also discussed.

The β - emitter, rhenium-188 ( 188 Re), has long been recognized as an attractive candidate for targeted cancer radionuclide therapy (TRNT). This transition metal shares chemical similarities with its congener element technetium, whose nuclear isomer technetium-99m ( 99m Tc) is the current workhorse of diagnostic nuclear medicine. The differences between these two elements have a significant impact on the radiolabelling methods and should always receive critical attention. This review aims to highlight what needs to be considered to design a successful radiopharmaceutical incorporating 118 Re. Some of the most effective strategies for preparing therapeutic radiopharmaceuticals with 188 Re are illustrated and rationalized using the concept of the inorganic functional group (core) and a simple ligand field theoretical model combined with a qualitative definition of frontiers orbitals. Of special interest are the Re(V) oxo and Re(V) nitrido functional groups. Suitable ligands for binding to these cores are discussed, successful clinical applications are summarized, and a prediction of viable future applications is presented. Rhenium-188 decays through the emission of a high energy beta particle (2.12 MeV max energy) and a half-life of 16.9 h. An ideal biological target would therefore be a high-capacity target site (transporters, potential gradients, tumour microenvironment) with less emphasis on saturable targets such as overexpressed receptors on smaller metastases.

Selective-intra-arterial radionuclide therapy (SIRT) using radiolabeled microspheres are being widely employed for the delivery of therapeutic radioisotope to liver cancers by exploiting the dual blood supply to liver. It delivers the therapeutic radiations to tumor and spares the healthy liver. Several radiolabeled microspheres formulations, labelled with 90 Y, are commercially available. However, high-cost leads to unaffordability for several patients. 188 Re-based therapy seems affordable due to commercial availability of 188 W/ 188 Re generator that have long shelf-life of more than 6 months. To provide affordable solution, the microsphere cold kit with quick and facile methodology for 188 Re radiolabeling has been developed. The microsphere cold kit has been characterized for their physicochemical properties. The Quality Control (QC) tests were also performed for clinical application. The feasibility studies were performed to study distribution and retention of 188 Re microspheres in tumor. The results demonstrated that the developed cold kit enables facile and quick radiolabeling with 188 Re. 188 Re microspheres showed good retention in tumor and found suitable for SIRT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In recent decades, the use of alpha; pure beta; or beta/gamma emitters in oncology, endocrinology, and interventional cardiology rheumatology, has proved to be an important alternative to the most common therapeutic regimens. Among radionuclides used for therapy in nuclear medicine, two rhenium radioisotopes are of particular relevance: rhenium-186 and rhenium-188. The first is routinely produced in nuclear reactors by direct neutron activation of rhenium-186 via 185 Re(n,γ) 186 Re nuclear reaction. Rhenium-188 is produced by the decay of the parent tungsten-188. Separation of rhenium-188 is mainly performed using a chromatographic 188 W/ 188 Re generator in which tungsten-188 is adsorbed on the alumina column, similar to the 99 Mo/ 99m Tc generator system, and the radionuclide eluted in saline solution. The application of rhenium-186 and rhenium-188 depends on their specific activity. Rhenium-186 is produced in low specific activity and is mainly used for labeling particles or diphosphonates for bone pain palliation. Whereas, rhenium-188 of high specific activity can be used for labeling peptides or bioactive molecules. One of the advantages of rhenium is its chemical similarity with technetium. So, diagnostic technetium analogs labeled with radiorhenium can be developed for therapeutic applications. Clinical trials promoting the use of 186/188 Re-radiopharmaceuticals is, in particular, are discussed.

Background: Selective inhibitory effects of rhenium(I)-diselenoether (Re-diSe) were observed in cultured breast malignant cells. They were attributed to a decrease in Reactive Oxygen Species (ROS) production. A concomitant decrease in the production of Transforming Growth Factor-beta (TGFβ1), Insulin Growth Factor 1 (IGF1), and Vascular Endothelial Growth Factor A (VEGFA) by the malignant cells was also observed., Aim: The study aimed to investigate the anti-tumor effects of Re-diSe on mice bearing 4T1 breast tumors, an experimental model of triple-negative breast cancer, and correlate them with several biomarkers., Material and Methods: 4T1 mammary breast cancer cells were orthotopically inoculated into syngenic BALB/c Jack mice. Different doses of Re-diSe (1, 10, and 60 mg/kg) were administered orally for 23 consecutive days to assess the efficacy and toxicity. The oxidative status was evaluated by assaying Advanced Oxidative Protein Products (AOPP), and by the dinitrophenylhydrazone (DNPH) test in plasma of healthy mice, non-treated tumor-bearing mice (controls), treated tumor-bearing mice, and tumors in all tumor-bearing mice. Tumor necrosis factor (TNFα), VEGFA, VEGFB, TGFβ1, Interferon, and selenoprotein P (selenoP) were selected as biomarkers., Results: Doses of 1 and 10 mg/kg did not affect the tumor weights. There was a significant increase in the tumor weights in mice treated with the maximum dose of 60 mg/kg, concomitantly with a significant decrease in AOPP, TNFα, and TGFβ1 in the tumors. SelenoP concentrations increased in the plasma but not in the tumors., Conclusion: We did not confirm the anti-tumor activity of the Re-diSe compound in this experiment. However, the transplantation of the tumor cells did not induce an expected pro-oxidative status without any increase of the oxidative biomarkers in the plasma of controls compared to healthy mice. This condition could be essential to evaluate the effect of an antioxidant drug. The choice of the experimental model will be primordial to assess the effects of the Re-diSe compound in further studies., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Amongst cancer patients, bone pain due to skeletal metastases is a major cause of morbidity. A number of beta-emitting radiopharmaceuticals have been used to provide internal radiotherapy of bone metastases and provide palliative pain relief. In this article we describe the different physical characteristics of the various beta emitting radionuclides which have been used in this clinical setting and the potential impact of differences in dose-rate on radiobiological outcomes. A detailed review of the biodistribution of these treatments, based on both in-vivo clinical investigations and post mortem autoradiography assessments is provided. These treatments result in physiological delivery of radiation doses to the target disease as well as to critical healthy organs. Particular attention is paid to the radiation doses received by normal bone tissue, bone marrow as well as metastatic bone disease. The underlying models of radiation transport within bone and bone marrow are reviewed alongside the practical steps that must be taken to acquire and analyse the information require for clinical dosimetry assessments. The role of whole body measurements, blood and faecal assays as well as both planar and tomographic gamma camera imaging are considered. In addition we review the rationale for allocating measured bone uptake between trabecular and cortical bone tissue. The difference between bone volume and bone surface seeking radiopharmaceuticals are also discussed. This review also extends to the development of preclinical models of bone metastases which may inform future dosimetric calculations. Finally, we also present a comprehensive review of the dosimetry of the established treatments 89 Strontium-chloride; 32 Phosphorus; 188 Rhenium-hydroxyethylidine disphosphonate; 186 Rhenium-1,1-hydroxyethylidene disphosphonate ( 186 Re-HEDP); 153 Samarium-ethylenediaminetetramethylene phosphonate; as well as the emerging treatments 188 Rhenium-zoledronic acid; 188 Rhenium-ibedronat; 177 Lutetium-zoledronic acid; and 177 Lutetium ethylenediaminetetramethylene phosphonate. This review highlights not only the inter treatment differences in the radiation absorbed doses delivered to metastatic disease by different radiopharmaceuticals but also the intra treatment differences which result in a large range of observed doses between patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: This study aimed to provide long-term clinical data about an innovative epidermal radioisotope therapy called Rhenium-SCT ® (Skin Cancer Therapy) for non-melanoma skin cancer (NMSC), based on the use of the non-sealed beta emitter rhenium-188., Material and Methods: 52 NMSC patients with a mean age of 71.7 years were treated with rhenium-188 skin cancer therapy between the years 2005 and 2014. An acryl matrix containing rhenium-188 was applied on a plastic foil covering the tumor. The treatment time for reaching a radiation dose of 50 Gy was calculated by a software program. Patients' characteristics and clinical follow-up data were collected and retrospectively analyzed., Results: Overall 55 lesions (32 BCC, 19 SCC, 2 M. Bowen and 2 extramammary Paget's disease (EMPD)) mainly in the head and neck region (72.3%) were treated. The average size of the irradiation area was 9.79 cm 2 and the mean treatment time 46.35 min. All lesions showed a complete remission after a follow-up period between 3 and more than 12 months. No complications or other post-interventional problems were reported., Conclusions: Rhenium-SCT ® is considered as an effective, rapid, safe, painless treatment mostly performed in a single therapeutic session, regardless of the shape complexity, anatomical site and number of lesions.

Background: Rhenium-188( 188 Re)-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 188 Re-lipiodol using freshly eluted 188 Re-sodium perrhenate from commercial Tungsten-188/ 188 Re generator following recommended procedures. Results: The overall yield of 188 Re-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 188 Re-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 188 Re-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 188 Re activity of low radioactive concentration.

Organometallic compounds are increasingly recognized as promising anticancer and antibiotic drug candidates. Among the transition metal ions investigated for these purposes, rhenium occupies a special role. Its tri- and dicarbonyl complexes, in particular, attract continuous attention due to their relative ease of preparation, stability and unique photophysical and luminescent properties that allow the combination of diagnostic and therapeutic purposes, thereby permitting, e.g., molecules to be tracked within cells. In this review, we discuss the anticancer and antibiotic properties of rhenium tri- and dicarbonyl complexes described in the last seven years, mainly in terms of their structural variations and in vitro efficacy. Given the abundant literature available, the focus is initially directed on tricarbonyl complexes of rhenium. Dicarbonyl species of the metal ion, which are slowly gaining momentum, are discussed in the second part in terms of future perspective for the possible developments in the field.

Background and Aim: High dose brachytherapy using a non sealed 188 Re-resin (Rhenium-SCT®, Oncobeta® GmbH, Munich, Germany) is a treatment option for non-melanoma skin cancer (NMSC). The aim of this prospective study was to assess the efficacy and the safety of a single application of Rhenium-SCT® in NMSC., Materials and Method: Fifty consecutive patients (15F, 35 M, range of age 56-97, mean 81) showing 60 histologically proven NMSCs were enrolled and treated with the Rhenium-SCT® between October 2017 and January 2020. Lesions were located on the face, ears, nose or scalp (n = 46), extremities (n = 9), and trunk (n = 5). Mean surface areas were 7.0 cm 2 (1-36 cm 2 ), mean thickness invasion was 1.1 mm (0.2-2.5 mm), and mean treatment time was 79 min (21-85 min). Superficial, mean, and target absorbed dose were 185 Gy, 63 Gy, and 31 Gy respectively. Patients were followed-up at 14, 30, 60, 90, and 180 days posttreatment, when dermoscopy and biopsy were performed. Mean follow-up was 20 months (range 3-33 months). Early skin toxicity was classified according to Common Terminology Criteria for Adverse Events (CTCAE). Cosmetic results were evaluated after at least 12 months according to Radiation Therapy Oncology Group (RTOG) scale., Results: At 6 months follow-up, histology and dermoscopy were available for 54/60 lesions, of which 53/54 (98%) completely responded. One patient showed a 1-cm 2 residual lesion that was subsequently surgically excised. Twelve months after treatment, 41/41 evaluable lesions were free from relapse. Twenty four months after treatment, 23/24 evaluable lesions were free of relapse. In 56/60 lesions early side effects, resolving within 32 days were classified as grades 1-2 (CTCAE). In the remaining 4/60 lesions, these findings were classified as grade 3 (CTCAE) and lasted up to 8-12 weeks but all resolved within 90 days. After at least 12 months (12-33 months), cosmetic results were excellent (30 lesions) or good (11 lesions)., Conclusion: High dose brachytherapy with Rhenium-SCT® is a noninvasive, reasonably safe, easy to perform, effective and well-tolerated approach to treat NMSCs, and it seems to be a useful alternative option when surgery or radiation therapy are difficult to perform or not recommended. In our population 98% of the treated lesions resolved completely after a single application and only one relapsed after 2 years. Larger patients' population and longer follow-up are needed to confirm these preliminary data and to find the optimal dose to administer in order to achieve complete response without significant side effects.

Most epithelial tumors recruit fibroblasts and other nonmalignant cells and activate them into cancer-associated fibroblasts. This often leads to overexpression of the membrane serine protease fibroblast-activating protein (FAP). It has already been shown that DOTA-bearing FAP inhibitors (FAPIs) generate high-contrast images with PET/CT scans. Since SPECT is a lower-cost and more widely available alternative to PET, 99m Tc-labeled FAPIs represent attractive tracers for imaging applications in a larger number of patients. Furthermore, the chemically homologous nuclide 188 Re is available from generators, which allows FAP-targeted endoradiotherapy. Methods: For the preparation of 99m Tc-tricarbonyl complexes, a chelator was selected whose carboxylic acids can easily be converted into various derivatives in the finished product, enabling a platform strategy based on the original tracer. The obtained 99m Tc complexes were investigated in vitro by binding and competition experiments on FAP-transfected HT-1080 (HT-1080-FAP) or on mouse FAP-expressing (HEK-muFAP) and CD26-expressing (HEKCD26) HEK cells and characterized by planar scintigraphy and organ distribution studies in tumor-bearing mice. Furthermore, a first-in-humans application was done on 2 patients with ovarian and pancreatic cancer, respectively. Results: 99m Tc-FAPI-19 showed specific binding to recombinant FAP-expressing cells with high affinity. Unfortunately, liver accumulation, biliary excretion, and no tumor uptake were observed on planar scintigraphy for a HT-1080-FAP-xenotransplanted mouse. To improve the pharmacokinetic properties, hydrophilic amino acids were attached to the chelator moiety of the compound. The resulting 99m Tc-labeled FAPI tracers revealed excellent binding properties (≤45% binding; >95% internalization), high affinity (half-maximal inhibitory concentration, 6.4-12.7 nM), and significant tumor uptake (≤5.4% injected dose per gram of tissue) in biodistribution studies. The lead candidate 99m Tc-FAPI-34 was applied for diagnostic scintigraphy and SPECT of patients with metastasized ovarian and pancreatic cancer for follow-up to therapy with 90 Y-FAPI-46. 99m Tc-FAPI-34 accumulated in the tumor lesions, as also shown on PET/CT imaging using 68 Ga-FAPI-46. Conclusion: 99m Tc-FAPI-34 represents a powerful tracer for diagnostic scintigraphy, especially when PET imaging is not available. Additionally, the chelator used in this compound allows labeling with the therapeutic nuclide 188 Re, which is planned for the near future., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Hypopharyngeal cancer (HPC) accounts for the lowest survival rate among all types of head and neck cancers (HNSCC). However, the therapeutic approach for HPC still needs to be investigated. In this study, a theranostic 188 Re-liposome was prepared to treat orthotopic HPC tumors and analyze the deregulated microRNA expressive profiles. The therapeutic efficacy of 188 Re-liposome on HPC tumors was evaluated using bioluminescent imaging followed by next generation sequencing (NGS) analysis, in order to address the deregulated microRNAs and associated signaling pathways. The differentially expressed microRNAs were also confirmed using clinical HNSCC samples and clinical information from The Cancer Genome Atlas (TCGA) database. Repeated doses of 188 Re-liposome were administrated to tumor-bearing mice, and the tumor growth was apparently suppressed after treatment. For NGS analysis, 13 and 9 microRNAs were respectively up-regulated and down-regulated when the cutoffs of fold change were set to 5. Additionally, miR-206-3p and miR-142-5p represented the highest fold of up-regulation and down-regulation by 188 Re-liposome, respectively. According to Differentially Expressed MiRNAs in human Cancers (dbDEMC) analysis, most of 188 Re-liposome up-regulated microRNAs were categorized as tumor suppressors, while down-regulated microRNAs were oncogenic. The KEGG pathway analysis showed that cancer-related pathways and olfactory and taste transduction accounted for the top pathways affected by 188 Re-liposome. 188 Re-liposome down-regulated microRNAs, including miR-143, miR-6723, miR-944, and miR-136 were associated with lower survival rates at a high expressive level. 188 Re-liposome could suppress the HPC tumors in vivo, and the therapeutic efficacy was associated with the deregulation of microRNAs that could be considered as a prognostic factor.

Objective: To assess the role of Lutetium-177(Lu-177) tin colloid for radiosynovectomy and compare it with Rhenium-188 (Re-188) tin colloid radiosynovectomy for alleviation of pain in patients with chronic inflammatory arthritis of knee., Methods: Patients of chronic inflammatory arthritis of the knee underwent pretherapeutic evaluation in a form of knee ultrasonogram, bone scan and clinical evaluation. Fifty-seven recruited patients were allocated at random to receive either intraarticular injections of Lu-177 tin colloid or Re-188 tin colloid. Eventually, 27 patients received Re-188 tin colloid and 30 patients received Lu-177 tin colloid. The joint was then immobilized for 2 days. Response evaluation was done using knee ultrasound, bone scan and clinical findings., Result: Of 30, 20 patients responded to radiosynovectomy in the Lu-177 tin colloid group compared to 21/27 patients in the Re-188 tin colloid group., Conclusion: Lu-177 tin colloid is an effective alternative to Re-188 tin colloid for radiosynovectomy in patients with chronic inflammatory knee arthritis.

Introduction: Radiocolloids labelled with less costly and more accessible radionuclides such as rhenium-188 are of interest to developing countries compared with those labelled with rhenium-186 and yttrium-90., Aim: This study was aimed to evaluate the efficacy and safety of radiosynovectomy using rhenium-188 in patients with chronic haemophilic synovitis and recurrent hemarthrosis., Methods: In this quasi-experimental prospective study, 20 haemophilic patients were evaluated at preinjection, and at 1, 3, 6 and 12 months after injection. Magnetic resonance imaging (MRI) was done to measure synovial thickness and to calculate Denver score. Joint radiographs were taken to measure the Pettersson score. The Gilbert questionnaire, Functional Independence Score in Hemophilia (FISH) and visual analogue scale (VAS) for pain were completed, and the number of bleeding episodes and factor consumption were recorded at each follow-up visit., Results: The number of bleeding episodes, the amount of factor consumption per month, VAS pain scores and synovial thickness decreased significantly over time (P < .05). Gilbert and FISH scores showed significant improvement (P < .001). However, Pettersson score and Denver score showed no significant changes after injection. Minor complications including temporary pain and swelling occurred in 20% of patients, and no major complication was observed after rhenium-188 injection., Conclusion: Our results indicated high clinical impact, efficacy, safety and low invasion of rhenium-188 in radiosynovectomy of haemophilic patients. Considering the availability and relatively low cost of rhenium-188 in developing countries, this can be a good treatment option for haemophilic patients with recurrent hemarthrosis, particularly when the synovial hypertrophy is not massive yet., (© 2019 John Wiley & Sons Ltd.)

Background Cetuximab is a fully humanized IgG1 subclass monoclonal that binds specifically to the human epidermal growth factor receptor (EGFR). Although EGFR is expressed in normal cells, the overexpression of EGFR is detected in many human cancers, such as colon, rectum and lung tumors. In this study, cetuximab with a combination of radiotherapy nuclear 188 Re achieved better therapeutic effect on lung cancer. Methods 188 Re-cetuximab administered by the i.v. route in human NCI-H292 lung tumor-bearing mice was investigated. NanoSPECT/CT images were taken to evaluate the distribution and tumor targeting of 188 Re-cetuximab in mice. The anti-tumor effect of 188 Re-cetuximab was assessed by the tumor growth inhibition, survival ratio. Results For nanoSPECT/CT imaging, a significant uptake in tumor was observed at 24 and 48 h following the injection of 188 Re-cetuximab. The anti-tumor effect of 188 Re-cetuximab was assessed by tumor growth inhibition and the survival ratio. The tumor-bearing mice treated with 188 Re-cetuximab showed a better mean tumor growth inhibition rate (MGI = 0.049) and longer median survival time and lifespan (62.50 d; 70.07%) than those treated with 188 Re-perrhenate and cetuximab only by single injection. A synergistic effect of tumor growth inhibition was observed with the combination index exceeding one for 188 Re-cetuximab (CI = 6.135 and 9.276). Conclusion The tumor targeting and localization of 188Re-cetuximab were confirmed in this study. Synergistic therapeutic efficacy was demonstrated for the radioimmunotherapy of 188 Re-cetuximab. The results of this study reveal the potential advantage and benefit obtained from 188 Re-cetuximab for diagnosis and therapy of oncology applications in the future.

: The role of the orthopedic surgeon is to use invasive and/or surgical methods to treat the musculoskeletal disorders suffered by persons with hemophilia, always within the context of a multidisciplinary team. Muscle hematomas must be diagnosed as early as possible and be subjected to continuous treatment until full resolution, as they are associated with the risk of severe complications (compartment syndromes and pseudotumors). Arthrocentesis (extraction of intra-articular blood) is recommended in cases of acute and profuse hemarthrosis. Synovectomy is mandatory in the case of synovitis. Radiosynovectomy plays a key role as it has been shown to reduce bleeding by 65%. Our department uses Yttrium-90 in knees and Rhenium-186 in elbows and ankles. Radiosynovectomy is our treatment of choice for synovitis whereas arthroscopic synovectomy is resorted to as second-line treatment. Total knee replacement (TKR) has shown itself to be effective for treating severe hemophilic arthropathy, although the infection risk in patients with hemophilia is higher than in patients with osteoarthritis (1-2 vs. 7%).

Background: In patients with hemophilia, radionuclide synoviorthesis, or the intra-articular injection of a radionuclide to decrease the synovial hypertrophy tissue, aims to decrease or avoid hemarthrosis., Aim: To evaluate the effectiveness of radionuclide synoviorthesis in hemophilia., Material and Methods: Observational retrospective study of the evolution of 107 male patients aged 3 to 54 years who were subjected to radionuclide synoviorthesis between 2007 and 2015., Results: Of 164 treated joints, in 65% treatment was successful, (defined as zero to two hemarthroses and absence of synovitis during the follow up period), in 17% it was partially successful (defined as two or less hemarthroses, but persistence of the synovitis) and failed in 18% of the procedures. No important complications were recorded., Conclusions: Radionuclide synoviorthesis has an overall 82% success rate, is minimally invasive, can be used at any age and is inexpensive We recommend its implementation in Chilean hemophilia treatment centers.

Hepatocellular carcinoma (HCC) is one of the leading causes of mortality worldwide. The aim of the present study was to evaluate the distribution and the therapeutic effect of 188 Re-Tin-colloid micro-particles in subcutaneous HCC-bearing mice. The synthesis and characterization of micro-particles labeled with the 188 Re isotope were performed. The micro-particles were injected into the tumor site subcutaneously in the BNL HCC-bearing mice with three treatment groups, normal saline, 188 Re micro-particles, and 188 Re-Tin-colloid micro-particles. The results of biodistribution showed that major radioactivity ( 188 Re) of 188 Re-Tin-colloid micro-particles (18.69 ± 4.28 %ID/g) remained at the tumor sites, compared with 188 Re micro-particles (0.21 ± 0.12 %ID/g), 24 h post injection. Following the injection of 188 Re-Tin-colloid micro-particles for 14 days, all BNL tumors in mice were regressed during the observation period. By contrast, all of the mice treated with normal saline or 188 Re micro-particles had died by 24 and 28 days, respectively. The 188 Re-Tin-colloid micro-particles demonstrated high accumulation and therapeutic potential in the subcutaneous HCC-bearing mice.

Nuclear nanomedicine, with its targeting ability and heavily loading capacity, along with its enhanced retention to avoid rapid clearance as faced with molecular radiopharmaceuticals, provides unique opportunities to treat tumors and metastasis. Despite these promises, this field has seen limited activities, primarily because of a lack of suitable nanocarriers, which are safe, excretable and have favorable pharmacokinetics to efficiently deliver and retain radionuclides in a tumor. Here, we introduce biodegradable laser-synthesized Si nanoparticles having round shape, controllable low-dispersion size, and being free of any toxic impurities, as highly suitable carriers of therapeutic 188 Re radionuclide. The conjugation of the polyethylene glycol-coated Si nanoparticles with radioactive 188 Re takes merely 1 hour, compared to its half-life of 17 hours. When intravenously administered in a Wistar rat model, the conjugates demonstrate free circulation in the blood stream to reach all organs and target tumors, which is radically in contrast with that of the 188 Re salt that mostly accumulates in the thyroid gland. We also show that the nanoparticles ensure excellent retention of 188 Re in tumor, not possible with the salt, which enables one to maximize the therapeutic effect, as well as exhibit a complete time-delayed conjugate bioelimination. Finally, our tests on rat survival demonstrate excellent therapeutic effect (72% survival compared to 0% of the control group). Combined with a series of imaging and therapeutic functionalities based on unique intrinsic properties of Si nanoparticles, the proposed biodegradable complex promises a major advancement in nuclear nanomedicine.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies. Often, patients present with inoperable and advanced disease. Selective internal radionuclide therapy offers prolonged survival and improved quality of life by delivering high radiation dose to the tumor with minimal complications. We report 2 inoperable cases of HCC treated with therapeutic dose of indigenously developed Re microspheres delivered to the hepatic lesions by transarterial catheterization. Follow-up CT revealed necrosis within the lesion, suggesting response to selective internal radionuclide therapy. Re microspheres may be a potential treatment option for inoperable HCC with or without portal vein thrombosis.

Despite improvements in the 5-year survival rate to over 80% in cancers, such as Hodgkin lymphoma and testicular cancer, more aggressive tumors including pancreatic and brain cancer still have extremely low survival rates. The establishment of chemoresistance, responsible for the reduction in treatment efficiency and cancer relapse, is one possible explanation for this setback. Metal-based compounds, a class of anticancer drugs, are largely used in the treatment of cancer. Herein, we will review the use of metal-based small molecules in chemotherapy, focusing on recent studies, and we will discuss how new nonplatinum-based agents are prompting scientists to increase drug specificity to overcome chemoresistance in cancer cells.

Radioimmunotherapy offers an effective way to direct ionizing radiation to cancer cells through attachment of radionuclides to antibodies while limiting negative effects of off-target irradiation. This, however, requires effective facile methods for attachment of therapeutic radionuclides onto antibodies. Herein, the authors report their efforts in evaluating N-succinimidyl S-acetylthioacetate (SATA), a commercially available reagent, for use as a bifunctional chelating agent (BCA) to attach 188 Rhenium ( 188 Re) onto h8C3, a humanized IgG antibody that can effectively target extracellular melanin present in malignant melanoma. Micro single photon emission computer tomography/computer tomography was used to determine an effective timeline for antibody uptake in B16-F10 tumor bearing C57BL6 mice guiding the selection of 188 Re with its 16.9 h physical half-life. Radio instant thin layer chromatography coupled with radio high-performance liquid chromatography was used to assess radioisotope incorporation, as well as stability during the labeling process for SATA conjugated h8C3. It was determined that despite the relatively mild conditions used, incorporation of the SATA conjugate resulted in antibody instability during labeling requiring a different BCA to facilitate rhenium incorporation onto the antibodies.

In the past several decades, many antimicrobial agents have been used in treating different fungal, bacterial, and viral infections. However, these agents have faced challenges such as pronounced side-effect profiles and pathogen resistance. In addition, a cure for many chronic infections such as human immunodeficiency virus (HIV) has not been achieved, and the incidence of opportunistic infections in immunocompromised patients has increased significantly in the past decades. Therefore, an alternative strategy for combating these infections is needed. Radioimmunotherapy (RIT) has been proposed to be a valuable tool in the management of such infections. The side-effects associated with RIT are minimal as the targeted antigens are only expressed on microbial or infected cells. RIT demonstrated impressive potency in eradicating pathogens in animal models and patient samples. Cryptococcus neoformans, HIV, and Bacillus anthracis are few examples of infections for which RIT has been an effective treatment using radionuclides such as bismuth-213 ( 213 Bi) or rhenium-188 ( 188 Re).

Rhenium-188-N-(DEDC) 2 /lipiodol (abbreviated as 188 ReN-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 [ 188 ReN(DEDC) 2 ] complex using sodium perrhenate (Na 188 ReO 4 ) 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 [ 188 ReN] 2+ intermediate. An error in this step can result in low radiochemical yield of [ 188 ReN] 2+ intermediate as well as sub-optimal pH of the reaction mixture for the second step, leading to poor radiochemical purity of 188 ReN-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 [ 188 ReN] 2+ intermediate, wherein > 95% radiochemical purity could be achieved within 5 min incubation at ambient temperature. Moreover, the novel route for the preparation of [ 188 ReN] 2+ intermediate may be applied to any radiopharmaceutical based on 188 ReN-core., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Radioembolization with radioactive microspheres has been an effective method for the treatment of liver lesions. The aim of this study was to prepare carrier-free 188 Re loaded poly (L-lactic acid) (PLLA) microspheres through 188 Re sulfide colloidal nanoparticles ( 188 Re-SC nanoparticles). The formation of 188 Re-SC nanoparticles was confirmed by ultraviolet-visible spectrophotometry. The labeling yield of 188 Re-SC nanoparticles was verified using the RTLC method. Effects of synthesis parameters on morphology and size of prepared 188 Re-sulfide colloidal-PLLA microspheres ( 188 Re-SC-PLLA microspheres) were studied by scanning electron microscopy. In vitro stability of 188 Re-SC-PLLA microspheres was investigated in normal saline at room temperature and in human serum at 37°C. In vivo distribution studies and gamma camera imaging were performed in healthy BALB/c mice. The microspheres could be prepared with sizes between 13 and 48 μm (modal value 29 μm) and radiolabeling efficiency >99%. After incubation, the microspheres were found stable in vitro up to 72 hours. The biodistribution after intravenous injection in healthy BALB/c mice showed high accumulation in lung as a first capture pathway organ for microsphere followed by great retention over 48 hours for these microspheres. These data show that 188 Re-SC-PLLA microspheres are suitable candidate for clinical studies., (Copyright © 2018 John Wiley & Sons, Ltd.)

Purpose: Hypoxic regions of tumors are less sensitive to radio- and chemotherapy, leading to poor prognosis of patients. One option to overcome the radioresistance is the irradiation of hypoxic tumors with high linear energy transfer (LET) α- or Auger electronemitters assuming their radiotoxicity would be less dependent on the cellular oxygenation status. Therefore, the aim of the present study was to determine whether irradiation with the intracellularly distributed Auger electron/γ-emitter 99m Tc using the tracer [ 99m Tc]TcHMPAO is a promising therapeutic option for the treatment of hypoxic tumor cells. Thus, the high LET α-particleemitter 223 Ra ([ 223 Ra]RaCl 2 ) and the low LET β-emitter 188 Re ([ 188 Re]NaReO 4 ) were studied in comparison to [99mTc]Tc-HMPAO., Materials and Methods: A431 tumor cells were incubated with [ 99m Tc]Tc-HMPAO (1-20 MBq/2 mL), [ 223 Ra]RaCl 2 (1.4-16.3 kBq/2 mL) or [ 188 Re]NaReO 4 (0.3-13.7 MBq/2 mL) under normoxic or hypoxic conditions. The degree of radiotoxicity was analyzed using the colony forming assay (CFA), and the intracellular radionuclide uptake of the radiotracers was quantified., Results: Hypoxic A431 cells are less radiosensitive to irradiation with [ 99m Tc]Tc-HMPAO or [ 188 Re]NaReO 4 than normoxic ones. In contrast, the radiosensitivity of A431 cells is almost independent of the oxygen status when treated with the [ 223 Ra]RaCl 2 ., Conclusions: We demonstrate that the Auger electron/γ-emitter 99m Tc ([ 99m Tc]Tc-HMPAO), which does not bound directly to the DNA, is not a promising therapeutic option for hypoxic tumor cells. But the high LET α-particle-emitter 223 Ra is more suitable for the treatment of hypoxic tumor cells than irradiation with [ 99m Tc]Tc-HMPAO or the low LET bemitter 188 Re., Zielsetzung: Hypoxische Tumorregionen sind bei Radio- und Chemotherapie weniger sensitiv als Tumorregionen mit ausreichender Sauerstoffversorgung. Dies verursacht eine schlechte Prognose für Tumorpatienten. Eine Option die Radioresistenz zu überwinden, stellt die Bestrahlung mit α-Partikel-Emittern oder Auger-Elektronen-Emittern mit einem hohen linearen Energietransfer (LET) dar. In dieser Studie soll untersucht werden, ob die Bestrahlung von hypoxischen Tumorzellen mit dem intrazellulär aufgenommenen γ- sowie Auger-Elektronen-Emitter 99m Tc unter Verwendung des Radiotracers [ 99m Tc]Tc-HMPAO eine vielversprechende Therapieoption darstellen könnte. Vergleichend wurde der Hoch-LET α-Partikel-Emitter 223 Ra ([ 223 Ra]RaCl 2 ) und der Niedrig-LET β-Emitter 188 Re ([ 188 Re]NaReO 4 ) eingesetzt., Methoden: A431 Tumorzellen wurden unter normoxischen oder hypoxischen Kulturbedingungen mit [ 99m Tc]Tc-HMPAO (1-20 MBq/2 ml), [ 223 Ra]RaCl 2 (1,4-16,3 kBq/2 ml) und [ 188 Re]NaReO 4 (0,3-13,7 MBq/2 ml) inkubiert. Zur Detektion der resultierenden strahlenbiologischen Wirkung wurde der Koloniebildungsassay angewendet. Zusätzlich wurde die intrazelluläre Aufnahme der Radiotracer quantifiziert., Ergebnisse: Nach Inkubation von [ 99m Tc]Tc-HMPAO sind hypoxische A431-Zellen weniger strahlensensitiv als normoxische Zellen. Im Gegensatz zur Behandlung mit [ 99m Tc]Tc-HMPAO oder [ 188 Re]NaReO 4 wurde bei Behandlung mit [ 223 Ra]RaCl 2 ein geringerer Einfluss des Sauerstoffstatus auf die Radiosensitivität von A431-Zellen gefunden., Schlussfolgerung: Damit konnte gezeigt werden, dass der nicht direkt an die DNA gebundene Auger-Elektronen-/ γ-Emitter 99m Tc ([ 99m Tc]Tc-HMPAO) die Radioresistenz von hypoxischen Tumorzellen nicht überwinden kann. Jedoch stellt der Hoch-LET α-Partikel-Emitter 223 Ra ([ 223 Ra]RaCl 2 ) eine bessere Behandlungsoption dar., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper., (Schattauer GmbH.)

The main applications of 188 Re in radionuclide therapies include trans-arterial liver radioembolization and palliation of painful bone-metastases. In order to optimize 188 Re therapies, the accurate determination of radiation dose delivered to tumors and organs at risk is required. Single photon emission computed tomography (SPECT) can be used to perform such dosimetry calculations. However, the accuracy of dosimetry estimates strongly depends on the accuracy of activity quantification in 188 Re images. In this study, we performed a series of phantom experiments aiming to investigate the accuracy of activity quantification for 188 Re SPECT using high-energy and medium-energy collimators. Objects of different shapes and sizes were scanned in Air, non-radioactive water (Cold-water) and water with activity (Hot-water). The ordered subset expectation maximization algorithm with clinically available corrections (CT-based attenuation, triple-energy window (TEW) scatter and resolution recovery was used). For high activities, the dead-time corrections were applied. The accuracy of activity quantification was evaluated using the ratio of the reconstructed activity in each object to this object's true activity. Each object's activity was determined with three segmentation methods: a 1% fixed threshold (for cold background), a 40% fixed threshold and a CT-based segmentation. Additionally, the activity recovered in the entire phantom, as well as the average activity concentration of the phantom background were compared to their true values. Finally, Monte-Carlo simulations of a commercial [Formula: see text]-camera were performed to investigate the accuracy of the TEW method. Good quantification accuracy (errors  <10%) was achieved for the entire phantom, the hot-background activity concentration and for objects in cold background segmented with a 1% threshold. However, the accuracy of activity quantification for objects segmented with 40% threshold or CT-based methods decreased (errors  >15%), mostly due to partial-volume effects. The Monte-Carlo simulations confirmed that TEW-scatter correction applied to 188 Re, although practical, yields only approximate estimates of the true scatter.

Introduction: Rhenium-186g (t 1/2 = 3.72 d) is a β - emitting isotope suitable for theranostic applications. Current production methods rely on reactor production by way of the reaction 185 Re(n,γ) 186g Re, which results in low specific activities limiting its use for cancer therapy. Production via charged particle activation of enriched 186 W results in a 186g Re product with a higher specific activity, allowing it to be used more broadly for targeted radiotherapy applications. This targets the unmet clinical need for more efficient radiotherapeutics., Methods: A target consisting of highly enriched, pressed 186 WO 3 was irradiated with protons at the Los Alamos National Laboratory Isotope Production Facility (LANL-IPF) to evaluate 186g Re product yield and quality. LANL-IPF was operated in a dedicated nominal 40 MeV mode. Alkaline dissolution followed by anion exchange chromatography was used to isolate 186g Re from the target material. Phantom and radiolabeling studies were conducted with the produced 186g Re activity., Results: A 186g Re batch yield of 1.38 ± 0.09 MBq/μAh or 384.9 ± 27.3 MBq/C was obtained after 16.5 h in a 205 μA average/230μA maximum current proton beam. The chemical recovery yield was 93% and radiolabeling was achieved with efficiencies ranging from 60-80%. True specific activity of 186g Re at EOB was determined via ICP-AES and amounted to 0.788 ± 0.089 GBq/μg (0.146 ± 0.017 GBq/nmol), which is approximately seven times higher than the product obtained from neutron capture in a reactor. Phantom studies show similar imaging quality to the gold standard 99m Tc., Conclusions: We report a preliminary study of the large-scale production and novel anion exchange based chemical recovery of high specific activity 186g Re from enriched 186 WO 3 targets in a high-intensity proton beam with exceptional chemical recovery and radiochemical purity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Internal radiation strategies hold great promise for glioblastoma (GB) therapy. We previously developed a nanovectorized radiotherapy that consists of lipid nanocapsules loaded with a lipophilic complex of Rhenium-188 (LNC 188 Re-SSS). This approach resulted in an 83 % cure rate in the 9L rat glioma model, showing great promise. The efficacy of LNC 188 Re-SSS treatment was optimized through the induction of a T-cell immune response in this model, as it is highly immunogenic. However, this is not representative of the human situation where T-cell suppression is usually encountered in GB patients. Thus, in this study, we investigated the efficacy of LNC 188 Re-SSS in a human GB model implanted in T-cell deficient nude mice. We also analyzed the distribution and tissue retention of LNC 188 Re-SSS. We observed that intratumoral infusion of LNCs by CED led to their complete distribution throughout the tumor and peritumoral space without leakage into the contralateral hemisphere except when large volumes were used. Seventy percent of the 188 Re-SSS activity was present in the tumor region 24 h after LNC 188 Re-SSS injection and no toxicity was observed in the healthy brain. Double fractionated internal radiotherapy with LNC 188 Re-SSS triggered survival responses in the immunocompromised human GB model with a cure rate of 50 %, which was not observed with external radiotherapy. In conclusion, LNC 188 Re-SSS can induce long-term survival in an immunosuppressive environment, highlighting its potential for GB therapy.

It has been shown that a rhenium-(I)-diselenoether complex had significant antitumor activity in MDA-MB231 tumor-bearing mice after repeated oral or intraperitoneal administrations for 4 weeks at safe doses of 10 mg/kg/day. It has also been suggested that lower doses could be as effective as this dose. We, thus, tested two doses (5 and 10 mg/kg). The drug was orally administered daily by gavage for 4 weeks and for a further 2 weeks with or without 15 mg/kg paclitaxel treatment (intravenously, once a week). This experiment was performed in MDA-MB 231 tumor-bearing mice, as a model of resistant breast tumor. However, in contrast to previous studies, the mice were pretreated with total body irradiation to increase the tumor growth. These two doses were safe, even in combination with paclitaxel. The expected tumor regression was not observed with the rhenium-(I)-diselenoether complex, and there was even a significant increase of the tumor volume in mice treated with 10 mg/kg versus controls. No synergism was observed with paclitaxel. We comment on the possible negative impact of radiotherapy on the antitumor activity of the drug. Plasma and tumor rhenium and selenium concentrations are also reported., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Although survival rates for cervical cancer have improved, they need further improvement in patients with distant metastases. The sodium iodine symporter (NIS) gene has often been used in cancer therapy and imaging. We examined the therapeutic effects of rhenium-188 (188Re) in a cervical cancer xenograft model expressing the NIS gene under the control of the tumor-specific human telomerase reverse transcriptase (hTERT) promoter. We constructed two recombinant lentiviral vectors expressing enhanced green fluorescent protein (eGFP) or the NIS gene driven by the hTERT promoter. To determine the tumor-specific transcriptional activity of the hTERT promoter, the eGFP-expressing vector was stably transfected into tumor cells and normal cells. A cervical cancer HeLa cell line stably expressing NIS (HeLa-TERTNIS) was created and examined in a similar way. HeLa and HeLa-TERTNIS tumor xenografts were transplanted in nude mice, and in vivo 188Re distribution was measured using micro-SPECT/CT imaging. The therapeutic effects of 188Re were assessed over 21 days on the basis of tumor volume and the immunohistochemical findings of excised tumors. eGFP expression controlled by the hTERT promoter was substantially higher in the tumor cells than normal cells. Quantitative PCR and western blotting confirmed that HeLa-TERTNIS cells expressed high levels of NIS mRNA and protein, respectively. Further, 188Re uptake and accumulation were significantly higher in HeLa-TERTNIS cells and xenografts than HeLa cells and xenografts. In vitro and in vivo, 188Re significantly reduced the survival of HeLa-TERTNIS cells and inhibited the growth of HeLa-TERTNIS xenografts, respectively. Immunohistochemical staining showed that HeLa-TERTNIS xenograft tumors expressed higher levels of NIS and caspase-3 and lower levels of Ki-67 than HeLa xenograft tumors. Our findings indicated that hTERT promoter-driven expression of the NIS gene in HeLa cells led to 188Re uptake and therapeutic effects. Thus, NIS-based gene therapy and imaging using the hTERT promoter and 188Re may be possible.

Background: Radiosynovectomy (RS) reduces the number of haemarthroses and the synovial size in chronic haemophilic synovitis. The purpose of this study was to quantitatively compare the effectiveness of two types of RS (yttrium-90 vs. rhenium-186) in terms of the objective improvement of haemarthroses and synovial size., Methods: Seventy RSs were performed in 70 joints (44 elbows, 26 ankles) of 70 haemophiliacs diagnosed with chronic synovitis. Yttrium-90 was used in 21 joints and rhenium-186 was used in 49 joints. The mean patient age was 20.61 years., Results: RS resulted in significant improvement in the three variables studied (six months before RS vs. six months after RS), namely in the number of episodes of haemarthrosis (67.8% improvement); the size of the synovium as measured by means of a clinical scale (43.8% improvement) and imaging techniques in millimetres (26.7% improvement). We did not find significant statistical differences between yttrium-90 and rhenium-186 regarding their efficacy. No correlation was found between the results and other variables: age, joint (ankle or elbow), presence or absence of radiological involvement, type of haemophilia (A or B), grade of haemophilia (mild, moderate or severe), previous haematological treatment (on demand or prophylaxis), and the presence or absence of inhibitor, Conclusions: Yttrium-90 RS and rhenium-186 RS were equally effective in reducing the number of haemarthroses and the size of the synovium in ankles and elbows in the short-term (6 months). No correlation was found between the results and other patients' characteristics., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To assess the outcome and adverse-effects of the radioisotope synoviorthesis in paediatric and adolescent patients with haemophilia., Material and Methods: Prospective study of historical cohort was conducted. A total of 20 consecutive haemophiliacs with a mean age of 13.1 years (range 4-17) were included with a mean follow-up of 64.9 months (range 18-109). The diagnosis of synovitis was established on the basis of clinical follow-up including radiological images (radiography and/or MRI). For evaluation, the classification proposed by Fernandez-Palazzi was used., Inclusion Criteria: Patients aged less than 18 years old with haemophilia and more than one haemarthrosis in less than 3 months remaining a chronic synovitis despite prophylactic therapy intensification., Exclusion Criteria: Any contraindication for radionuclide synoviorthesis. Twenty-seven radioisotope synoviorthesis with (90)Y-citrate-colloid and/or (186)Re-sulphide-colloid were done. The effectiveness of the procedure was assessed through pre and posttreatment clinical comparison at 6 months after radioisotope synoviorthesis., Results: Nineteen of the 27 synoviorthesis (70.3%) had a good or excellent response and 8 joints (29.7%) had partial response. It was necessary to repeat the procedure in 3 joints in 3 different patients, obtaining in all cases a good or excellent response. We appreciated inflammatory reaction after procedure in 4 cases (14.8%), which improved with analgesics and nonsteroidal anti-inflamatory drugs. None of the patients presented malignant or premalignant lesions during the follow-up., Conclusion: The radionuclide synoviorthesis is a very effective procedure in paediatric and adolescent patients with hemophilia, being a minimally invasive procedure, easy to perform, safe and with minimal side effects., (Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.)

Cervical cancer caused by the infection with the human papillomavirus (HPV) remains the fourth leading killer of women worldwide. Therefore, more efficacious treatments are needed. We are developing radioimmunotherapy (RIT) of HPV-positive cervical cancers by targeting E6 and E7 viral oncoproteins expressed by the cancer cells with the radiolabeled monoclonal antibodies (mAbs). To investigate the influence of different radionuclides on the RIT efficacy-we performed RIT of experimental cervical cancer with Rhenium-188 ((188) Re) and Lutetium-177 ((177) Lu)-labeled mAb C1P5 to E6. The biodistribution of (188) Re- and (177) Lu-labeled C1P5 was performed in nude female mice bearing CasKi cervical cancer xenografts and the radiation dosimetry calculations for the tumors and organs were carried out. For RIT the mice were treated with 7.4 MBq of either (188) Re-C1P5 or (177) Lu-C1P5 or left untreated, and observed for their tumor size for 28 days. The levels of (188) Re- and (177) Lu-C1P5 mAbs-induced double-strand breaks in CasKi tumors were compared on days 5 and 10 post treatment by staining with anti-gamma H2AX antibody. The radiation doses to the heart and lungs were similar for both (177) Lu-C1P5 and (188) Re-C1P5. The dose to the liver was five times higher for (177) Lu-C1P5. The doses to the tumor were 259 and 181 cGy for (177) Lu-C1P5 and (188) Re-C1P5, respectively. RIT with either (177) Lu-C1P5 or (188) Re-C1P5 was equally effective in inhibiting tumor growth when each was compared to the untreated controls (P = 0.001). On day 5 there was a pronounced staining for gamma H2AX foci in (177) Lu-C1P5 group only and on day 10 it was observed in both (177) Lu-C1P5 and (188) Re-C1P5 groups. (188) Re- and (177) Lu-labeled mAbs were equally effective in arresting the growth of CasKi cervical tumors. Thus, both of these radionuclides are candidates for the clinical trials of this approach in patients with advanced, recurrent or metastatic cervical cancer., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The systemic radionuclide therapy with bone affinity substances is an effective therapy in bone palliative treatment. Studies with radiolabeled Bisphosphonate or strontium-89 show reduction of pain in 70-80% and about 20% of treated patients are pain-free. The generator product rhenium-188 represents an interesting radionuclide for bone pain palliation. It is readily available and with appropriate patient numbers is very cost-effective. Radiopharmaceuticals with Re-188 show a comparable effectiveness in bone pain palliation and bone marrow toxicity as the other known radioactive Bisphosphonate. Repeat courses of treatment with rhenium-188 HEDP even a slightly increased survival could be observed. Using therapy with alpha emitters Radium-223 in prostate cancer patients with bone metastases there was observed a prolongation of survival by 3,6 months compared with placebo. Two drugs are created in Russia on the basis of Re-188. Phosphoren is an analog of Re-188-HEDP. It showed properties similar to them in clinical studies. Complex Re-188-zoledronic acid (Zoleren) is a unique development that combines the therapeutic effect of zoledronic acid and Re-188.

The combination of reduced-intensity conditioning, (188)rhenium anti-CD66 radioimmunotherapy, and in vivo T cell depletion was successfully applied in elderly patients with acute myeloid leukemia or myelodysplastic syndrome. Within a prospective phase II protocol, we investigated whether a dose reduction of alemtuzumab (from 75 mg to 50 mg MabCampath) would improve leukemia-free survival by reducing the incidence of relapse. Fifty-eight patients (median age, 67 years; range, 54 to 76) received radioimmunotherapy followed by fludarabine 150 mg/m(2) and busulfan 8 mg/kg combined with either 75 mg (n = 26) or 50 mg (n = 32) alemtuzumab. Although we observed a trend towards a shorter duration of neutropenia in the 50 mg group (median, 19 versus 21 days; P = .07), the time from transplantation to neutrophil and platelet engraftment as well as the overall incidence of engraftment did not differ. The incidence of severe acute graft-versus-host disease tended to be higher after the lower alemtuzumab dose (17% versus 4%; P = .15). No significant differences in the cumulative incidences of relapse (38% versus 35%; P = .81) or nonrelapse mortality (46% versus 27%; P = .31) were observed. Accordingly, disease-free and overall survival were not significantly different between groups. Although the feasibility of radioimmunotherapy plus reduced-intensity conditioning could be demonstrated in elderly patients, the dose reduction of alemtuzumab had no positive impact on overall outcome., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

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.

Pancreatic malignancies, the fourth leading cause of cancer deaths, have an aggressive behavior with poor prognosis, resulting in a 5-year survival rate of only 4%. It is typically a silent malignancy until patients develop metastatic disease. Targeted radionuclide therapies of cancer such as radiolabeled peptides, which bind to the receptors overexpressed by cancer cells and radiolabeled antibodies to tumor-specific antigens provide a viable alternative to chemotherapy and external beam radiation of metastatic cancers. Multiple clinical trials of targeted radionuclide therapy of pancreatic cancer have been performed in the last decade and demonstrated safety and potential efficacy of radionuclide therapy for treatment of this formidable disease. Although a lot of progress has been made in treatment of pancreatic neuroendocrine tumors with radiolabeled (90)Y and (177)Lu somatostatin peptide analogs, pancreatic adenocarcinomas remain a major challenge. Novel approaches such as peptides and antibodies radiolabeled with alpha emitters, pre-targeting, bispecific antibodies and biological therapy based on the radioactive tumorlytic bacteria might offer a potential breakthrough in treatment of pancreatic adenocarcinomas.

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.

Objective: The present study relates to a method for preparing 188Re-labeled human serum albumin microspheres (HSAM) by 188Re(I)-tricarbonyl ion(188Re(OH2)3(CO)3)+). This radioactive particle can be subjected to radioembolization for liver tumor., Methods: The particle sizes and conformations of HSA microspheres were analyzed by Particle sizes-Malvern mastersizer and Scanning Electron Microscope (SEM). For preparing 188Re(I)-tricarbonyl ion, the 188ReO4- was eluted from a 188W/188Re generator with saline. The radio labeling efficiency was analyzed with high-performance liquid chromatography (HPLC). Amino borane-reduced 188ReO4-was interacted with carbon oxide to form (188Re(OH2)3(CO)3]+). For preparing 188Re-HSA microspheres, the 188Re(I)-tricarbonyl ion was added into a vial with HSA microspheres. The in vitro stability was investigated. The rat was injected with 188Re-HSA microspheres via hepatic artery route. Nano-SPECT/CT Imaging was acquired after injection of 188Re-HSA microspheres., Results: The shape of HSA microsphere was rough surfaced sphere or oval-shaped. The particle size was distributed between 20 and 35μm. In the RP-HPLC-UV chromatography, the yield of 188Re(I)-tricarbonyl ion was 75-80%. The labeling efficiency of 188Re-HSA microspheres in this method was more than 85%. After incubation, the 188Re(I)-tricarbonyl ion labeled HSA microspheres were found to be stable in vitro in normal saline and rat plasma. The result of Nano-SPECT/CT Imaging quantification analysis indicated that the percentage of injection dose %ID was maintained at 95% ID-88% ID from 2 to 72h after injection with 188Re- HSA microspheres., Conclusions: The method of 188Re(I)-tricarbonyl ion labeled HSA microspheres can proceed with high labeling yield. Furthermore, this method provided a convenient method for radio-labeling of HSA microspheres with 188Re as well as a kit for manufacturing., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: In this study, the (188)Re-labeled PEGylated nanoliposome ((188)Re-liposome) was prepared and evaluated as a therapeutic agent for glioma., Materials and Methods: The reporter cell line, F98(luc) was prepared via Lentivector expression kit system and used to set up the orthotopic glioma-bearing rat model for non-invasive bioluminescent imaging. The maximum tolerated dose applicable in Fischer344 rats was explored via body weight monitoring of the rats after single intravenous injection of (188)Re-liposome with varying dosages before the treatment study. The OLINDA/EXM 1.1 software was utilized for estimating the radiation dosimetry. To assess the therapeutic efficacy, tumor-bearing rats were intravenously administered (188)Re-liposome or normal saline followed by monitoring of the tumor growth and animal survival time. In addition, the histopathological examinations of tumors were conducted on the (188)Re-liposome-treated rats., Results: By using bioluminescent imaging, the well-established reporter cell line (F98(luc)) showed a high relationship between cell number and its bioluminescent intensity (R(2)=0.99) in vitro; furthermore, it could also provide clear tumor imaging for monitoring tumor growth in vivo. The maximum tolerated dose of (188)Re-liposome in Fischer344 rats was estimated to be 333 MBq. According to the dosimetry results, higher equivalent doses were observed in spleen and kidneys while very less were in normal brain, red marrow, and thyroid. For therapeutic efficacy study, the progression of tumor growth in terms of tumor volume and/or tumor weight was significantly slower for the (188)Re-liposome-treated group than the control group (P<0.05). As a result, the lifespan of glioma-bearing rats treated with (188)Re-liposome was prolonged 10.67% compared to the control group., Conclusion: The radiotherapeutic evaluation by dosimetry and survival studies have demonstrated that passive targeting (188)Re-liposome via systemic administration can significantly prolong the lifespan of orthotopic glioma-bearing rats while maintaining reasonable systemic radiation safety. Therefore, (188)Re-liposome could be a potential therapeutic agent for glioblastoma multiforme treatment.

Radioimmunotherapy has shown that the use of monoclonal antibodies combined with a radioisotope like (131)I or (90)Y still remains ineffective for solid and radioresistant tumour treatment. Previous simulations have revealed that an increase in the number of (90)Y labelled to each antibody or nanoobject could be a solution to improve treatment output. It now seems important to assess the treatment output and toxicity when radionuclides such as (90)Y, (177)Lu, (131)I, (124)I, and (188)Re are used. Tumour control probability (TCP) and normal tissue complication probability (NTCP) curves versus the number of radionuclides per nanoobject were computed with MCNPX to evaluate treatment efficacy for solid tumours and to predict the incidence of surrounding side effects. Analyses were carried out for two solid tumour sizes of 0.5 and 1.0 cm radius and for nanoobject (i.e., a radiolabelled antibody) distributed uniformly or nonuniformly throughout a solid tumour (e.g., Non-small-cell-lung cancer (NSCLC)). (90)Y and (188)Re are the best candidates for solid tumour treatment when only one radionuclide is coupled to one carrier. Furthermore, regardless of the radionuclide properties, high values of TCP can be reached without toxicity if the number of radionuclides per nanoobject increases.

Purpose: The development of radioimmunotherapy has provided an impressive alternative approach in improving trastuzumab therapy. However, the mechanisms of trastuzumab and radiation treatment combined to increase therapeutic efficacy are poorly understood. Here, we try to examine the efficacy of cytotoxicity and apoptosis induction for (188)Re-HYNIC-trastuzumab in cancer cell lines with various levels of Her2., Materials and Methods: Fluorescence flow cytometry was used to detect the alterations of apoptosis induction after (188)Re-HYNIC-trastuzumab treatment in two breast cancer cell lines with different levels of HER2 (BT-474 and MCF-7) and a colorectal carcinoma cell line (HT-29) for control., Results: Our results indicated that (188)Re-HYNIC-trastuzumab led to cell death of breast cancer cells specifically in HER2 level-dependent and radioactivity dose-dependent fashions. In BT-474 cells, 370 kBq/ml of (188)Re-HYNIC-trastuzumab enhanced the cytotoxicity to a level nearly 100-fold that of trastuzumab-alone treatment. The results also revealed that the mitochondria-dependent pathway attenuated irradiation-induced apoptosis in HER2-expressing breast cancer cells after (188)Re-HYNIC-trastuzumab treatment. In contrast, only after 48 h of (188)Re-HYNIC-trastuzumab treatment, BT-474 cells exhibited typical apoptotic changes, including exposure of phospholipid phosphatidylserine on the cell surface, or fragmented DNA formation, in a radioactivity dose-dependent manner., Conclusion: Briefly, our study demonstrates that (188)Re-labeled HYNIC-trastuzumab not only enhances cell death in a radioactivity dose-dependent fashion, but may also prolong the effects of apoptosis involved with the mitochondria-dependent pathway in HER2-overexpressing breast cancer cells. It is possible that the (188)Re-HYNIC-trastuzumab treatment induced a second round of apoptosis to prolong the effects of cell kill in these cancer cells. These data revealed that (188)Re-HYNIC-trastuzumab has the potential for use as a therapeutic radiopharmaceutical agent in HER2-overexpressing breast cancer cell treatment.