Re-188-tricarbonyl tamoxifen as a theranostic radiopharmaceutical for estrogen receptor expressing breast cancers: radiolabeling, characterization and in-vitro cytotoxic assessment.

PURPOSE: Development of a novel theranostic radiopharmaceutical for estrogen receptor, expressing unresectable primary and metastatic breast cancers. METHODS: Tamoxifen was radiolabeled with Rhenium-188 (Re-188) through tricarbonyl core. Radiolabeled complex was characterized by 1proton nuclear magnetic resonance spectroscopy and Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF). Various quality control tests such as sterility, apyrogenicity, and radiochemical purity (RCP) were performed to assess the suitability of the radiopharmaceutical for intravenous administration. In-vitro cell culture studies were performed for cytotoxic assessment. In addition to this, exposure due to different doses of Re-188-tricarbonyl tamoxifen was also calculated. RESULTS: Re-188-tricarbonyl and Re-188-tricarbonyl tamoxifen showed more than 99% RCP. Sample was found to be sterile and pyrogens levels were within the permissible limit. Re-188-tricarbonyl tamoxifen was successfully characterized by MALDI-TOF and 1H-NMR spectroscopy. Re-188 (1.480 MBq) and tamoxifen (0.027 or 0.054 µM) individually showed 36 and 70% cell death, respectively. However, radiolabeled complex (Re-188-tricarbonyl tamoxifen) with the same amount of radioactivity (1.480 MBq) increased the cell death to more than 90% with one-fifth to one-tenth molar concentration of tamoxifen (0.0054 µM). CONCLUSION: Re-188-tricarbonyl tamoxifen can be synthesized in-house in radiopharmacy lab. Radionuclide therapy with Re-188-tricarbonyl tamoxifen can be given using 10 times less amount of tamoxifen as compared to cold tamoxifen.

Freeze-dried microspheres for selective intra-arterial radionuclide therapy: an affordable solution.

OBJECTIVE: Selective intra-arterial radionuclide therapy (SIRT) using radiolabelled microspheres is for the delivery of therapeutic radioisotope to liver cancers and thus, sparing healthy liver. Several radiolabelled microspheres are commercially available. The main issue associated with these microspheres is affordability. Re-188 is a generator produced radionuclide, emits high energy therapeutic beta particle and imageable gamma photons for pre- and post-therapy dosimetry. METHODS: Tc-99m/Re-188 labelled microspheres have been developed and quality control tests have been performed for suitable clinical use. The clinical studies with Re-188 microspheres for SIRT have been performed. Post-therapy images were acquired for dosimetry. RESULTS: The microspheres were found to possess spherical morphology of less than 20 µm size. The quality control revealed the suitability of microspheres for intravenous administration. The preliminary studies in thirty patients demonstrated good retention in tumor and high tumor to normal liver ratio. Re-188 microspheres were well tolerated by patients. Same microspheres labelled with either Tc-99m or Re-188 were used for pretherapy dosimetry and Re-188 labeled microspheres for therapy (SIRT) as a single-day procedure. CONCLUSION: The freeze-dried microspheres may emerge as highly cost-effective candidates for both pre-therapy dosimetry and SIRT and may benefit a large population with inoperable liver cancer.

Development of Lu-177-trastuzumab for radioimmunotherapy of HER2 expressing breast cancer and its feasibility assessment in breast cancer patients.

HER2/neu is over expressed in 20-25% of breast cancers. HER2 breast cancers are aggressive and are associated with poor prognosis. The aim of this study was to develop the clinical grade Lu-177-trastuzumab and its preliminary evaluation for specific tumor targeting in HER2 positive breast cancer patients. Trastuzumab was conjugated to bifunctional chelator, DOTA, and characterized for integrity and the number of molecules conjugated. Radiolabeling of DOTA-conjugated trastuzumab was optimized using Lu-177. Quality control parameters including radiochemical purity, stability, sterility, pyrogenicity and immunoreactivity were assessed. A preliminary pilot study was conducted on breast cancer patients (n = 6 HER2 positive and n = 4 HER2 negative) to evaluate the ability of Lu-177-trastuzumab for HER2 specific tumor targeting. The conjugates were efficiently labeled with Lu-177 with high radiochemical purity (up to 91%) and specific activity (6-13 µCi/µg). Lu-177-trastuzumab was stable up to 12 hr post labeling. The radioimmunoassay demonstrated good antigen binding ability and specificity for HER2 receptor protein. The patient studies showed the localization of Lu-177-trastuzumab at primary as well as metastatic sites (HER2 positive) in the planar and SPECT/CT images. No tracer uptake was observed in HER2 negative patients that indicated the specificity of Lu-177-trastuzumab. The study demonstrated that in-house developed Lu-177-trastuzumab has specific targeting ability for HER2 expressing lesions and may in future become a palliative treatment option in the form of targeted radionuclide therapy for disseminated HER2 positive breast cancer.

Nanotamoxifen Delivery System: Toxicity Assessment After Oral Administration and Biodistribution Study After Intravenous Delivery of Radiolabeled Nanotamoxifen.

Tamoxifen is the most prescribed anticancer oral drug for increasing overall survival and decreasing recurrence and the risk of contralateral disease. However, some side effects, such as endometrial and liver tumors, thromboembolic disorders, and drug resistance, are associated with long-term tamoxifen treatment. We assessed the hematologic and organ toxicity after oral administration of three different doses of nanotamoxifen formulations. We also performed biodistribution studies of Technetium-99m ((99m)Tc)-nanotamoxifen after intravenous administration. The results demonstrated that nanotamoxifen was well-tolerated, with no adverse effect on biochemical parameters of blood and at the cellular level. Nitric oxide (NO) levels indicated no free radical formation. Oral nanotamoxifen is well-tolerated, with no hepatic or renal toxicity. Intravenous nanotamoxifen has potential to escape the liver, and is known for producing the harmful metabolite 4-hydroxytamoxifen (4OH-tamoxifen), which can cause uterine cancer.

Dimercaptosuccinic acid: A multifunctional cost effective agent for imaging and therapy.

Dimercaptosuccinic acid (DMSA) is an analog of dimercaprol used as metal chelating moiety in variety of conditions. In nuclear medicine itself two types of Tc-99m DMSA complexes are used, trivalent and pentavalent forms. In this review, we have discussed the mechanism of uptake of both complexes as well as diagnostic and therapeutic application in a clinical scenario.