Reactor produced [64Cu]CuCl2 as a PET radiopharmaceutical for cancer imaging: from radiochemistry laboratory to nuclear medicine clinic.

OBJECTIVE: Copper-64 is a useful theranostic radioisotope that is attracting renewed interest from the nuclear medicine community in the recent times. This study aims to demonstrate the utility of research reactors to produce clinical-grade 64Cu via 63Cu(n,γ)64Cu reaction and use it in the form of [64Cu]CuCl2 as a radiopharmaceutical for PET imaging of cancer in human patients. METHODS: Copper-64 was produced by irradiation of natural CuO target in a medium flux research reactor. The irradiated target was radiochemically processed and detailed quality control analyses were carried out. Sub-acute toxicity studies were carried out with different doses of Cu in Wistar rats. The biological efficacy of the radiopharmaceutical was established in preclinical setting by biodistribution studies in melanoma tumor bearing mice. After getting regulatory approvals, [64Cu]CuCl2 formulation was clinically used for PET imaging of prostate cancer and glioblastoma patients. RESULTS: Large-scale (~ 30 GBq) production of 64Cu could be achieved in a typical batch and it was adequate for formulation of clinical doses for multiple patients. The radiopharmaceutical met all the purity requirements for administration in human subjects. Studies carried out in animal model showed that the toxicity due to "cold" Cu in clinical dose of [64Cu]CuCl2 for PET scans would be negligible. Clinical PET scans showed satisfactory uptake of the radiopharmaceutical in the primary cancer and its metastatic sites. CONCLUSIONS: To the best of our knowledge, this is the first study on use of reactor produced [64Cu]CuCl2 for PET imaging of cancer in human patients. It is envisaged that this route of production of 64Cu would aid towards affordable availability of this radioisotope for widespread clinical use in countries with limited cyclotron facilities.

A simple and robust method for radiochemical separation of no-carrier-added 64Cu produced in a research reactor for radiopharmaceutical preparation.

Copper-64 is an excellent theranostic radiometal that is gaining renewed attention of the clinical community in the recent times. In order to meet the increasing demand of this radiometal, we have demonstrated the viability of its production via 64Zn (n,p) 64Cu reaction in a nuclear reactor. A semi-automated radiochemical separation module based on selective extraction of 64Cu as dithizonate complex was developed. The maximum available activity at the end of irradiation was ~ 700 MBq. The overall yield of 64Cu after the separation process was >85% and it could be obtained with ~12 GBq/µg specific activity, >99.9% radionuclidic purity and >98% radiochemical purity. The separated 64Cu could be utilized for preparation of a wide variety of radiopharmaceuticals.

Barium titanate microparticles as potential carrier platform for lanthanide radionuclides for their use in the treatment of arthritis.

Since the inception of radiation synovectomy, a host of radioactive colloids and microparticles incorporating suitable therapeutic radionuclides have been proposed for the treatment of arthritis. The present article reports the synthesis and evaluation of barium titanate microparticles as an innovative and effective carrier platform for lanthanide radionuclides in the preparation of therapeutic agents for treatment of arthritis. The material was synthesized by mechanochemical route and characterized by X-ray diffraction, scanning electron microscopy, surface area, and particle size distribution analyses. Loading of lanthanide radionuclides (166 Ho, 153 Sm, 177 Lu, and 169 Er) on the microparticles was achieved in high yield (> 95%) resulting in the formulation of loaded particulates with excellent radiochemical purities (> 99%). Radiolanthanide-loaded microparticles exhibited excellent in vitro stability in human serum. In vitro diethylene triamine pentaacetic acid challenge study indicated fairly strong chemical association of lanthanides with barium titanate microparticles. Long-term biodistribution studies carried out after administration of 177 Lu-loaded microparticles into one of the knee joints of normal Wistar rats revealed near-complete retention of the formulation (> 96% of the administered radioactivity) within the joint cavity even 14 days post-administration. The excellent localization of the loaded microparticles was further confirmed by sequential whole-body radio-luminescence imaging studies carried out using 166 Ho-loaded microparticles.

Hydroxyapatite (HA) microparticles labeled with (32)P - A promising option in the radiation synovectomy for inflamed joints.

In the present article we describe a systematic approach pursued for the synthesis of (32)P-labeled hydroxyapatite (HA) microparticles (1-10µm size range) using no carrier added (NCA) (32)P produced in a nuclear reactor and animal evaluation of its utility as an expected viable radiopharmaceutical for the treatment of pain intensive arthrosis. NCA (32)P was produced via the (32)S(n,p)(32)P route in nuclear reactor with high radionuclidic purity (99.95±0.01%, n=5). Phosphorus-32-labeled hydroxyapatite microparticles (1-10µm size range) were synthesized with high radiochemical purity (99.0±0.3% n=12) under optimized conditions and the formulation showed excellent in vitro stability in saline as well as in rat serum. Intra-articular administration of the radiolabeled particles in the knee joints of normal Wistar rats showed near-complete retention of activity within the synovial cavity upto 1 month post-administration. The radiochemical formulation thus demonstrated promising features as a radiopharmaceutical for treatment of arthritis with excellent logistic advantage for shipment to sites distant from the production facility thanks to the suitable nuclear decay properties of (32)P.

Prospects of medium specific activity (177) Lu in targeted therapy of prostate cancer using (177) Lu-labeled PSMA inhibitor.

Targeted radionuclide therapy using (177) Lu-labeled peptidomimetic inhibitor of prostate specific membrane antigen (PSMA) viz. PSMA-617 is emerging as one the most effective strategies for management of metastatic prostate cancer, which is one of the leading causes of cancer related death. The aim of the present study is to develop a robust and easily adaptable protocol for formulation of therapeutic dose of (177) Lu-PSMA-617 at hospital radiopharmacy using moderate specific activity (177) Lu available at an affordable cost. Extensive radiochemical studies were performed to optimize the required [PSMA-617] / [Lu] ratio and other parameters to formulate 7.4 GBq dose of (177) Lu-PSMA-617. Based on these, 7.4 GBq therapeutic dose of (177) Lu-PSMA-617 was formulated by incubating 160 µg of PSMA-617 with indigenously produced (177) LuCl3 (555 GBq/µg specific activity of (177) Lu) at 90 °C for 30 min. The radiochemical purity of the formulation was 98.3 ± 0.6% (n = 7) which was retained to the extent of >95% after 7 d in normal saline at room temperature and >96% after 2 d in human serum at 37 °C. Preliminary clinical studies showed specific targeting of the agent in the lesion sites and similar physiological distribution as in diagnostic (68) Ga-PSMA-11 PET scans performed earlier. The developed optimized protocol for formulating therapeutic dose of (177) Lu-PSMA-617 could be useful for large number of nuclear medicine therapy clinics across the world having access to moderate specific activity (177) Lu at an affordable cost.

Practicality of production of ³²P by direct neutron activation for its utilization in bone pain palliation as Na3[³²P]PO4.

Large-scale production of ³²P for its clinical use in palliative care of painful bone metastasis in the form of Na3[³²P]PO4 (³²P-sodium orthophosphate) has been practiced for six decades. The classical route of production of ³²P by (n,p) reaction on high purity elemental sulfur yields no-carrier-added (NCA) ³²P. Since high specific activity ³²P is not essential for the formulation of Na3[³²P]PO4 for bone pain palliation, an alternate route of production of ³²P by direct neutron capture using elemental phosphorus target [(31)P(n,γ)³²P] was envisaged and its suitability for use in bone pain palliation was evaluated. Toward this, irradiation of elemental red phosphorus target was carried out at a neutron flux of 8×10¹³ n/cm².s for 60 days and this yielded ³²P with a specific activity of 230±15 MBq/mg (6.2±0.4 mCi/mg) having >99.9% radionuclidic purity. About 370-555 MBq (10-15 mCi) doses of Na3[³²P]PO4 were formulated in sterile saline (pH 7.4) using the ³²P produced. The radiochemical purity of the formulation was found to be ~99% with respect to PO4³â». The formulation exhibited good in vitro stability in saline and in human serum. Biodistribution studies carried out in normal Wistar rats revealed comparable pharmacokinetic properties of the formulation prepared using (n,γ) produced ³²P with that of NCA ³²P produced by (n,p) route. Besides having the advantages of simplicity in radiochemical processing and minimum radioactive waste generation, use of the proposed production route in place of the traditional ³²S(n,p)³²P route would result in better utilization of irradiation volume of research reactors.