Reactor-produced radionuclides at the University of Missouri Research Reactor

Appl. Radiat. lsot. Vol. 49, No. 4, pp. 295-297, 1998

Pergamon PII: S0969-8043(97)00038-9

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Reactor-produced Radionuclides at the University of Missouri Research Reactor G A R Y J. E H R H A R D T ,

A L A N R. K E T R I N G

a n d L Y N N M. A Y E R S

University of Missouri Research Reactor and Departments of Radiology, Chemistry and Nuclear Engineering, Columbia, MO, 65211, U.S.A. A revolution in radiotherapy has been developing in recent years, based on more sophisticated targeting methods including radioactive intra-arterial microspheres, chemically-guided bone agents, labeled monoclonal antibodies, and isotopically-tagged polypeptide receptor-binding agents. The isotopes of choice for these applications are reactor-produced beta emitters such as Sm-153, Re-186, Re-188, Ho-166, Lu-177, and Rh-105. The University of Missouri Research Reactor (MURR) has been in the forefront of research into means of preparing, handling, and supplying these high specific activity isotopes in quantities appropriate not only for research, but also for patient trials in the U.S. and around the world. Considerable effort has been expended to develop techniques for irradiation, handling, and shipping isotopes worldwide. The MURR has also served as a highly reliable production source for isotopes, with one of the best operating histories of any isotope production reactor in the world. © 1998 Elsevier Science Ltd. All rights reserved.

Nuclear medicine today is primarily a diagnostic modality, with over 90% of studies utilizing Tc-99m agents to detect disease states as diverse as reduced myocardial perfusion, bone metastases, and kidney disorders. Strenuous efforts have been made in the past to greatly extend nuclear medicine into therapy for malignancies and rheumatoid arthritis, but, with the notable exception of agents such as 1-131 iodide and P-32 chromic phosphate colloid, these attempts foundered on the problem of inadequate selectivity for the target tissues. In recent years, more sophisticated targeting methods have been developed that render wider use of internal, unsealed source radiotherapy (nuclear medicine radiotherapy) once again an attractive proposition (Volkert et al., 1991). These new methods include more sophisticated administration of radioactive microspheres, labeled small molecules, isotopically-tagged monoclonal antibodies or antibody fragments, and labeled polypeptide receptor agents. Reactor-produced beta emitters are widely regarded as the radioisotopes of choice for many of these therapeutic applications. Although alpha emitters produce the best cytotoxicity due to their high Linear Energy Transfer (LET) radiation, their use is limited by the extremely short range of alpha particles in tissue. It is difficult for an alpha emitter to achieve complete killing of a tumor, particularly since homogenous uptake is more the exception than the rule. Strategies exist for using alpha emitters to kill circulating malignant cells or to infarct a tumor

by destroying its vasculature (Kennel and Mirzadeh, 1996), but these are as yet somewhat conjectural. Beta emitters have typical ranges from 1 to 10 mm, and thus provide more homogenous tumor dosage. Although the low LET emissions are somewhat less efficient at cell killing, many years of experience with 1-131 and with external beam radiotherapy clearly demonstrate that low LET radiation is efficacious in the treatment of malignancies, given proper targeting and dosage. The University of Missouri Research Reactor (MURR) has played a prominent role in the revival of interest in therapeutic nuclear medicine, combining an active radiopharmaceutical research program with a capable isotope production facility. The M U R R ' s capacity to supply therapeutic radioisotopes is enhanced by its high neutron flux of 4.5 × 10 ~4 (thermal) in the flux trap, around-the-clock operating schedule, and excellent long-term availability ( M U R R has run > 90% of the time routinely for many years). The availability of flux trap space on a 155 h cycle has made possible supply of relatively short-lived (n,v) isotopes in the high specific activities often needed for immunoglobulin or receptor agent labeling, while avoiding unacceptable build-up of long-lived impurities. Additionally, in the course of its 30 years of operation, the M U R R has built a reputation for responsiveness to the needs of the research and industrial community of isotope users. Development of therapeutic radiopharmaceuticals and initial clinical trials have posed challenging

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problems in isotope supply. By definition, therapy isotopes generate high dose rates, especially when producing sufficient quantities to treat patients in ascending dose trials. Ideally, high extremity doses to personnel are best avoided by using remote processing. However, hot cells individually dedicated to each isotope in clinical trials are prohibitively expensive, and funds are rarely available for them until some promise of success is achieved. A paradoxical situation arises where funding for remote handling facilities is not usually forthcoming until the trials are successful, which of course cannot occur unless the isotope is available. A similar situation arises with regard to cost recovery for lower activity isotope production: researchers doing basic, smallscale research with a unique radionuclide normally cannot afford to pay full cost recovery until some success has been achieved. Researchers at the M U R R have tackled the former problem with in-house developed plastic beta shielding and relatively inexpensive glove boxes, taking advantage of the fact that most therapy isotopes have relatively low energy and low abundance gamma emissions. The inability of many users to pay full cost recovery for new isotopes has been a continuing problem. Most of the processing effort at the M U R R involves preparing targetry prior to irradiation, then opening the irradiated vial in a glove box, dissolving its contents, transferring to an appropriate container for handling by the user, and performing quality control. This simple dissolution approach is suitable for Sm-153, Re-186, Ho-166, and Lu-177. The incorporation of tungsten-188 into a W-188/Re-188 gel generator requires a more complicated process. Rh-105 and Cu-64 must be chemically separated from their Ru- 104 and Zn-64 targets by distillation and ion exchange chromatography, respectively. Another critical consideration is the completion of a well-documented and accurate shipment. With more than 1500 customized radioactive shipments prepared by M U R R each year, coupled with the exceedingly low tolerance of the NRC for shipping errors, considerable attention is devoted to careful documentation and shipment. The applications of MURR-produced radioisotopes are many and varied. Agents that localize at metastatic bone cancer sites and relieve the often intense pain associated with these lesions have been a major focus of radiotherapy investigations. Mallinckrodt Medical, Inc. has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for Re-186 HEDP (Maxon et al., 1991), a therapy agent which chemically resembles and complements Tc-99m phosphonate diagnostic agents. M U R R played a large part in the development of this new product. A similar bone agent, Sm-153 EDTMP (Eary et al., 1993), was developed by the University of Missouri and M U R R in collaboration with the Dow Chemical Company. The samarium agent has also undergone trials in over

1000 patients and its N D A is also under consideration by the U.S. F D A under sponsorship by Cytogen and DuPont Merck, Inc. Both of these agents are about 80% effective in providing pain relief. Radioisotope production for bone agents reflects the consideration that high specific activity is desirable, but not essential. To optimize production within the practical constraints of stable isotope target supply and irradiation space, isotopically enriched Re-185 and Sm-152 are irradiated in the M U R R flux trap to produce Re-186 and Sm-153 at specific activities of 3-4 Ci/mg. Rhenium is irradiated as the metal and dissolved by the industrial recipient in hydrogen peroxide; samarium is irradiated as the oxide and dissolved in hydrochloric acid. A related agent with similar production parameters is Ho-166 DOTMP, a bone agent that appears to be useful as a bone marrow ablation agent in the treatment of multiple myeloma in patient trials at M. D. Anderson Cancer Center (Bayouth et al., 1995). In this treatment, massive doses of Ho-166 serve to ablate the patient's diseased marrow with acceptable levels of toxicity, followed by transplantation to recolonize the patient's marrow after the Ho-166 has decayed. In this therapy, the high beta energy (1.8 MeV maximum) and short half-life (26.8 h) of Ho-166 are crucial in order to provide sufficient range to irradiate all marrow and to decay rapidly enough to permit prompt transplantation. For the ascending dose trials of this agent, M U R R has developed a dedicated remote processing facility and a production strategy to supply over 10 Ci of Ho-166 for each patient's treatment regime. Aside from its use as a bone agent in the form of Sm-153 EDTMP, Sm-153 is a component of Sm-153 hydroxyapatite microspheres which are being developed by Mallinckrodt Medical, Inc. as a radiation synovectomy agent (Clunie et al., 1995). Some 10-20 Ci of Sm-153 samarium chloride solution are prepared routinely at M U R R in a dedicated, remotely-operated mini-hot cell for this research. Radiolabeled biological agents such as monoclonal antibodies and polypeptide receptor agents can only be injected in small quantities due to their antigenicity or to limited numbers of receptor sites, and thus require very high specific activity isotopes. The preparation of high specific activity (n,y) isotopes such as Re-186 and Lu-177 for patient trials has been a major effort at MURR. Rhenium-186 at a specific activity of about 3.5 Ci/mg has been extensively used in clinical radioimmunotherapy trials sponsored by NeoRx Corp. (Breitz et al., 1995), while Lu-177 at up to 30 Ci/mg is currently in use for similar trials (Schott et al., 1994). A great deal of effort has also gone into routine preparation of no-carrier-added Rh-105 made by the indirect route of Ru-104 (n,7) Ru-105, followed by beta decay to Rh-105 and removal of target Ru-104 by distillation as the tetroxide. A similar route is used to obtain

Reactor-produced radionuclides at the University of Missouri Research Reactor no-carrier-added Cu-64, which is being investigated at Washington University (St. Louis) as a PET radioimmunotherapy agent (Anderson et al., 1995). Radioisotope generators represent a means of obtaining a convenient supply of short-lived, carrier-free daughter isotopes from a longer-lived parent isotope. The W-188/Re-188 generator system produces the 17 h half-life, technetium-like Re-188 from 69 day half-life W-188. Unfortunately, W-188 can be produced only by double neutron capture and thus is always in low specific activity, which represents a problem for conventional ion-exchange column generators. Researchers at M U R R have successfully developed and continue to refine a "gel" generator system in which gram quantities of tungsten are processed into a column filling that allows the Re-188 product to diffuse out in saline solution, representing a more practical approach. Recent efforts have concentrated on optimizing gel preparation parameters (Ehrhardt et al., 1995). A simple means of separating carrier-free Ho-166 from its parent Dy-166 using hot atom effects rather than tedious column chromatography is also under development. Scientists at M U R R and UM-Rolla have developed activatable glass microspheres doped with yttrium, samarium, or holmium for intra-arterial injection into tumors (Ehrhardt and Day, 1987). The microspheres are just large enough to be trapped in the tumor capillary bed and deliver a highly localized beta dose. One agent, Y-90 Therasphere ~, was approved in 1991 in Canada for treating liver cancer, while the samarium and holmium microspheres show promise for pre-surgical sterilization of kidney tumors. In light of the many new targeting and production technologies now being developed and tested, it appears that the future is bright for continued expansion of therapeutic nuclear medicine. While bone agents such as Sm-153 EDTMP and Re-186 HEDP show the most promise for immediate utility, recent favorable action by the FDA on diagnostic receptor agents and antibody products such as Octreotide ~ and Oncoscint~ suggest that high specific activity Re-186, Ho-166, Lu-177 and Re-188 may also find their places in the therapy armamentarium. Unfortunately, the ongoing closure of U.S. reactor facilities and consequent scarcity of high neutron flux isotope production facilities cast a shadow on these developments. Development of these therapy agents depends upon a consistent and reasonably priced

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supply of isotope. This new generation of radiotherapeutic drugs for the treatment of cancer, rheumatoid arthritis, and other maladies will be successfully developed in the U.S. only if the necessary research with reactor isotopes can occur expeditiously and at reasonable cost. The price of this failing to occur is not only the loss of U.S. leadership in nuclear medicine, but also unnecessary suffering by perhaps millions of Americans.

References Anderson, C. J., Schwartz, A. and Connet, J. M. et al.. (1995) Preparation, biodistribution and dosimetry of copper-64 labeled anti-colorectal carcinoma monoclonal antibody fragments 1A3-F(ab')z. J. Nuel. Med. 36, 850-858. Bayouth, J. E., Macey, D. J. and Kasi, L. P. et al.. (1995) Pharmacokinetics, dosimetry, and toxicity of holmium166 DOTMP for bone marrow ablation in multiple myeloma. J. Nucl. Med. 36, 730-737. Breitz, H. B., Durham, J. S. and Fisher, D. R. et al. (1995) Pharmacokinetics and normal organ dosimetry following intraperitoneal rhenium-186 labeled monoclonal antibody. J. Nucl. Med. 36, 754-761. Clunie, G., Lui, D., Cullum, I., Edwards, J. C. W. and Ell, P. J. (1995) Samarium-153 particulate hydroxyapatite radiation synovectomy: Biodistribution data for chromic knee synovitis. J. Nucl. Med. 36, 51-57. Eary, J. F., Collins, C. and Stabin, M. et al.. (1993) Samarium-153 EDTMP biodistribution and dosimetry estimation. J. Nucl. Med. 43, 1031-1036. Ehrhardt, G. J. and Day, D. E. (1987) Therapeutic use of Y-90 microspheres. Nucl. Med. Biol. 14, 233-242. Ehrhardt, G. J., Ketring, A. R., Liang, Q., Miller, R. A., Holmes, A. and Wolfangel, R. G. (1995) Refinement of the peroxide process for making W-188/Re-188 and Mo-99/Tc-99m gel radioisotope generators for nuclear medicine. In Technetium and Rhenium in Chemistry and Nuclear Medicine, eds. M. Nicolini, G. Bandoli and U. Mazzi, Vol. 4. SGEditoriali, Padova, Italy. Kennel, S. J. and Mirzadeh, S. (1996) Vascular Targeting for Radioimmunotherapy with Bi-213. Nucl. Div. Abstr. 021, Book of Abstracts, 212th National Meeting of the American Chemical Society, Orlando, FL. Maxon, H. R. III, Schroder, L. E., Hertzberg, V. S., Thomas, S. R., Englaro, E. E., Samaratunga, R., Smith, H., Moulton, J. S., Williams, C. C., Ehrhardt, G. J. and Schneider, H. J. (1991) Re-186 (Sn) HEDP for treatment of painful osseous metastases: Results of a double-blind crossover comparison with placebo. J. Nucl. Med. 32, 1877. Schott, M. E., Schlom, J. and Siler, K. et al.. (1994) Biodistribution and preclinical radioimmunotherapy studies using radiolanthanide-labeled immunoconjugates. C A N C E R 73, 993-998. Volkert, W. A., Goeckeler, W. F., Ehrhardt, G. J. and Ketring, A. R. (1991) Therapeutic radionuclides: Production and decay property considerations. J. Nucl. Med. 32, 174-185.