Gary J. Ehrhardt

Metallofullerene Drug Design

Abstract Endohedral lanthanide metallofullerenes are new molecules that may have useful medicinal properties. In particular, endohedral holmium metallofullerenes have been utilized in a model metallofullerene radiotracer study. The 165 Ho metallofullerenes were chemically functionalized to impart water solubility and then neutron activated to 166 Ho in order to determine their biodistribution and metabolism properties. The results have been evaluated for potential applications of lanthanide metallofullerenes as new diagnostic or therapeutic radiopharmaceuticals. Use of metallofullerenes in conventional diagnostic radiology (MRI contrast and X-ray imaging agents) has also been considered.

Rhenium-186 hydroxyethylidene diphosphonate for the treatment of painful osseous metastases

Rhenium-186 (tin)hydroxyethylidene diphosphonate (HEDP) is a new radiopharmaceutical that localizes in skeletal metastases in patients with advanced cancer. A single intravenous administration of approximately 34 mCi (1,258 MBq) resulted in significant improvement in pain in 33 of 43 evaluable patients (77%) following the initial injection, and in 7 of 14 evaluable patients (50%) following a second treatment. Patients responding to treatment experienced an average decrease in pain of about 60%, with one in five treatments resulting in a complete resolution of pain. The only adverse clinical reaction was the occurrence after about 10% of the administered doses of a mild, transient increase in pain within a few days following injection. Statistically significant but clinically unimportant decreases in total white blood cell counts and total platelet counts were observed within the first 8 weeks following the injection; no other toxicity was apparent. Rhenium-186(Sn)HEDP is a useful new compound for the palliation of painful skeletal metastases.

Therapeutic Use of 90Y Microspheres

Glass microspheres 20-30 microns in diameter containing either 31P or 89Y that can be activated by neutron bombardment to 32P or 90Y respectively, have been produced for intra-arterial radiotherapy of liver tumors. The spheres are insoluble in body fluids, non-toxic, and can concentrate in liver tumors of animals by direct injection into the hepatic artery. This gives a higher radiation dose to the tumor than can be achieved with external beam therapy. Trials in rabbits and dogs have proven successful and this product (90Y TheraSpheres) is now entering limited human clinical trials.

Preparation and properties of radioactive rhenium glass microspheres intended for in vivo radioembolization therapy

Rhenium glass microspheres composed of metallic rhenium particles dispersed within a magnesium alumino borate glass matrix were produced by sintering ReO2 powder and glass frit at 1050 degrees C. The in vitro chemical durability of radioactive and nonradioactive microspheres was determined from chemical corrosion tests on microspheres immersed in phosphate-buffered saline (PBS) solution at 37 degrees C. The dosimetric properties of these microspheres also were calculated. The rhenium glass microspheres are chemically durable in body fluids and release < 1.2% of radioactive rhenium after being immersed in PBS solution for 32 days at 37 degrees C. Therapeutic radioactive rhenium activities can be obtained in < 10 h by neutron activation of these microspheres in a thermal neutron flux of 8 x 10(13) cm(-2)s(-1). A 50 mg injection of radioactive rhenium glass microspheres containing 3.7 GBq of 186Re and 8.5 GBq of 188Re could deliver a 100 Gy dose to a cancerous liver while limiting the total body dose from rhenium dissolution in vivo to approximately 1 mGy.

Reactor-produced radionuclides at the University of Missouri Research Reactor

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.

PRODUCTION OF RADIOLANTHANIDES AND RADIOTHERAPY RESEARCH AT MURR

Many lanthanide radionuclides, having various nuclear properties but similar chemical properties, are considered suitable for different radiotherapeutic applications. This paper describes the production of a number of radiolanthanides (e.g.153Sm,166Dy,166Ho,161Tb and177Lu) and the radiotherapy research involving these radionuclides at the University of Missouri Research Reactor Center (MURR).

Experience with aluminum perrhenate targets for reactor production of high specific activity Re-186

Abstract An alternative method for the production of multicurie quantities of (n, gamma) Re-186 has been investigated utilizing irradiation of sub-milligram-sized targets of water-soluble, Re-185-enriched aluminum perrhenate in high neutron fluxes (∼4 × 1014 cm2 s−1) for up to 2 weeks. These targets can be accurately aliquoted from solution and dried in quartz vials prior to irradiation, immobilizing them and preventing their dispersal upon opening. Aluminum functions as an excellent counterion because of its high valence and because it forms only short-lived radioactivities under neutron bombardment. Approximately 190, multi-curie-sized Re-186 targets have been irradiated and processed, recovering typically ∼85% of the Re-186 activity in 0.5 ml water and employing only glove box techniques. This product exhibits >98% of the radiorhenium in the chemical form of perrhenate ion by ITLC and has a specific activity of about 3 Ci/mg Re. Similar experience has been obtained using Re-187-enriched aluminum perrhenate for the production of Re-188. Aluminum perrhenate is thus a suitable target for a high flux reactor, permitting easy recovery of rhenium activities in suitable chemical form in an oxidant-free, neutral aqueous solution which is practical for development of radiopharmaceutical kits for new applications. In addition, the short processing time and simple manipulations required by this target contribute to radiation safety.

Labeling of antibodies with 64Cu using a conjugate containing a macrocyclic amine chelating agent

The conjugation of a model antibody (rabbit-anti-HSA-IgG) with a functionalized derivative of cyclam (1-(3-aminopropyl)-4-methyl-1,4,8,11-tetraazacyclotetradecane) is reported. Coupling of this derivative to the antibodies was accomplished using commercially available heterobifunctional coupling agents. The conjugation technique produced minimal effects on the antibody binding activity. 64Cu complexes with this cyclam derivative have excellent stability in human serum and aqueous solutions containing 1 mM EDTA. The high stability of these Cu-complexes suggests that this system, or other analogous systems, may be useful for production of stable 67Cu-immunotherapeutic agents.

Ventilation imaging with Kr-81m

Sixty-five patients with suspected pulmonary embolism were studied prospectively with both Kr-81 m and Xe-133 ventilation imaging and Tc-99m MAA perfusion imaging. The krypton images, perfusion scintigrams and chest radiographs were read independently of the xenon images, perfusion scintigrams and chest radiographs by three observers. The studies of 53 patients were interpreted as normal or as indicative of a low or intermediate probability for pulmonary embolism with both gases. One study indicated intermediate probability with Xe-133 due to diffuse, severe xenon retention but low probability with Kr-81 m because of close ventilation-perfusion correspondence. The studies of 9 patients indicated a high probability of embolism with both gases, while those of two additional patients (one with emboli at angiography) indicated a high probability only with Kr-81m. While essential agreement between Xe-133 and Kr-81m ventilation imaging was found in most patients, the significant difference in interpretation in 2 of 11 patients with probable pulmonary embolism suggests that a controlled, prospective trial with pulmonary angiography is warranted before Kr-81m is employed for routine clinical use.

186Re/188Re labeled polypeptide microspheres as a potential radiation synovectomy agent

Polypeptide microspheres containing polycysteine crosslinked with polylysine were prepared and radiolabeled with186Re and188Re. High labeling yields with the microspheres with both186Re and188Re (97%) were obtained, and above 99% retention of radiolabels in water in 24 hours was obtained. Rhenum-186 labeled polycysteine and polylysine microspheres (1∶1 ratio, 20 μm as mean diameter) were injected intra-articularly into the rear stifes (knee joints) of normal New Zealand white rabbits. About 87% of injected dose was retained in rabbit stifles and adjacent tissues in 96 hours after injection, while most of the activity lost from the joints was excreted in the urine. Due to its simplicity of preparation and radiolabeling, versatility, and biodegradability, this type of conjugate system may become the therapeutics of choice for radiation synovectomy.