Development of an electrochemical 90 Sr-90 Y generator for separation of 90 Y suitable for targeted therapy

90 Y of high specific activity and very high radionuclidic purity (>99.998%) is essential for targeted therapy. Since the current methods used for the preparation of 90 Y from 90 Sr are not adaptable for use in a central/hospital radiopharmacy, a simple 90 Sr-90 Y generator system based on electrochemical separation technique was developed. METHODS: Two-cycle electrolysis procedure was developed for separation of 90 Y from 90 Sr in nitrate solution. The first electrolysis was performed for 90 min in 90 Sr(NO3)2 feed solution at pH 2-3 at a potential of -2.5 V with 100-200 mA current using platinum electrodes. The second electrolysis was performed for 45 min in 3 mM HNO3 at a potential of -2.5 V with 100 mA current. In this step, the cathode from the first electrolysis containing 90 Y was used as anode along with a fresh circular platinum electrode as cathode. The 90 Y deposited on the circular cathode after the second electrolysis was dissolved in acetate buffer to obtain 90 Y acetate, suitable for radiolabeling. RESULTS: >96% recovery of 90 Y could be achieved in each cycle, with an overall decay corrected yield of >90%. The recovered 90 Y had high radionuclidic purity with barely 30.2+/-15.2 kBq (817+/-411 nCi) of 90 Sr per 37 GBq (1 Ci) of 90 Y (0.817+/-0.411 ppm). Consistent and repeated separation could be demonstrated using up to 1.85 GBq (50 mCi) of 90 Sr. The generator was named "Kamadhenu," the eternally milk-yielding Indian mythological cow. CONCLUSIONS: A technique suitable for adaptation at central radiopharmacies for obtaining therapeutic quantities of pure 90 Y has been developed.     

The Relative Distributions of Radioactive Yttrium and Strontium and the Secondary Deposition of 90Y Built up from 90Sr

Weanling rabbits were injected intravenously with one of three solutions: (1) ⁹⁰Sr (free from ⁹⁰Y), (2) ⁹⁰Sr + ⁹⁰Y in equilibrium, and (3) ⁹¹Y, to compare the relative distributions of strontium and yttrium and to establish whether ⁹⁰Y formed by ⁹⁰Sr decay escaped from sites of its original deposition. The animals were sacrificed at different times up to 30 days after injection, and samples of bone and soft tissues were assayed by means of a beta scintillation counter. The measurements on bone showed the concentrations (in µc/g of bone) of strontium and yttrium to be approximately equal. Soft tissues showed a much higher concentration of yttrium than of strontium, but those having highest concentrations of yttrium also had relatively high concentrations of strontium, namely cartilage, pituitary and kidney.

Measurements of the ⁹⁰Y built up when ⁹⁰Sr (free from ⁹⁰Y) was injected showed that ⁹⁰Y was built up in the liver in excess of the amount predicted from the deposition of ⁹⁰Sr.     

A new and convenient method for purification of 86Y using a Sr(II) selective resin and comparison of biodistribution of 86Y and 111In labeled Herceptin

A simple and rapid procedure was developed for purification of cyclotron produced 86Y via the 86Sr(p,n) 86Y reaction. A commercially available Sr(II) selective resin was used to separate 86Y from the cyclotron irradiated Sr(II) target with a recovery of the enriched Sr(II) target while yielding a 75-80% recovery of 86Y suitable for radiolabeling either proteins or peptides. To demonstrate the utility of this methodology, the anti-HER2 monoclonal antibody Herceptin was radiolabeled with the purified 86Y and compared to 111In labeled Herceptin. The biodistribution study demonstrated that 111In-Herceptin, while a suitable surrogate for 90Y in the major organs, did not parallel the uptake of 86Y-Herceptin in the bone, and thus may not accurately predict the level of 90Y accumulation in the bone for clinical RIT applications. This result exemplifies the requirement of employing appropriate matched pair isotopes for imaging and therapy to insure that dosimetry considerations may be addressed accurately.     

Transfer standard for beta decay radionuclides in radiotherapy.

The measurement of the activity of therapeutic radiopharmaceuticals prior to the administration to patients is normally achieved via the use of radionuclide calibrators. An accurate measurement of the activity of pure beta-emitters is complex. Calibration problems can be solved by combining a primary calibration with a 90Y reference solution and a 90Sr/90Y transfer standard with a solid source, simulating geometric effects caused by high energetic beta radiation. The recent development of a 90Sr/90Y transfer standard for this purpose is reported.     

Yttrium-90 -- current status, expected availability and applications of a high beta energy emitter

Yttrium-90 ((90)Y, T(1/2) 64.14 h) is a key example of a high beta energy-emitting radionuclide which is available from the strontium-90 ((90)Sr)/(90)Y radionuclide generator system. Clinical uses of (90)Y-labeled radiopharmaceutical agents have been pursued for many years and many applications have proven to be clinical effective. These most notably include the application of 90Y-labeled antibodies for a variety of applications such as for effective treatment of non-Hodgkin's lymphoma. One of the major advantages for use of (90)Y is ready availability from the very long-lived (90)Sr parent (T(1/2) 28.78 y). Because of the importance of maintaining generator performance and minimizing parent breakthrough, this paper describes development, use and quality control of both high capacity cation adsorption-type and electrochemical generator systems. In addition, the preparation and targeting to tumors in mice of DOTA-conjugated Nimotuzamab (h-R3) antibody which recognizes the external domain of the EPFR antibody radiolabeled with (90)Y obtained from the electrochemical generator is also described. As a key example for clinical applications of (90)Y, the use of (90)Y-labeled biotin for intra-operative pre-targeting for radionuclide therapy (IART?) of breast cancer is also described.     

Reduction of skeletal accumulation of radioactivity by co-injection of DTPA in [90Y-DOTA0,Tyr3]octreotide solutions containing free 90Y3+

Peptide receptor-targeted radionuclide therapy is nowadays being performed with radiolabeled DOTA-conjugated peptides, such as [90Y-DOTA0,Tyr3]octreotide (also known as OctreoTher or 90Y-DOTATOC). The incorporation of 90Y3+ is typically > or = 99%, however, since a total patient dose can be as high as 26 GBq or 700 mCi the amount of free 90Y3+ (= non-DOTA-incorporated) can be substantial. Free 90Y3+ accumulates in bone with undesired radiation of bone marrow as a consequence. 90Y-DTPA is excreted rapidly via the kidneys. Incorporation of free 90Y3+ into 90Y-DTPA might prevent this fraction from being accumulated into bone, therefore we have investigated: the biodistribution in rats of 90YCl3, [90Y-DOTA0,Tyr3]octreotide, and 90Y-DTPA; possibilities to complex 10% of free 90Y3+ in a [90Y-DOTA0,Tyr3]octreotide containing solution into 90Y-DTPA prior to intravenous injection; and effects of 10% free 90Y3+ in [90Y-DOTA0,Tyr3]octreotide solution, in the presence and in the absence of excess DTPA, on the biodistribution of in rats. The following results are presented: 90YCl3 showed high skeletal uptake (i.e., 1% ID (injected dose) per gram femur, with main localization in the epiphyseal plates) and a 24 h total body retention of 74% ID; 90Y-DTPA had rapid renal clearance, and 24 h total body retention of < 5% ID; added free 90Y3+ in [90Y-DOTA0,Tyr3]octreotide solution could rapidly be incorporated into 90Y-DTPA at room temperature; and accumulation of 90Y3+ in femur, blood, and liver was related to the amount of free 90Y3+, whereas these accumulations could be prevented by the addition of DTPA. In conclusion, the addition of excess DTPA to [90Y-DOTA0,Tyr3]octreotide with incomplete 90Y-incorporation is recommended.     

Strontium-89 therapy for the pain of osseous metastases

A Phase I and II study has been conducted of the safety and efficacy of 89Sr (injected i.v. as the chloride) to alleviate bone pain due to osseous metastatic disease. Potential attendant hematologic toxicity was also examined. Strontium-90 impurities were always less than 1.5%, employing a new quality control technique which detects the 90Y "daughter". Thirty-eight patients with pain due to osseous metastases requiring regular narcotic more than twice a day, documented by an abnormal bone scan and radiography, received 45 doses (1-4.5 mCi, 16-70 microCi/kg) of 89Sr after informed consent. The performance status (Karnofsky scale) ranged from 20-80%. One patient had complete pain relief while 22 other doses yielded at least a 25% reduction in narcotic requirement lasting at least 1 mo and/or 20% improvement in Karnofsky scale rating. Two patients had marked to complete relief in tumor sites which were not fractured, with no change in fracture pain. Twenty-two did not respond. Response was independent of narcotic requirements, tumor type, or Karnofsky status. No hematologic toxicity occurred. Strontium-89 may be useful as adjuvant therapy for diffuse bone pain, but a double-blind study comparing it to other nonnarcotic modalities is required.     

Role of diluent on the separation of Y from Sr by solvent extraction and supported liquid membrane using T2EHDGA as the extractant

The separation behaviour of ⁹⁰Y from ⁹⁰Sr was investigated by diluent variation using solvent extraction and supported liquid membrane techniques employing N,N,N′,N′-tetra-2-ethylhexyldiglycolamide (T2EHDGA) as the extractant. Both D_Y (distribution ratio of Y(III)) and S.F. (separation factor) were found to be high in the solvent extraction studies when chloroform was used as the diluent. Subsequent supported liquid membrane (SLM) studies using PTFE flat sheet membranes containing 0.2 M T2EHDGA in various diluents indicated the trend of Y transport as xylene>hexone>chloroform>carbon tetrachloride>n-dodecane+30% iso-decanol mixture. However, the Sr(II) transport rates were also high with xylene, hexone, and carbon tetrachloride as the diluents which led us to carry out subsequent studies using chloroform and n-dodecane+30% iso-decanol mixture. Acid variation studies in chloroform system indicated an interesting phenomena of increasing Y(III) transport and decreasing Sr(II) transport with increasing acid concentration. Separation of ⁹⁰Y from a mixture of ⁹⁰Sr and ⁹⁰Y was also attempted.     

Chemistry for commercial scale production of yttrium-90 for medical research

Studies were initiated at Oak Ridge National Laboratory (ORNL) in 1982 for the radiolabeling of resin microspheres with yttrium-90 (⁹⁰Y) for liver cancer therapy. Yttrium-90 is the decay product of strontium-90 (⁹⁰Sr). Subsequently, ⁹⁰Y became a major radioisotope of choice for labeling antibodies for therapeutic trials in the treatment of other forms of cancer. A 25-Ci ⁹⁰Y generator or ⁹⁰Sr cow was placed in service to supply the anticipated needs of customers. In vivo use of ⁹⁰Y required that the ⁹⁰Sr contamination levels be kept below 10 μCi/Ci ⁹⁰Y (corrected to preparation time). Also, it was necessary to remove trace metals that interfered in the ⁹⁰Y antibody radiolabeling process, giving low radiolabeling yields. Di-(2-ethylhexyl) phosphoric acid (HDEHP) in dodecane has been used routinely at ORNL to extract ⁹⁰Y and thereby give a product that meets the radiochemical purity required with respect to ⁹⁰Sr. Methods were also developed to remove interfering trace elements to provide acceptable labeling yields.     

Production of large quantities of 90Y by ion-exchange chromatography using an organic resin and a chelating agent

The performance of a system composed of an organic cation exchanger (Dowex 50Wx8) and a chelating agent (EDTA) previously described for the successful production of (90)Y via a (90)Sr/(90)Y generator is assessed under dynamic conditions. In an attempt to overcome the established limitation of ion-exchange resins for the separation of subcurie quantities of activity, (90)Y is repeatedly isolated from an 11.8-GBq (320 mCi) (90)Sr cow using a three-column tandem arrangement. The high recovery and radionuclidic purity obtained for (90)Y and the parameters of the separation (time, eluant concentration, pH and flow rate range) strongly suggest that Ci quantities of (90)Y can be handled satisfactorily by the ion-exchange method. No replacement or treatment of the cow, low waste generation and (90)Sr losses less than 0.1% after each run were observed during the present study which, in combination with the low cost of this resin, may result in an attractive alternate method for the production of large quantities of (90)Y.     

~(90)Sr-~(90)Y对人良性前列腺增生细胞增殖与凋亡影响的研究

目的　探讨放射性核素90 Sr 90 Y对良性前列腺增生 (BPH)组织细胞增殖与凋亡的影响。方法　采用DNA原位末端标记法和免疫组织化学法分别测定BPH组织和经放射性核素90 Sr 90 Y腔内照射后的BPH组织中细胞凋亡和Ki 67的表达情况。结果　经90 Sr 90 Y腔内照射后的BPH组织中增殖指数 (PI)较未照射组明显下降 (P <0 0 1 ) ,而两者细胞凋亡指数 (AI)相比差异无显著性 (P >0 0 5)。结论　放射性核素90 Sr 90 Y腔内照射可抑制前列腺细胞增殖 ,未发现诱导细胞凋亡的证据     

Measurement of 90sr in aqueous samples using liquid scintillation counting with full spectrum DPM method.

90Sr activity was measured with the full spectrum DPM (FS-DPM) counting method after plotting the quench correction curves of 90Sr and 90Y, and the FS-DPM method was applied to determine the 90Sr in liquid waste samples. The optimum regions of 90Sr and 90Y were set for measuring 90Sr with the dual label DPM (DL-DPM) method. The direct measurement of purified 90Sr with spectrum unfolding techniques could overcome the disadvantages of the DL-DPM method. The activities of 90Sr in the 90Sr/90Y standardized solution measured with the FS-DPM protocols were close to the true activity. The concentrations of 90Sr in the liquid waste samples measured with the FS-DPM counting method were compared with those obtained with conventional methods.     

Distribution pattern of 90Sr and 137Cs in the Nile delta and the adjacent regions after Chernobyl accident.

Strontium and cesium contents in surface soil samples across the Nile Delta and the north coast of Egypt after the Chernobyl accident have been investigated. The concentration of 137Cs and 90Sr was determined using a high resolution gamma spectrometer based on hyperpure germanium detector (HPGe) and a liquid scintillation counter (LSC) respectively. 90Sr was determined through its decay product 90Y using Cerenkov counting. The determination of 90Sr was based on tributylphosphate (TBP) extraction of yttrium from nitric acid extract of ashed samples. The radioactivity of soils ranged between 18.5 and 2175 Bq/m2 with a mean of 652 Bq/m2 and 234 and 3129 Bq/m2 with a mean of 760 Bq/m2 for 137Cs and 90Sr respectively. An estimated absorbed dose equivalent due to the measured deposit of 137Cs was found to be 0.062 murem/h.     

Separation of 90Y from 90Sr using zirconium vanadate as the ion exchanger.

The sorption and desorption behaviour of several radionuclides, including 241Am, 152,154Eu, 233U, 137Cs, 90Sr and 90Y was studied under varying acidities using zirconium vanadate as ion exchanger. The sorption follows the order: Cs > Eu > Am >Y > U, while Sr was not taken up by the ion exchanger. A radiochemical separation scheme for the 90Y daughter from its 90Sr parent using zirconium vanadate ion exchanger has been developed. The exchanger was synthesized and characterized in our laboratory.     

Performance of a prototype of an extrapolation minichamber in various radiation beams.

An extrapolation minichamber was developed for measuring doses from weakly penetrating types of radiation. The chamber was tested at the radiotherapeutic dose level in a beam from a (90)Sr+(90)Y check source, in a beam from a plane (90)Sr+(90)Y ophthalmic applicator, and in several reference beams from an X-ray tube. Saturation, ion collection efficiency, stabilization time, extrapolation curves, linearity of chamber response vs. air kerma rate, and dependences of the response on the energy and irradiation angle were characterized. The results are satisfactory; they show that the chamber can be used in the dosimetry of (90)Sr+(90)Y beta particles and low-energy X-ray beams.     

Improved chemistry for the production of yttrium-90 for medical applications

A novel extraction chromatographic method for the preparation of ⁹⁰Y of high chemical and radiochemical purity has been developed. After an initial purification of a ⁹⁰Sr stock solution and a suitable period of ⁹⁰Y ingrowth, the solution is passed through a series of strontium-selective chromatographic columns, each of which lowers the ⁹⁰Sr content of the mixture by a factor of ∼ 10³. The ⁹⁰Y remaining is freed from any residual ⁹⁰Sr, from its ⁹⁰Zr daughter, and from any remaining impurities by passing the sample through a final column designed to selectively retain yttrium.     

Generator-produced yttrium-90 for radioimmunotherapy

Yttrium-90 is often considered to possess many favorable properties for radioimmunotherapy applications. Among these is its availability as a radionuclide generator product by decay of its parent, 90Sr. Nevertheless, most present and planned clinical trials with 90Y-labeled antibodies employ radioactivity obtained not from an in-house generator, but from commercial sources. To prepare for clinical trials at this institution with 90Y labeled to diethylenetriaminepentaacetic acid- (DTPA) coupled antibodies, we have adapted previously published procedures and have developed others to prepare antibodies labeled with generator produced 90Y for human use. Up to 25 mCi of 90Sr have been loaded without evidence of radiolytic degradation to the Dowex 50 cation exchange resin which serves as the solid support for the generator. Using 0.003M ethylenetriaminetetraacetic acid (EDTA) as eluant, elution efficiency averages 98% and 90Sr breakthrough averages 0.002%. The EDTA is destroyed remotely and the activity is dissolved in 0.5M acetate, pH 6. In this form, 90Y may be used to label DTPA-coupled proteins at specific activities of 1-3 mCi/mg (an order of magnitude improvement in specific activity results from the purification of 90Y by cation exchange prior to labeling). When properly labeled, size exclusion HPLC shows 90% or greater radiochemical purity and recovery without postlabeling purification. We conclude that these techniques provide a 90Y-labeled protein preparation which is safe for administration to patients.     

Optimal radiation shielding for beta and bremsstrahlung radiation emitted by 89Sr and 90Y: validation by empirical approach and Monte Carlo simulations

Objective

High-energy beta emitters such as Strontium-89 (⁸⁹Sr) and Yttrium-90 (⁹⁰Y) are becoming increasingly popular nuclear therapy sources in Japan for treating cancer. Various characteristics of materials must be considered when designing radiation protection device for high-energy beta emitters. We empirically measured and simulated dose equivalents of beta and bremsstrahlung radiation arising from ⁸⁹Sr and ⁹⁰Y radiation shielded with various materials and determined optimal shielding materials against these sources.

Methods

The dose equivalents of ⁸⁹Sr and ⁹⁰Y determined experimentally using an ionization chamber survey meter were compared with those of Monte Carlo simulations. The relative dose equivalents of beta and bremsstrahlung radiation separately transmitted by changing the thickness of acrylic, aluminum, iron, lead and tungsten shielding materials were simulated.

Results

Dose equivalents were consistent between the empirical measurements and the simulation to within ±5 %. Shielding ability was more effective in the order of tungsten, lead, iron, aluminum and acrylic against both ⁸⁹Sr and ⁹⁰Y. The amount of beta and bremsstrahlung radiation transmitted through tungsten and lead was relatively small. Although such high-density material generates much bremsstrahlung radiation, it absorbs the bremsstrahlung radiations.

Conclusions

Tungsten was the optimal material for efficient shielding against ⁸⁹Sr and ⁹⁰Y radiation and preferable among operators. The present findings provide useful information about how to define an appropriate shielding strategy for high-energy beta emitters.     

Influence of oestrogen on the excretion of strontium-90 and -85 in mice.

Groups of male CBA-mice were treated with oestrogenic hormones alone or in combination with 85Sr and 90Sr. The strontium retention was measured in special skeleton parts and also by means of whole body counting. After a period of increasing bone weight in mice treated with oestrogen and 90Sr, there were signs of a serious breakdown of that newly formed 'oestrogenic' bone tissue. The strontium retention was in no case found higher in animals treated with both the hormones and 90Sr when compared to those treated with 90Sr alone. The life span was shortened in mice given the combined treatment. The results support the theories that at the same time irradiated and stimulated cell populations are exposed to a larger risk for induction of tumours and that the irradiation injury cannot be referred entirely to the irradiation dose in a physical sense.     

Activity measurements of 18F and 90Y with commercial radionuclide calibrators for nuclear medicine in Switzerland

The activity of radiopharmaceuticals in nuclear medicine is measured before patient injection with radionuclide calibrators. In Switzerland, the general requirements for quality controls are defined in a federal ordinance and a directive of the Federal Office of Metrology (METAS) which require each instrument to be verified. A set of three gamma sources (Co-57, Cs-137 and Co-60) is used to verify the response of radionuclide calibrators in the gamma energy range of their use. A beta source, a mixture of ⁹⁰Sr and ⁹⁰Y in secular equilibrium, is used as well. Manufacturers are responsible for the calibration factors. The main goal of the study was to monitor the validity of the calibration factors by using two sources: a ⁹⁰Sr/⁹⁰Y source and a ¹⁸F source. The three types of commercial radionuclide calibrators tested do not have a calibration factor for the mixture but only for ⁹⁰Y. Activity measurements of a ⁹⁰Sr/⁹⁰Y source with the ⁹⁰Y calibration factor are performed in order to correct for the extra-contribution of ⁹⁰Sr. The value of the correction factor was found to be 1.113 whereas Monte Carlo simulations of the radionuclide calibrators estimate the correction factor to be 1.117. Measurements with ¹⁸F sources in a specific geometry are also performed. Since this radionuclide is widely used in Swiss hospitals equipped with PET and PET-CT, the metrology of the ¹⁸F is very important. The ¹⁸F response normalized to the ¹³⁷Cs response shows that the difference with a reference value does not exceed 3% for the three types of radionuclide calibrators.