Safety and efficacy of targeted alpha therapy with 213Bi-DOTA-substance P in recurrent glioblastoma.

Treatment options for recurrent glioblastoma multiforme (GBM) are very limited. GBM cells express high levels of the GPCR neurokinin type 1 receptor (NK-1R), and a modified substance P can be used as its ligand for the tumor cell targeting. Targeted alpha therapy with DOTA-Substance P labeled with the short range alpha emitter 213Bi allows for selective irradiation and killing of tumor cells. MATERIAL AND METHODS: Twenty patients with recurrent GBM were included into the study following a standard therapy. 1-2 intracavitary or intratumoral port-a-cath systems were stereotactically inserted. Patients were treated with 1-7 doses of 213Bi-DOTA-Substance P (213Bi-DOTA-SP) in 2-month intervals. 68Ga-DOTA-Substance P (68Ga-DOTA-SP) was co-injected with 213Bi-DOTA-SP to assess the biodistribution using PET/CT. Therapeutic response was monitored with performance status and MRI imaging. RESULTS: Treatment with activity up to 11.2 GBq 213Bi-DOTA-SP was well tolerated with only mild and transient adverse reactions. The median progression free survival was 2.7 months. The median overall survival from the first diagnosis was 23.6 months and median survival after recurrence was 10.9 months. The median survival time from the start of 213Bi-DOTA-SP was 7.5 months. CONCLUSIONS: Treatment of recurrent GBM with 213Bi-DOTA-SP is safe and well tolerated. The median overall survival after recurrence of 10.9 months compares favorably to the available alternative treatment options. Once the supply of high activity 225Ac/213Bi radionuclide generators is secured, targeted alpha therapy with 213Bi-DOTA-SP may evolve as a promising novel option to treat recurrent GBM.

Prolonged survival in secondary glioblastoma following local injection of targeted alpha therapy with 213Bi-substance P analogue.

BACKGROUND: Glioblastoma multiforme (GBM), the most common malignant brain tumor, mainly manifests as a primary de novo and less frequently as a secondary glial neoplasm. GBM has been demonstrated to overexpress the NK-1 receptor and substance P can be used as a ligand for targeted therapy. Alpha emitters, e.g. 213Bi, that deposit their high energy within a short range allow the selective irradiation of tumor cells while sparing adjacent neuronal structures. MATERIAL AND METHODS: Among 50 glioma patients of different subtypes that have to date been treated with targeted alpha therapy at the Medical University Warsaw, we report here the data on nine patients with secondary GBM. Following surgery, chemo- and radiotherapy, recurrent GBM was treated by intracavitary injection of 1-6 doses of 0.9-2.3 GBq 213Bi- DOTA-[Thi8,Met(O2)11]-substance P (213Bi-DOTA-SP) in 2-month intervals. 68Ga-DOTA-[Thi8,Met(O2)11]-substance P (68Ga-DOTA-SP) was co-injected with the therapeutic doses to assess biodistribution using PET/CT. Therapeutic response was monitored with MRI. RESULTS: Treatment with activities ranging from 1.4 to 9.7 (median 5.8) GBq 213Bi- DOTA-SP was well tolerated with only mild transient adverse reactions, mainly headaches due to a transient perfocal edema reaction. The median progression free survival and overall survival time following the initiation of alpha therapy was 5.8 and 16.4 months, respectively. The median overall survival time from the first diagnosis was 52.3 months. Two out of nine patients are still alive 39 and 51 months, respectively, after the initiation of the therapy. CONCLUSIONS: Targeted alpha therapy of secondary GBM with 213Bi-DOTA-SP is safe and well tolerated and may evolve as a promising novel therapeutic option for secondary GBM.

Treatment of carcinoma in situ of the urinary bladder with an alpha-emitter immunoconjugate targeting the epidermal growth factor receptor: a pilot study.

PURPOSE: Patients with carcinoma in situ (CIS) of the bladder refractory to bacillus Calmette-Guérin (BCG) treatment are usually treated with cystectomy. Therefore, new treatment options with preservation of the urinary bladder are needed. The objective of the study was to investigate the feasibility, safety and efficacy of a novel targeted alpha-emitter immunotherapy for CIS after BCG treatment failure. METHODS: A pilot study was conducted in 12 patients (age range 64-86 years, ten men, two women) with biopsy-proven CIS of the bladder refractory to BCG treatment. The patients were treated intravesically with a single instillation (one patient was treated twice) of the alpha-emitter 213Bi coupled to an anti-EGFR antibody (366-821 MBq). The primary aims of the study were to determine the feasibility of treatment with the 213Bi-immunoconjugate and evaluation of adverse effects. Therapeutic efficacy was monitored by histological mapping of the urinary bladder 8 weeks after treatment and at different time points thereafter. RESULTS: The study proved that intravesical instillation of the 213Bi-immunoconjugate targeting EGFR is feasible. No adverse effects were observed and all blood and urine parameters determined remained in their normal ranges. Therapeutic efficacy was considered satisfactory, in that three of the 12 patients showed no signs of CIS 44, 30 and 3 months after treatment. CONCLUSION: Intravesical instillation of 213Bi-anti-EGFR monoclonal antibody was well tolerated and showed therapeutic efficacy. Repeated instillation and/or instillation of higher activities of the 213Bi-immunoconjugate might lead to better therapeutic outcomes. A phase I clinical trial is planned.

Flagellin peptide flg22 gains access to long-distance trafficking in Arabidopsis via its receptor, FLS2.

Diverse pathogen-derived molecules, such as bacterial flagellin and its conserved peptide flg22, are recognized in plants via plasma membrane receptors and induce both local and systemic immune responses. The fate of such ligands was unknown: whether and by what mechanism(s) they enter plant cells and whether they are transported to distal tissues. We used biologically active fluorophore and radiolabeled peptides to establish that flg22 moves to distal organs with the closest vascular connections. Remarkably, entry into the plant cell via endocytosis together with the FLS2 receptor is needed for delivery to vascular tissue and long-distance transport of flg22. This contrasts with known routes of long distance transport of other non-cell-permeant molecules in plants, which require membrane-localized transporters for entry to vascular tissue. Thus, a plasma membrane receptor acts as a transporter to enable access of its ligand to distal trafficking routes.

Results of a Direct Search Using Synchrotron Radiation for the Low-Energy (229)Th Nuclear Isomeric Transition.

We report the results of a direct search for the (229)Th (I(π)=3/2(+)←5/2(+)) nuclear isomeric transition, performed by exposing (229)Th-doped LiSrAlF(6) crystals to tunable vacuum-ultraviolet synchrotron radiation and observing any resulting fluorescence. We also use existing nuclear physics data to establish a range of possible transition strengths for the isomeric transition. We find no evidence for the thorium nuclear transition between 7.3 eV and 8.8 eV with transition lifetime (1-2) s≲τ≲(2000-5600) s. This measurement excludes roughly half of the favored transition search area and can be used to direct future searches.

LaPO4 nanoparticles doped with actinium-225 that partially sequester daughter radionuclides.

Nanoscale materials have been envisioned as carriers for various therapeutic drugs, including radioisotopes. Inorganic nanoparticles (NPs) are particularly appealing vehicles for targeted radiotherapy because they can package several radioactive atoms into a single carrier and can potentially retain daughter radioisotopes produced by in vivo generators such as actinium-225 ((225)Ac, t(1/2) = 10 d). Decay of this radioisotope to stable bismuth-209 proceeds through a chain of short-lived daughters accompanied by the emission of four α-particles that release >27 MeV of energy. The challenge in realizing the enhanced cytotoxic potential of in vivo generators lies in retaining the daughter nuclei at the therapy site. When (225)Ac is attached to targeting agents via standard chelate conjugation methods, all of the daughter radionuclides are released after the initial α-decay occurs. In this work, (225)Ac was incorporated into lanthanum phosphate NPs to determine whether the radioisotope and its daughters would be retained within the dense mineral lattice. Further, the (225)Ac-doped NPs were conjugated to the monoclonal antibody mAb 201B, which targets mouse lung endothelium through the vasculature, to ascertain the targeting efficacy and in vivo retention of radioisotopes. Standard biodistribution techniques and microSPECT/CT imaging of (225)Ac as well as the daughter radioisotopes showed that the NPs accumulated rapidly in mouse lung after intravenous injection. By showing that excess, competing, uncoupled antibodies or NPs coupled to control mAbs are deposited primarily in the liver and spleen, specific targeting of NP-mAb 201B conjugates was demonstrated. Biodistribution analysis showed that ∼30% of the total injected dose of La((225)Ac)PO(4) NPs accumulated in mouse lungs 1 h postinjection, yielding a value of % ID/g >200. Furthermore, after 24 h, 80% of the (213)Bi daughter produced from (225)Ac decay was retained within the target organ and (213)Bi retention increased to ∼87% at 120 h. In vitro analyses, conducted over a 1 month interval, demonstrated that ∼50% of the daughters were retained within the La((225)Ac)PO(4) NPs at any point over that time frame. Although most of the γ-rays from radionuclides in the (225)Ac decay chain are too energetic to be captured efficiently by SPECT detectors, appropriate energy windows were found that provided dramatic microSPECT images of the NP distribution in vivo. We conclude that La((225)Ac)PO(4)-mAb 201B conjugates can be targeted efficiently to mouse lung while partially retaining daughter products and that targeting can be monitored by biodistribution techniques and microSPECT imaging.

Nuclear data for reactor production of 131Ba and 133Ba.

The newest radioisotope for brachytherapy treatment of prostate cancer is 131Cs (t1/2 = 9.69 d, 100% EC). Generated via electron capture decay of 131Ba (t1/2 = 11.6 d, 100% EC), 131Cs has been used in brachytherapy for prostate cancer since 2004. The 131Ba parent is produced through neutron capture of enriched 130Ba in a nuclear reactor. For large-scale production of 131Ba, an accurate knowledge of production and burnup cross sections of 131Ba are essential. In this paper, we report two group cross sections (thermal and resonance integrals) for 130Ba and 131Ba and a new measure of the half-life of 131Ba. Targets consisting of milligram quantities of enriched 130Ba (∼35%) were irradiated in Oak Ridge National Laboratory's High Flux Isotope Reactor at thermal and resonance neutron fluxes of (1.9-2.1) × 1015 and (5.8-7.0) × 1013 neutrons·cm-2 s-1, respectively, for durations ranging from 3 to 26 days. In addition, cadmium covered samples of 130Ba were irradiated for 1 hour at 12.6% full reactor power (10.7 MW). The yield of 131Ba approaches a saturation value of ∼60 GBq (∼1.6 Ci) per mg of 130Ba for 20 days irradiation at a thermal neutron flux of 1.8 × 1015 n·s-1·cm-2, with a thermal/epithermal ratio of ∼30. Under the above experimental conditions, the two group cross sections of 130Ba are 6.9 ±â€¯0.5 b (thermal, σ0) and 173 ±â€¯7 b (resonance, I0). These values represent the sum of cross sections to metastable and ground states of 131Ba. For 131Ba, the empirically measured thermal cross section is 200 ±â€¯50 b assuming an I0/σ0 of 10. This cross section is reported for the first time. Further, the half-life of 131Ba was remeasured to be 11.657 ±â€¯0.008 d. Lastly, this study also resulted in the co-production of 133Ba (t1/2 = 10.52 y, 100% EC). The experimental yield of 133Ba is ∼370 MBq (∼10 mCi) per mg of 132Ba (thin target) for one cycle irradiation in the High Flux Isotope Reactor, and measured two-group 132Ba cross sections are 7.2 ±â€¯0.2 b and 39.9 ±â€¯1.3 b. These values also represent the sum of cross sections to metastable and ground states of 133Ba.

Overview of the First NRG Oncology-National Cancer Institute Workshop on Dosimetry of Systemic Radiopharmaceutical Therapy.

In 2018, the National Cancer Institute and NRG Oncology partnered for the first time to host a joint workshop on systemic radiopharmaceutical therapy (RPT) to specifically address dosimetry issues and strategies for future clinical trials. The workshop focused on current dosimetric approaches for clinical trials, strategies under development that would optimize dose reporting, and future desired or optimized approaches for novel emerging radionuclides and carriers in development. In this article, we review the main approaches that are applied clinically to calculate the absorbed dose. These include absorbed doses calculated over a variety of spatial scales, including whole body, organ, suborgan, and voxel, the last 3 of which are achievable within the MIRD schema (S value) and can be calculated with analytic methods or Monte Carlo methods, the latter in most circumstances. This article will also contrast currently available methods and tools with those used in the past, to propose a pathway whereby dosimetry helps the field by optimizing the biologic effect of the treatment and trial design in the drug approval process to reduce financial and logistical costs. We also briefly discuss the dosimetric equivalent of biomarkers to help bring a precision medicine approach to RPT implementation when merited by evidence collected during early-phase trial investigations. Advances in the methodology and related tools have made dosimetry the optimum biomarker for RPT.

Synthesis and Stability of Actinium-225 Endohedral Fullerenes, 225Ac@C60.

We report the first synthesis of 225Ac (t 1/2 = 10 days) endohedral fullerenes,225Ac@C60. The 225Ac@C60 was produced with a 12 ± 2% efficiency by applying an electrical arc discharge between a source of α-particle emitter 225Ac (∼1 mCi, electroplated on a Pt disk) and a thin coat of "preformed" C60 on an Al disk (C60 thickness of ∼0.25 mg/cm2). After formation by electrical arc discharge, the resulting radiofullerenes on the Al disk were dissolved in toluene under anaerobic conditions and converted to a malonate derivative using the Bingel reaction. Subsequent to repeated washings of the organic phase with dilute acidic solutions to remove exohedral 225Ac, ∼45% of 225Ac activity was retained in the organic phase, which resisted extraction into the aqueous phase. Failure to extract the 225Ac from the organic phase provided definitive evidence that the 225Ac is located inside of the fullerene. The formation of 225Ac@C60 was further confirmed using a classical hot-atom chemistry technique in which the organic phase containing purified endohedral 225Ac@C60 malonate was contacted with fresh dilute acid to repeatedly extract the ionic 4.8 m 221Fr and 45.6 m 213Bi activities (decay daughters of 225Ac), which were released by molecular disruption due to nuclear recoil. The result from the extraction experiments was further supported by a series of thin-layer chromatography and high-pressure liquid chromatography analysis of the organic phase containing 225Ac@C60 or 225Ac@C60 malonate. Taken together, studies show that, like polydentate chelators, single-wall fullerenes are not capable of retaining the 225Ac decay daughters.

203/212Pb Theranostic Radiopharmaceuticals for Image-guided Radionuclide Therapy for Cancer.

Receptor-targeted image-guided Radionuclide Therapy (TRT) is increasingly recognized as a promising approach to cancer treatment. In particular, the potential for clinical translation of receptor-targeted alpha-particle therapy is receiving considerable attention as an approach that can improve outcomes for cancer patients. Higher Linear-energy Transfer (LET) of alpha-particles (compared to beta particles) for this purpose results in an increased incidence of double-strand DNA breaks and improved-localized cancer-cell damage. Recent clinical studies provide compelling evidence that alpha-TRT has the potential to deliver a significantly more potent anti-cancer effect compared with beta-TRT. Generator-produced 212Pb (which decays to alpha emitters 212Bi and 212Po) is a particularly promising radionuclide for receptor-targeted alpha-particle therapy. A second attractive feature that distinguishes 212Pb alpha-TRT from other available radionuclides is the possibility to employ elementallymatched isotope 203Pb as an imaging surrogate in place of the therapeutic radionuclide. As direct non-invasive measurement of alpha-particle emissions cannot be conducted using current medical scanner technology, the imaging surrogate allows for a pharmacologically-inactive determination of the pharmacokinetics and biodistribution of TRT candidate ligands in advance of treatment. Thus, elementally-matched 203Pb labeled radiopharmaceuticals can be used to identify patients who may benefit from 212Pb alpha-TRT and apply appropriate dosimetry and treatment planning in advance of the therapy. In this review, we provide a brief history on the use of these isotopes for cancer therapy; describe the decay and chemical characteristics of 203/212Pb for their use in cancer theranostics and methodologies applied for production and purification of these isotopes for radiopharmaceutical production. In addition, a medical physics and dosimetry perspective is provided that highlights the potential of 212Pb for alpha-TRT and the expected safety for 203Pb surrogate imaging. Recent and current preclinical and clinical studies are presented. The sum of the findings herein and observations presented provide evidence that the 203Pb/212Pb theranostic pair has a promising future for use in radiopharmaceutical theranostic therapies for cancer.

Innovation, Impact, and Strategic Importance of Alpha-Emitting Radionuclides.

This talk briefly reviews the earlier work in the field and highlights the contributions of colleagues whose clear vision paved the road for success of TAT. The talk primarily will focus on the development of the radioisotopes for application in TAT. The challenges regarding release of daughter radioisotopes will be briefly discussed, and a summary of the alternative approaches for production of 225Ac will be presented.

Measurement of neutron capture cross section of 187W for production of 188W.

Tungsten-188 (t1/2 = 69.4 d) is routinely produced by double neutron capture using highly enriched 186W target, 186W(n,γ)187W(n,γ)188W reaction, at the ORNL 85 MWt High Flux Isotope Reactor. While the thermal neutron cross section for the first reaction, 186W(n,γ)187W, is well known, the single reported 64 b cross-section for the second reaction, 187W(n,γ)188W, cannot be validated by experimental results that yield lower than expected activities of 188W. In this study, we report a new value for the thermal neutron capture cross section of 187W. After confirming the neutron capture cross section of 186W (σ0 = 37.8 ±â€¯1.8 b for thermal and I0 = 476 ±â€¯25 b for resonance integrals with σ0/I0 = 12.6 ±â€¯0.4) in two short irradiations, longer irradiations (1-10 d) were performed to obtain a value of 6.5 ±â€¯0.8 b for the σ0 of 187W, which is lower than the adopted value by a factor of 10. Due to the short half-life of 187W (t1/2 = 23.7 d), the σ0 for 187W was obtained empirically by comparing the 188W experimental yields with the theoretical yields generated by code IsoChain and varying the 187W cross section while keeping all other parameters constant.

Reactor production of promethium-147.

In this paper, we describe the 147Pm production yields and level of impurities from several targets that consisted of milligram quantities of highly enriched 146Nd oxide irradiated at the High Flux Isotope Reactor (HFIR) at Oak Ridge National Laboratory for durations ranging from 24 to 180 h. A comparison between theoretical and experimental data are also presented, and attempts were made to empirically evaluate the neutron capture cross-sections of 41.3-d 148mPm and 5.4-d 148gPm. For a one-cycle irradiation (~24 days), 147Pm yield reaches a maximum value of 101.8 MBq/mg (2.75 mCi/mg) at 60 days after the end of bombardment. Because of large neutron capture cross-sections of 147Pm, the yield of 147Pm does not significantly increase with longer irradiation. Our estimates of the thermal neutron capture cross-section and resonance integral for 146Nd at 1.48 ±â€¯0.05 b and 2.56 ±â€¯0.25 b, respectively, were consistent with the reported values. The effective neutron capture cross-section of 147Pm to 148mPm was 53.3 ±â€¯2.7 b-a factor of 2 lower than the 98.7 ±â€¯6.5 b calculated from reported cross-sections. The measured σeff to the ground state (5.37-d 148gPm) was 82.0 ±â€¯4.1 b; ~34% lower than the value of 139 ±â€¯10 b calculated from reported cross-sections. In this work, we also describe the development of a chemical process based on extraction and ion-exchange chromatography for separation of 147Pm from milligram quantities of 146Nd and other impurities. Sequential separation of Pm from the Nd target and from other radioisotopic impurities (153Gd and 154&155Eu, 192Ir, and 60Co) was achieved using a LN extraction resin in HCl media followed by further purification of Pm from 60Co and 192Ir using a low cross-linking cation exchange resin. Based on these data, we estimated that two rounds of purification under our experimental conditions can provide a mass separation factor of >104 between Pm and Nd. Our data indicate that curie quantities of 147Pm with suitable chemical and radioisotopic purity for applications in beta voltaic batteries can be produced by irradiating gram quantities of highly enriched 146Nd in the flux trap of HFIR for one cycle.

The fate of MAb-targeted Cd(125m)Te/ZnS nanoparticles in vivo.

INTRODUCTION: Nanoparticles (NP) have potential as carriers for drugs and radioisotopes. Quantitative measures of NP biodistribution in vivo are needed to determine the effectiveness of these carriers. We have used a model system of radiolabeled quantum dots to document the competition between efficient vascular targeting and interaction of the NP with the reticuloendothelial (RE) system. METHODS: We have prepared (125m)Te-labeled CdTe NP that are capped with ZnS. Te-125m has a half-life and decay characteristics very similar to those for (125)I. The synthesized particles are stable in aqueous solution and are derivatized with mercaptoacetic acid and then conjugated with specific antibody. To evaluate specific targeting, we used the monoclonal antibody MAb 201B that binds to murine thrombomodulin expressed in the lumen of lung blood vessels. The MAb-targeted NP were tested for targeting performance in vivo using single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging, tissue autoradiography and standard organ biodistribution techniques. Biodistribution was also determined in mice that had been depleted of phagocytic cells by use of clodronate-loaded liposomes. RESULTS: Cd(125m)Te/ZnS NP coupled with MAb 201B retained radioisotope and antibody activity and accumulated in lung (>400% injected dose [ID]/g) within 1 h of intravenous injection. Control antibody-coupled NP did not accumulate in lung (<10% ID/g) but accumulated in liver and spleen. Images from microSPECT/CT and autoradiography studies of the targeted NP document this specific uptake and demonstrate uniform distribution in lung with minor accumulation in liver and spleen. Within a few hours, a large fraction of lung-targeted NP redistributed to spleen and liver or was excreted. We hypothesized that NP attract phagocytic cells that engulfed and removed them from circulation. This was confirmed by comparing biodistribution of targeted NP in normal mice versus those depleted of phagocytic cells. In mice treated with clodronate liposomes, accumulation of NP in liver was reduced by fivefold, while accumulation in lung at 1 h was enhanced by approximately 50%. By 24 h, loss of the targeted NP from lung was inhibited by several-fold, while accumulation in liver and spleen remained constant. Thus, the treated mice had a much larger accumulation and retention of the NP at the target site and a decrease in dose to other organs except spleen. CONCLUSION: Nanoparticles composed of CdTe, labeled with (125m)Te and capped with ZnS, can be targeted with MAb to sites in the lumen of lung vasculature. In clodronate-treated mice, which have a temporary depletion of phagocytic cells, accumulation in liver was reduced dramatically, whereas that in spleen was not. The targeting to lung was several-fold more efficient in clodronate-treated mice due to larger initial accumulation and better retention of the MAb-targeted NP at that site. This model system indicates that targeting of NP preparations is a competition between the effectiveness of the targeting agent and the natural tendency for RE uptake of the particles. Temporary inhibition of the RE system may enhance the usefulness of NP for drug and radioisotope delivery.

Simultaneous Separation of Actinium and Radium Isotopes from a Proton Irradiated Thorium Matrix.

A new method has been developed for the isolation of 223,224,225Ra, in high yield and purity, from a proton irradiated 232Th matrix. Herein we report an all-aqueous process using multiple solid-supported adsorption steps including a citrate chelation method developed to remove >99.9% of the barium contaminants by activity from the final radium product. A procedure involving the use of three columns in succession was developed, and the separation of 223,224,225Ra from the thorium matrix was obtained with an overall recovery yield of 91 ± 3%, average radiochemical purity of 99.9%, and production yields that correspond to physical yields based on previously measured excitation functions.

Automated cassette-based production of high specific activity [203/212Pb]peptide-based theranostic radiopharmaceuticals for image-guided radionuclide therapy for cancer.

A method for preparation of Pb-212 and Pb-203 labeled chelator-modified peptide-based radiopharmaceuticals for cancer imaging and radionuclide therapy has been developed and adapted for automated clinical production. Pre-concentration and isolation of radioactive Pb2+ from interfering metals in dilute hydrochloric acid was optimized using a commercially-available Pb-specific chromatography resin packed in disposable plastic columns. The pre-concentrated radioactive Pb2+ is eluted in NaOAc buffer directly to the reaction vessel containing chelator-modified peptides. Radiolabeling was found to proceed efficiently at 85°C (45min; pH 5.5). The specific activity of radiolabeled conjugates was optimized by separation of radiolabeled conjugates from unlabeled peptide via HPLC. Preservation of bioactivity was confirmed by in vivo biodistribution of Pb-203 and Pb-212 labeled peptides in melanoma-tumor-bearing mice. The approach has been found to be robustly adaptable to automation and a cassette-based fluid-handling system (Modular Lab Pharm Tracer) has been customized for clinical radiopharmaceutical production. Our findings demonstrate that the Pb-203/Pb-212 combination is a promising elementally-matched radionuclide pair for image-guided radionuclide therapy for melanoma, neuroendocrine tumors, and potentially other cancers.

Radiometric evaluation of diglycolamide resins for the chromatographic separation of actinium from fission product lanthanides.

Actinium-225 is a potential Targeted Alpha Therapy (TAT) isotope. It can be generated with high energy (≥ 100MeV) proton irradiation of thorium targets. The main challenge in the chemical recovery of 225Ac lies in the separation from thorium and many fission by-products most importantly radiolanthanides. We recently developed a separation strategy based on a combination of cation exchange and extraction chromatography to isolate and purify 225Ac. In this study, actinium and lanthanide equilibrium distribution coefficients and column elution behavior for both TODGA (N,N,N',N'-tetra-n-octyldiglycolamide) and TEHDGA (N,N,N',N'-tetrakis-2-ethylhexyldiglycolamide) were determined. Density functional theory (DFT) calculations were performed and were in agreement with experimental observations providing the foundation for understanding of the selectivity for Ac and lanthanides on different DGA (diglycolamide) based resins. The results of Gibbs energy (ΔGaq) calculations confirm significantly higher selectivity of DGA based resins for LnIII over AcIII in the presence of nitrate. DFT calculations and experimental results reveal that Ac chemistry cannot be predicted from lanthanide behavior under comparable circumstances.

Carbon Nanofiber Arrays: A Novel Tool for Microdelivery of Biomolecules to Plants.

Effective methods for delivering bioprobes into the cells of intact plants are essential for investigating diverse biological processes. Increasing research on trees, such as Populus spp., for bioenergy applications is driving the need for techniques that work well with tree species. This report introduces vertically aligned carbon nanofiber (VACNF) arrays as a new tool for microdelivery of labeled molecules to Populus leaf tissue and whole plants. We demonstrated that VACNFs penetrate the leaf surface to deliver sub-microliter quantities of solution containing fluorescent or radiolabeled molecules into Populus leaf cells. Importantly, VACNFs proved to be gentler than abrasion with carborundum, a common way to introduce material into leaves. Unlike carborundum, VACNFs did not disrupt cell or tissue integrity, nor did they induce production of hydrogen peroxide, a typical wound response. We show that femtomole to picomole quantities of labeled molecules (fluorescent dyes, small proteins and dextran), ranging from 0.5-500 kDa, can be introduced by VACNFs, and we demonstrate the use of the approach to track delivered probes from their site of introduction on the leaf to distal plant regions. VACNF arrays thus offer an attractive microdelivery method for the introduction of biomolecules and other probes into trees and potentially other types of plants.

Reactor production of Thorium-229.

Limited availability of (229)Th for clinical applications of (213)Bi necessitates investigation of alternative production routes. In reactor production, (229)Th is produced from neutron transmutation of (226)Ra, (228)Ra, (227)Ac and (228)Th. Irradiations of (226)Ra, (228)Ra, and (227)Ac targets at the Oak Ridge National Laboratory High Flux Isotope Reactor result in yields of (229)Th at 26 days of 74.0±7.4MBq/g, 260±10MBq/g, and 1200±50MBq/g, respectively. Intermediate radionuclide yields and cross sections are also studied.

Biodistribution of 225Ra citrate in mice: retention of daughter radioisotopes in bone.

Alpha-particle-emitting radionuclides have potential for therapy of localized disease due to their high linear energy transformation and short pathlengths. Radiometals that home naturally to bone can be exploited for this purpose, and 223Ra (t(1/2)=11.4 days) recently has been studied for therapy of bone tumors in mice and rats. Actinium-225 (t(1/2)=10 days) is also an attractive radioisotope for endoradiotherapy. In a single decay of a 225Ac nucleus and its subsequent decay daughters, over 27 MeV ( approximately 90% of total energy) is released by sequential emission of four alpha particles, ranging in energy from 5.7 to 8.4 MeV. Although Ac3+ does not home naturally to bone, its parent radioisotope 225Ra (beta(-), t(1/2)=15 days) can be used as an in vivo source for 225Ac. Thus, injection of 225Ra takes advantage of the bone-homing properties of radium coupled with the significant amount of energy released from the 225Ac decay chain. Our data confirm that a large fraction of radium citrate injected intravenously into mice localizes rapidly in bone. Injected doses per gram (ID/g) for 225Ra range from 25% in skull to about 10% in sternum. Once deposited, the 225Ra remains in the bone with a biological half life of >40 days. Furthermore, >95% of the daughter radioisotope, 225Ac, is retained in the bone. However, a significant fraction of one of the daughter radioisotopes, 213Bi, is found in kidney. The biodistribution data indicate that 225Ra injection should be a powerful agent for killing cells associated with bone; however, the toxicity of this radioisotope which is similar to that of other alpha emitters limits the dose that can be tolerated.