Recent Program-Supported Publications

Abstract

Alzheimer disease is a neurodegenerative disorder with limited treatment options. It is characterized by the presence of several biomarkers, including amyloid-β aggregates, which lead to oxidative stress and neuronal decay. Targeted α-therapy (TAT) has been shown to be efficacious against metastatic cancer. TAT takes advantage of tumor-localized α-particle emission to break disease-associated covalent bonds while minimizing radiation dose to healthy tissues due to the short, micrometer-level, distances traveled. We hypothesized that TAT could be used to break covalent bonds within amyloid-β aggregates and facilitate natural plaque clearance mechanisms.

Abstract

This work investigated the indirect production of ⁴⁷Sc from natural Ca targets via ⁴⁸Ca(γ,n)⁴⁷Ca→⁴⁷Sc + β⁻ + ν ¯ e with incident electron energies of 30, 35, and 40 MeV. The ⁴⁷Ca production yields were simulated using the PHITS Monte Carlo simulation code and compared to experimental data. The simulated production rates for all three irradiations are in good agreement with experimental data within uncertainties. As a demonstration of the ⁴⁷Ca/⁴⁷Sc generator system, one of the irradiated CaCO₃ targets was dissolved in nitric acid, and ⁴⁷Sc was isolated from the target material using commercially available Eichrom DGA resin. The ⁴⁷Sc was allowed to grow in, and the purification process was repeated with promising ⁴⁷Sc and Ca recovery yields.

Intravascularly administered radiation therapy using beta (β-)-emitting radioisotopes has relied on either intravenously injected radiolabeled peptides that target cancer or radiolabeled microspheres that are trapped in the tumor following intra-arterial delivery. More recently, targeted intravenous radiopeptide therapies have explored the use of alpha (α)-particle emitting radioisotopes, but microspheres radiolabeled with α-particle emitters have not yet been studied. Here, FDA-approved macroaggregated albumin (MAA) particles were radiolabeled with Bismuth-212 (Bi-212-MAA) and evaluated using clonogenic and survival assays in vitro and using immune-competent mouse models of breast cancer. The in vivo biodistribution of Bi-212-MAA was investigated in Balb/c and C57BL/6 mice with 4T1 and EO771 orthotopic breast tumors, respectively. The same orthotopic breast cancer models were used to evaluate the treatment efficacy of Bi-212-MAA. Our results showed that macroaggregated albumin can be stably radiolabeled with Bi-212 and that Bi-212-MAA can deliver significant radiation therapy to reduce the growth and clonogenic potential of 4T1 and EO771 cells in vitro. Additionally, Bi-212-MAA treatment upregulated γH2AX and cleaved Caspase-3 expression in 4T1 cells. Biodistribution analyses showed 87–93% of the Bi-212-MAA remained in 4T1 and EO771 tumors 2 and 4 h after injection. Following single-tumor treatments with Bi-212-MAA there was a significant reduction in the growth of both 4T1 and EO771 breast tumors over the 18-day monitoring period. Overall, these findings showed that Bi-212-MAA was stably radiolabeled and inhibited breast cancer growth. Bi-212-MAA is an exciting platform to study α-particle therapy and will be easily translatable to larger animal models and human clinical trials.

Abstract

Lu-177-based, targeted radiotherapeutics/endoradiotherapies are an emerging clinical tool for the management of various cancers. The chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) remains the workhorse for such applications but can limit apparent molar activity or efficient charge modulation, which can impact target binding and, as a consequence, target efficacy. Previously, our lab had developed the small, rare earth selective bifunctional chelator, picaga, as an efficient bifunctional chelator for scandium and lutetium isotopes. Here, we assess the performance of these constructs for therapy in prostate-specific membrane antigen (PSMA)-expressing tumor xenografts. To assess the viability of picaga conjugates in conjunction with long in vivo circulation, a picaga conjugate functionalized with a serum albumin binding moiety, ¹⁷⁷Lu-picaga-Alb53-PSMA, was also synthesized. A directly comparative, low, single 3.7 MBq dose treatment study with Lu-PSMA-617 was conducted. Treatment with ¹⁷⁷Lu-picaga-Alb53-PSMA resulted in tumor regression and lengthened median survival (54 days) when compared with the vehicle (16 days), ⁴⁷Sc-picaga-DUPA-, ¹⁷⁷Lu-picaga-DUPA-, and ¹⁷⁷Lu-PSMA-617-treated cohorts (21, 23, and 21 days, respectively).

The newest radioisotope for brachytherapy treatment of prostate cancer is ¹³¹Cs (t_1/2 = 9.69 d, 100% EC). Generated via electron capture decay of ¹³¹Ba (t_1/2 = 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 ± 0.5 b (thermal, σ⁰) and 173 ± 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 ± 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 ± 0.008 d. Lastly, this study also resulted in the co-production of ¹³³Ba (t_1/2 = 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 ± 0.2 b and 39.9 ± 1.3 b. These values also represent the sum of cross sections to metastable and ground states of ¹³³Ba.

A number of accelerator-based isotope production facilities utilize 100- to 200-MeV proton beams due to the high production rates enabled by high-intensity beam capabilities and the greater diversity of isotope production brought on by the long-range of high-energy protons. However, nuclear reaction modeling at these energies can be challenging because of the interplay between different reaction modes and a lack of existing guiding cross-section data.

Molecular imaging is a non-invasive process that enables the visualization, characterization, and quantitation of biological processes at the molecular and cellular level. With the emergence of theragnostic agents to diagnose and treat disease for personalized medicine there is a growing need for matched pairs of isotopes. Matched pairs offer the unique opportunity to obtain patient specific information from SPECT or PET diagnostic studies to quantitate in vivo function or receptor density to inform and tailor therapeutic treatment. There are several isotopes of arsenic that have emissions suitable for either or both diagnostic imaging and radiotherapy. Their half-lives are long enough to pair them with peptides and antibodies which take longer to reach maximum uptake to facilitate improved patient pharmacokinetics and dosimetry then can be obtained with shorter lived radionuclides. Arsenic-72 even offers availability from a generator that can be shipped to remote sites and thus enhances availability. Arsenic has a long history as a diagnostic agent, but until recently has suffered from limited availability, lack of suitable chelators, and concerns about toxicity have inhibited its use in nuclear medicine. However, new production methods and novel chelators are coming online and the use of radioarsenic in the pico and nanomolar scale is well below the limits associated with toxicity. This manuscript will review the production routes, separation chemistry, radiolabeling techniques and in vitro/in vivo studies of three medically relevant isotopes of arsenic (arsenic-74, arsenic-72, and arsenic-77).

Targeted alpha therapy (TAT) is an area of research with rapidly increasing importance as the emitted alpha particle has a significant effect on inducing cytotoxic effects on tumor cells while mitigating dose to normal tissues. Two significant isotopes of interest within the area of TAT are thorium-227 and actinium-225 due to their nuclear characteristics. Both isotopes have physical half-lives suitable for coordination with larger biomolecules, and additionally actinium-225 has potential to serve as an in vivo generator. In this review, the authors will discuss the production, purification, labeling reactions, and biological studies of actinium-225 and thorium-227 complexes and clinical studies.

“Isotope harvesting” is a technique that offers access to exotic radionuclides created as by-products during nuclear science research. Ongoing exploratory work at the National Superconducting Cyclotron Laboratory (NSCL) is directed towards the production and extraction of rare radionuclides from a flowing-water target and intends to pave the way for future harvesting efforts at the upcoming Facility for Rare Isotope Beams (FRIB). Here we present the collection of ⁶²Zn from an aqueous matrix irradiated with a 150 MeV per nucleon ⁷⁸Kr beam, while synergistically capturing other gaseous reaction products. In addition to the production rate for ⁶²Zn (9.08(30) × 10^{−5 62}Zn per incoming ⁷⁸Kr), the rates of formation for several other radionuclides were determined as well. The purification of ⁶²Zn from a large number of co-produced radionuclides was performed by anion exchange chromatography, allowing the isolation of 80.5(5.2)% of the generated ⁶²Zn. With the decay of ⁶²Zn the radioactive daughter ⁶²Cu is generated, and with the isolation of pure ⁶²Cu eluate, the principle of a medical radionuclide generator could be demonstrated. To illustrate the applicability of the obtained ⁶²Zn, the isolated product was used in free and DTPA-labelled form in a proof of principle plant uptake study with garden cress employing phosphor imaging for visualization.

An experiment was performed at the National Superconducting Cyclotron Laboratory using a 140 MeV/nucleon ⁴⁸Ca beam and a flowing-water target to produce ⁴⁷Ca for the first time with this production route. A production rate of 0.020 ± 0.004 ⁴⁷Ca nuclei per incoming beam particle was measured. An isotope harvesting system attached to the target was used to collect radioactive cationic products, including ⁴⁷Ca, from the water on a cation-exchange resin. The ⁴⁷Ca collected was purified using three separation methods optimized for this work: (1) DGA extraction chromatography resin with HNO₃ and HCl, (2) AG MP-50 cation-exchange resin with an increasing concentration gradient of HCl, and (3) AG MP-50 cation-exchange resin with a methanolic HCl gradient. These methods resulted in ≥99 ± 2% separation yield of ⁴⁷Ca with 100% radionuclidic purity within the limits of detection for HPGe measurements. Inductively coupled plasma-optical emission spectrometry (ICP-OES) was used to identify low levels of stable ions in the water of the isotope harvesting system during the irradiation and in the final purified solution of ⁴⁷Ca. For the first time, this experiment demonstrated the feasibility of the production, collection, and purification of ⁴⁷Ca through isotope harvesting for the generation of ⁴⁷Sc for nuclear medicine applications.