Recent Program-Supported Publications

Terbium-155 (t_1/2 = 5.32 days) is one of four medically relevant radioisotopes of terbium. It is of interest to the field as a suitable diagnostic counterpart for therapeutic radiolanthanides, as its decay scheme includes γ-rays that are suitable for single photon emission computed tomography (SPECT) imaging. Additionally, ¹⁵⁵Tb has an Auger electron (AE) yield that is viable for AE therapy. There are several direct and indirect production routes that can produce ¹⁵⁵Tb. Two possible direct routes include proton irradiation on gadolinium targets via ¹⁵⁵Gd(p,n)¹⁵⁵Tb and ¹⁵⁶Gd(p,2n)¹⁵⁵Tb. The ¹⁵⁵Gd(p,n)¹⁵⁵Tb reaction is accessible at incident proton beam energies of ∼10 MeV, whereas the ¹⁵⁶Gd(p,2n)¹⁵⁵Tb nuclear reaction requires ∼18 MeV. This study aims to investigate the production of ¹⁵⁵Tb from ^natGd through the ^natGd(p,x) nuclear reaction, wherein both (p,n) and (p,2n) reactions were leveraged, and the purification using a three-column ion chromatography method. Using this system, recoveries of radioterbium of up to 97% were achieved in addition to high recoveries of the Gd target material, illustrating the suitability of this technique for enriched targets.

Terbium-161 (¹⁶¹Tb) is emerging as a promising radionuclide for cancer therapy due to its favorable nuclear properties that are similar to clinically established lutetium-177 (¹⁷⁷Lu) along with its therapeutic edge arising from the higher number of Auger and conversion electrons per decay. These low energy electrons result in higher cytotoxicity within a short range of the decaying nuclei to enhance therapeutic efficacy. Despite these promising characteristics, a significant challenge remains in the lack of a domestic ¹⁶¹Tb supply in the United States, which poses an obstacle to the advancement of ¹⁶¹Tb-based radiopharmaceutical research and development. This study developed a reliable cation-exchange high-performance liquid chromatography-based method for purification of reactor-produced ¹⁶¹Tb at quantities suitable to support research and preclinical studies. The purified ¹⁶¹Tb product showed high radionuclidic purity with excellent radiochemical purity, and the successful labeling studies with the DOTA chelator and DOTA-TATE peptide demonstrated the effective incorporation of the purified ¹⁶¹Tb into radiopharmaceuticals designed for targeted cancer therapy.

The formation of a stable alkyl At–C bond occurs during the shipment of ²¹¹At on a 3-octanone-impregnated column and the reactivity of ²¹¹At stripped from columns has been studied. The ²¹¹At could not be recovered from the 3-octanone organic phase using nitric acid or sodium hydroxide, even up to 10 and 15.7 M, respectively. Several reducing and oxidizing agents, including hydrazine, hydroxylamine, ascorbic acid, ceric ammonium nitrate, potassium permanganate, sodium hypochlorite, and calcium hypochlorite were used to promote the recovery of ²¹¹At. The most effective reducing agent was hydroxylamine, where ∼70% of the ²¹¹At was recovered, while among oxidizing agents ceric ammonium nitrate, potassium permanganate, and sodium hypochlorite all showed near quantitative recovery of ²¹¹At. These results indicate an At–C bond is being formed during the shipment of the column and a redox reaction is required for bond cleavage to occur. DFT calculations have been used to propose several products of an AtO⁺-3-octanone reaction, with 4-astato-5-hydroxy-octa-3-one being the most probable.

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.

To clinically advance the growing arsenal of radiometals available to image and treat cancer, chelators with versatile binding properties are needed. Herein, we evaluated the ability of the py₂[18]dieneN₆ macrocycle PYTA to interchangeably bind and stabilize ²²⁵Ac³⁺, [¹⁷⁷Lu]Lu³⁺, [¹¹¹In]In³⁺ and [⁴⁴Sc]Sc³⁺, a chemically diverse set of radionuclides that can be used complementarily for targeted alpha therapy, beta therapy, single-photon emission computed tomography (SPECT) imaging, and positron emission tomography (PET) imaging, respectively. Through NMR spectroscopy and X-ray diffraction, we show that PYTA possesses an unusual degree of flexibility for a macrocyclic chelator, undergoing dramatic conformational changes that enable it to optimally satisfy the disparate coordination properties of each metal ion. Subsequent radiolabeling studies revealed that PYTA quantitatively binds all 4 radiometals at room temperature in just minutes at pH 6. Furthermore, these complexes were found to be stable in human serum over 2 half-lives. These results surpass those obtained for 2 state-of-the-art chelators for nuclear medicine, DOTA and macropa. The stability of ²²⁵Ac–PYTA and [⁴⁴Sc]Sc–PYTA, the complexes having the most disparity with respect to metal-ion size, was further probed in mice. The resulting PET images (⁴⁴Sc) and ex vivo biodistribution profiles (⁴⁴Sc and ²²⁵Ac) of the PYTA complexes differed dramatically from those of unchelated [⁴⁴Sc]Sc³⁺ and ²²⁵Ac³⁺. These differences provide evidence that PYTA retains this size-divergent pair of radionuclides in vivo. Collectively, these studies establish PYTA as a new workhorse chelator for nuclear medicine and warrant its further investigation in targeted constructs.

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.