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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Targeted Alpha Particle Therapy Remodels the Tumor Microenvironment and Improves Efficacy of Immunotherapy

The tumor microenvironment (TME) can severely impair immunotherapy efficacy by repressing the immune system. In a multiple myeloma (MM) murine model, we investigated the impact of targeted alpha particle therapy (TAT) on the immune TME. TAT was combined with an adoptive cell transfer of CD8 T cells (ACT), and the mechanisms of action of this combination were assessed at the tumor site.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Proton Therapy for Breast Cancer: A Consensus Statement From the Particle Therapy Cooperative Group Breast Cancer Subcommittee

Radiation therapy plays an important role in the multidisciplinary management of breast cancer. Recent years have seen improvements in breast cancer survival and a greater appreciation of potential long-term morbidity associated with the dose and volume of irradiated organs. Proton therapy reduces the dose to nontarget structures while optimizing target coverage. However, there remain additional financial costs associated with proton therapy, despite reductions over time, and studies have yet to demonstrate that protons improve upon the treatment outcomes achieved with photon radiation therapy. There remains considerable heterogeneity in proton patient selection and techniques, and the rapid technological advances in the field have the potential to affect evidence evaluation, given the long latency period for breast cancer radiation therapy recurrence and late effects. In this consensus statement, we assess the data available to the radiation oncology community of proton therapy for breast cancer, provide expert consensus recommendations on indications and technique, and highlight ongoing trials’ cost-effectiveness analyses and key areas for future research.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2024

Tumor targeted alpha particle therapy with an actinium-225 labelled antibody for carbonic anhydrase IX

Selective antibody targeted delivery of α particle emitting actinium-225 to tumors has significant therapeutic potential. This work highlights the design and synthesis of a new bifunctional macrocyclic diazacrown ether chelator, H 2 MacropaSqOEt, that can be conjugated to antibodies and forms stable complexes with actinium-225. The macrocyclic diazacrown ether chelator incorporates a linker comprised of a short polyethylene glycol fragment and a squaramide ester that allows selective reaction with lysine residues on antibodies to form stable vinylogous amide linkages. This new H 2 MacropaSqOEt chelator was used to modify a monoclonal antibody, girentuximab (hG250), that binds to carbonic anhydrase IX, an enzyme that is overexpressed on the surface of cancers such as clear cell renal cell carcinoma. This new antibody conjugate (H 2 MacropaSq-hG250) had an average chelator to antibody ratio of 4 : 1 and retained high affinity for carbonic anhydrase IX. H 2 MacropaSq-hG250 was radiolabeled quantitatively with [ 225 Ac]Ac III within one minute at room temperature with micromolar concentrations of antibody and the radioactive complex is stable in human serum for >7 days. Evaluation of [ 225 Ac]Ac(MacropaSq-hG250) in a mouse xenograft model, that overexpresses carbonic anhydrase IX, demonstrated a highly significant therapeutic response. It is likely that H 2 MacropaSqOEt could be used to modify other antibodies providing a readily adaptable platform for other actinium-225 based therapeutics.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2023

Evaluation of Candidate Theranostics for 227 Th/ 89 Zr Paired Radioimmunotherapy of Lymphoma

227 Th is a promising radioisotope for targeted α-particle therapy. It produces 5 α-particles through its decay, with the clinically approved 223 Ra as its first daughter. There is an ample supply of 227 Th, allowing for clinical use; however, the chemical challenges of chelating this large tetravalent f-block cation are considerable. Using the CD20-targeting antibody ofatumumab, we evaluated chelation of 227 Th 4+ for α-particle–emitting and radiotheranostic applications. Methods: We compared 4 bifunctional chelators for thorium radiopharmaceutical preparation: S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 2-(4-isothicyanatobenzyl)-1,2,7,10,13-hexaazacyclooctadecane-1,4,7,10,13,16-hexaacetic acid (p-SCN-Bn-HEHA), p-isothiacyanatophenyl-1-hydroxy-2-oxopiperidine-desferrioxamine (DFOcyclo*-p-Phe-NCS), and macrocyclic 1,2-HOPO N-hydroxysuccinimide (L804-NHS). Immunoconstructs were evaluated for yield, purity, and stability in vitro and in vivo. Tumor targeting of the lead 227 Th-labeled compound in vivo was performed in CD20-expressing models and compared with a companion 89 Zr-labeled PET agent. Results: 227 Th-labeled ofatumumab-chelator constructs were synthesized to a radiochemical purity of more than 95%, excepting HEHA. 227 Th-HEHA-ofatumumab showed moderate in vitro stability. 227 Th-DFOcyclo*-ofatumumab presented excellent 227 Th labeling efficiency; however, high liver and spleen uptake was revealed in vivo, indicative of aggregation. 227 Th-DOTA-ofatumumab labeled poorly, yielding no more than 5%, with low specific activity (0.08 GBq/g) and modest long-term in vitro stability (<80%). 227 Th-L804-ofatumumab coordinated 227 Th rapidly and efficiently at high yields, purity, and specific activity (8 GBq/g) and demonstrated extended stability. In vivo tumor targeting confirmed the utility of this chelator, and the diagnostic analog, 89 Zr-L804-ofatumumab, showed organ distribution matching that of 227 Th to delineate SU-DHL-6 tumors. Conclusion: Commercially available and novel chelators for 227 Th showed a range of performances. The L804 chelator can be used with potent radiotheranostic capabilities for 89 Zr/ 227 Th quantitative imaging and α-particle therapy.

227Th↗
DOE OSTI2022

Basis for the ICRP’s updated biokinetic model for systemic astatine

The International Commission on Radiological Protection (ICRP) recently updated its biokinetic models for workers in a series of reports called the OIR (occupational intakes of radionuclides) series. A new biokinetic model for astatine (At), the heaviest member of the halogen family, was adopted in OIR Part 5 (ICRP in press). Occupational intakes of radionuclides: Part 5). Furthermore, this paper provides an overview of available biokinetic data for At; describes the basis for the ICRP's updated model for At; and tabulates dose coefficients for intravenous injection of each of the two longest lived and most important At isotopes, 211 At and 210 At. At-211 (T 1/2 = 7.214 h) is a promising radionuclide for use in targeted α-particle therapy due to several favourable properties including its half-life and the absence of progeny that could deliver significant radiation doses outside the region of α-particle therapy. At-210 (T 1/2 = 8.1 h) is an impurity generated in the production of 211 At in a cyclotron and represents a potential radiation hazard via its long-lived progeny 210 Po (T 1/2 = 138 days). Tissue dose coefficients for injected 210 At and 211 At based on the updated model are shown to differ considerably from values based on the ICRP's previous model for At, particularly for the thyroid, stomach wall, salivary glands, lungs, spleen, and kidneys.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2022

225 Ac-MACROPATATE: A Novel α-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

Neuroendocrine tumors (NETs) express somatostatin receptors (SSTRs) 2 and 5. Modified variants of somatostatin, the cognate ligand for SSTR2 and SSTR5, are used in treatment for metastatic and locoregional disease. Peptide receptor radionuclide therapy with 177 Lu-DOTATATE (DOTA-octreotate), a β-particle–emitting somatostatin derivative, has demonstrated survival benefit in patients with SSTR-positive NETs. Despite excellent results, a subset of patients has tumors that are resistant to treatment, and alternative agents are needed. Targeted α-particle therapy has been shown to kill tumors that are resistant to targeted β-particle therapy, suggesting that targeted α-particle therapy may offer a promising treatment option for patients with 177 Lu-DOTATATE–resistant disease. Although DOTATATE can chelate the clinically relevant α-particle–emitting radionuclide 225 Ac, the labeling reaction requires high temperatures, and the resulting radioconjugate has suboptimal stability. Methods: We designed and synthesized MACROPATATE (MACROPA-octreotate), a novel radioconjugate capable of chelating 225 Ac at room temperature, and assessed its in vitro and in vivo performance. Results: MACROPATATE demonstrated comparable affinity to DOTATATE (dissociation constant, 21 nM) in U2-OS-SSTR2, a SSTR2-positive transfected cell line. 225 Ac-MACROPATATE demonstrated superior serum stability at 37°C over time compared with 225 Ac-DOTATATE. Biodistribution studies demonstrated higher tumor uptake of 225 Ac-MACROPATATE than of 225 Ac-DOTATATE in mice engrafted with subcutaneous H69 NETs. Therapy studies showed that 225 Ac-MACROPATATE exhibits significant antitumor and survival benefit compared with saline control in mice engrafted with SSTR-positive tumors. However, the increased accumulation of 225 Ac-MACROPATATE in liver and kidneys and subsequent toxicity to these organs decreased its therapeutic index compared with 225 Ac-DOTATATE. Conclusion: 225 Ac-MACROPATATE and 225 Ac-DOTATATE exhibit favorable therapeutic efficacy in animal models. Because of elevated liver and kidney accumulation and lower administered activity for dose-limiting toxicity of 225 Ac-MACROPATATE, 225 Ac-DOTATATE was deemed the superior agent for targeted α-particle peptide receptor radionuclide therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Production, purification and availability of 211 At: Near term steps towards global access

We report the promising characteristics of the 7.2-h radiohalogen 211 At have long been recognized; including having chemical properties suitable for labeling targeting vectors ranging from small organic molecules to proteins, and the emission of only one α-particle per decay, providing greater control over off-target effects. Unfortunately, the impact of 211 At within the targeted α-particle therapy domain has been constrained by its limited availability. Paradoxically, the most commonly used production method – via the 209 Bi(α,2n) 211 At reaction – utilizes a widely available natural material (bismuth) as the target and straightforward cyclotron irradiation methodology. On the other hand, the most significant impediment to widespread 211 At availability is the need for an accelerator capable of generating ≥28 MeV α-particles with sufficient beam intensities to make clinically relevant levels of 211 At. In this review, current methodologies for the production and purification of 211 At – both by the direct production route noted above and via a 211 Rn generator system – will be discussed. The capabilities of cyclotrons that currently produce 211 At will be summarized and the characteristics of other accelerators that could be utilized for this purpose will be described. Finally, the logistics of networks, both academic and commercial, for facilitating 211 At distribution to locations remote from production sites will be addressed.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Coded aperture and Compton imaging for the development of 225 Ac‐based radiopharmaceuticals

Abstract Background Targeted alpha‐particle therapy (TAT) has great promise as a cancer treatment. Arguably the most promising TAT radionuclide that has been proposed is 225 Ac. The development of 225 Ac‐based radiopharmaceuticals has been hampered due to the lack of effective means to study the daughter redistribution of these agents in small animals at the preclinical stage. Purpose The ability to directly image the daughters, namely 221 Fr and 213 Bi, via their gamma‐ray emissions would be a boon for preclinical studies. That said, conventional medical imaging modalities, including single photon emission computed tomography (SPECT) based on nonmultiplexed collimation, cannot be employed due to sensitivity limitations. Methods As an alternative, we propose the use of both coded aperture and Compton imaging with the former modality suited to the 218‐keV gamma‐ray emission of 221 Fr and the latter suited to the 440‐keV gamma‐ray emission of 213 Bi. Results This work includes coded aperture images of 221 Fr and Compton images of 213 Bi in tumor‐bearing mice injected with 225 Ac‐based radiopharmaceuticals. Conclusions These results are the first demonstration of visualizing and quantifying the 225 Ac daughters in small animals through the application of coded aperture and Compton imaging.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

A new center for heavy ion research

Progress in cancer therapy with ions heavier than protons, i.e., helium, carbon, oxygen and neon, requires research and development capability. Ion research activity, however, is limited from the absence of U.S. accelerator facilities offering ion beams for therapy – placing the U.S. significantly behind Europe and Asia. With dramatic advances in beam delivery and compact accelerators, the potential exists to create a facility that can play a leadership role in particle therapy and ion-based research. This paper announces summary details of a new center for ion therapy research under construction in Waco, TX, in collaboration with recognized accelerator entities both academic and industrial. The advanced accelerator technologies will produce beams for both clinical and research applications, offering a complete range of ions, intensities and energies required by the medical community, including the capability to perform ultra-high dose irradiation (FLASH) research. FLASH, a recent research initiative, which has the potential of reducing cancer treatment toxicities, is an important if not critical capability for a competitive research center – requiring beam intensities well beyond those provided by current medical accelerators. Building a state-of-the-art cancer research center within a comprehensive facility will provide the resources to promote ion therapy in the U.S, including, preclinical/clinical trials and protocols between modalities, and also support broad ion R&D.

43 PARTICLE ACCELERATORS↗
DOE OSTI2023

Enhancing Radionuclide Production Capabilities at the Duke University Medical Center Cyclotron with a Focus on Astatine-211

Radionuclides play an important role in a diverse array of fields including physics, chemistry, agriculture, materials science, national security, medical research and patient care. Establishing a reliable domestic supply of key radionuclides is critical to our national competitiveness in these areas. Regarding medical applications, targeted alpha-particle therapy (TAT) has become of great interest to basic researchers and clinicians alike and is emerging as a valuable and cost-effective approach for cancer treatment. Unfortunately, progress in TAT, particularly with regard to its clinical translation, has been severely hampered by the limited availability of the most promising radionuclides at a reasonable cost, and with appropriate chemical and radiochemical purity. In this project, we have attempted to address this problem by focusing on production of the 7.2-h half-life α-particle emitter, 211 At, which has long been considered to be one of the most promising radionuclides for TAT. We note that he critical importance of improving the supply of 211 At in the United States was noted in the Funding Opportunity Announcement related to this project. At Duke University, we have a CS-30 cyclotron that is one of the few accelerators in the United States that has an alpha-particle beam that has enough energy to make useful quantities of 211 At. With this cyclotron, we have been able to produce more 211 At than anywhere else in the world because of our unique internal cyclotron target system. However, the CS-30 cyclotron is nearly 40 years old and was no longer reliable. In addition, its operation required considerable skill, largely because it had analog control systems, and vital parts including old-fashioned power supplies, were becoming unavailable. For these reasons, the current project was undertaken to evaluate all the subsystems of the CS-30 cyclotron and replace, repair, and update them. With help from our consultant, Ionetix, this has now been accomplished. We believe that because of this work, the CS-30 can reliably supply 211 At for basic research and clinical trials both at Duke and beyond.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

A heavy-ion production channel of 149 Tb via 63 Cu bombardment of 89 Y

We report the radionuclide 149 Tb (t 1/2 = 4.1 h) is a potential theranostic isotope which can simultaneously be used for targeted-alpha-particle therapy and positron-emission tomography. Feasibility experiments were performed to test a near-symmetric heavy-ion reaction of 63 Cu bombardment on monoisotopic 89 Y. The indirect reaction was studied to avoid isomer production. Offline gamma spectroscopy was used to quantify thick-target physical yields and experimental results show modest agreement to the fusion-evaporation code PACE4. A near-symmetric fission yield was also observed.

149Tb↗
DOE OSTI2020

Extraction chromatography of 225 Ac and lanthanides on N,N-dioctyldiglycolamic acid /1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide solvent impregnated resin

The alpha-emitter 225 Ac (t 1/2 = 9.92 d) is currently under development for targeted alpha-particle therapy of cancer, and accelerator production of 225 Ac via proton irradiation of thorium targets requires robust separations of 225 Ac from chemically similar fission product lanthanides. Additionally, the lanthanide elements represent critical components in modern technologies, and radiolanthanides such as 140 Nd (t 1/2 = 3.37 d) also have potential application in the field of nuclear medicine. The ionic liquid, 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([Bmim][NTf 2 ]), combined with the diglycolamide extractant, N,N-dioctyldiglycolamic acid (DODGAA), was adsorbed on macroporous resin support to produce a solvent impregnated resin (SIR) that was investigated for separations of 225 Ac and lanthanides. The equilibrium distribution coefficients (Kd) of the rare earth elements (Sc(III), Y(III), Ln(III)), 225 Ac(III), Th(IV), and U(VI) on the prepared DODGAA/[Bmim][NTf 2 ]-SIR were determined from batch adsorption experiments in HCl and HNO 3 media. The DODGAA/[Bmim][NTf2]-SIR exhibited preferential uptake of the heavier lanthanide elements while allowing for the separation of the lighter lanthanides. Column separations utilizing the DODGAA/[Bmim][NTf 2 ]-SIR were effective at separating the lighter lanthanides from each other, and separating 225 Ac from a mixture of lanthanides, 213 Bi, and 225 Ra without the need for additional complexing agents.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

Development of CD46 targeted alpha theranostics in prostate cancer using 134 Ce/ 225 Ac-Macropa-PEG 4 -YS5

Rationale: 225 Ac, a long-lived α-emitter with a half-life of 9.92 days, has garnered significant attention as a therapeutic radionuclide when coupled with monoclonal antibodies and other targeting vectors. Nevertheless, its clinical utility has been hampered by potential off-target toxicity, a lack of optimized chelators for 225 Ac, and limitations in radiolabeling methods. In a prior study evaluating the effectiveness of CD46-targeted radioimmunotherapy, we found great therapeutic efficacy but also significant toxicity at higher doses. To address these challenges, we have developed a radioimmunoconjugate called 225 Ac-Macropa-PEG 4 -YS5, incorporating a stable PEGylated linker to maximize tumoral uptake and increase tumor-to-background ratios. Our research demonstrates that this conjugate exhibits greater anti-tumor efficacy while minimizing toxicity in prostate cancer 22Rv1 tumors. Methods: We synthesized Macropa.NCS and Macropa-PEG 4/8 -TFP esters and prepared Macropa-PEG 0/4/8 -YS5 (with nearly ~1:1 ratio of macropa chelator to antibody YS5) as well as DOTA-YS5 conjugates. These conjugates were then radiolabeled with 225 Ac in a 2 M NH 4 OAc solution at 30 °C, followed by purification using YM30K centrifugal purification. Subsequently, we conducted biodistribution studies and evaluated antitumor activity in nude mice (nu/nu) bearing prostate 22Rv1 xenografts in both single-dose and fractionated dosing studies. Micro-PET imaging studies were performed with 134 Ce-Macropa-PEG 0/4/8 -YS5 in 22Rv1 xenografts for 7 days. Toxicity studies were also performed in healthy athymic nude mice. Results: As expected, we achieved a >95% radiochemical yield when labeling Macropa-PEG 0/4/8 -YS5 with 225 Ac, regardless of the chelator ratios (ranging from 1 to 7.76 per YS5 antibody). The isolated yield exceeded 60% after purification. Such high conversions were not observed with the DOTA-YS5 conjugate, even at a higher ratio of 8.5 chelators per antibody (RCY of 83%, an isolated yield of 40%). Biodistribution analysis at 7 days post-injection revealed higher tumor uptake for the 225 Ac-Macropa-PEG 4 -YS5 (82.82 ± 38.27 %ID/g) compared to other conjugates, namely 225 Ac-Macropa-PEG 0/8 -YS5 (38.2 ± 14.4/36.39 ± 12.4 %ID/g) and 225 Ac-DOTA-YS5 (29.35 ± 7.76 %ID/g). The PET Imaging of 134 Ce-Macropa-PEG 0/4/8 -YS5 conjugates resulted in a high tumor uptake, and tumor to background ratios. In terms of antitumor activity, 225 Ac-Macropa-PEG 4 -YS5 exhibited a substantial response, leading to prolonged survival compared to 225 Ac-DOTA-YS5, particularly when administered at 4.625 kBq doses, in single or fractionated dose regimens. Chronic toxicity studies observed mild to moderate renal toxicity at 4.625 and 9.25 kBq doses. Conclusions: Our study highlights the promise of 225 Ac-Macropa-PEG 4 -YS5 for targeted alpha particle therapy. The 225 Ac-Macropa-PEG 4 -YS5 conjugate demonstrates improved biodistribution, reduced off-target binding, and enhanced therapeutic efficacy, particularly at lower doses, compared to 225 Ac-DOTA-YS5. Incorporating theranostic 134 Ce PET imaging further enhances the versatility of macropa-PEG conjugates, offering a more effective and safer approach to cancer treatment. Overall, this methodology has a high potential for broader clinical applications.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Heavy Ion Minibeam Therapy: Side Effects in Normal Brain

The purpose of this work was to investigate whether minibeam therapy with heavy ions might offer improvements of the therapeutic ratio for the treatment of human brain cancers. To assess neurotoxicity, we irradiated normal juvenile rats using 120 MeV lithium-7 ions at an absorbed integral dose of 20 Gy. Beams were configured either as a solid parallel circular beam or as an array of planar parallel minibeams having 300-micron width and 1-mm center-to-center spacing within a circular array. We followed animals for 6 months after treatment and utilized behavioral testing and immunohistochemical studies to investigate the resulting cognitive impairment and chronic pathologic changes. We found both solid-beam therapy and minibeam therapy to result in cognitive impairment compared with sham controls, with no apparent reduction in neurotoxicity using heavy ion minibeams instead of solid beams under the conditions of this study.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Magneto-structural and induction heating properties of MFe2O4 (M?=?Co, Mn, Zn) MNPs for magnetic particle hyperthermia application

The thermal decomposition approach was used for the synthesis of MFe2O4 magnetic nanoparticles (MNPs) by substituting M as Co, Mn, and Zn. The obtained MNPs were characterized for magneto-structural properties using X-Ray diffraction patterns, FTIR, Raman and Mossbauer spectroscopy techniques which confirm the formation of phase pure cubic spinel ferrite with space group Fd3m and five Raman active modes. The size, morphology, and compositional analysis was performed using HRTEM and EDX where the size of MNPs was found to be less than 10 nm that attains superparamagnetism. The magnetic hyperthermia performance of obtained MNPs was evaluated by induction heating experiments at magnetic field range 13.3 to 26.7 kAm-1. The specific absorption rate (SAR) and intrinsic loss power (ILP) values were determined at different magnetic fields within the human tolerable range and correlated with magneto-structural properties to evaluate its potential for possible magnetic particle hyperthermia therapy.

Magnetic nanoparticles, complex-decomposition, mag↗
DOE OSTI2023

Treatment of Prostate Cancer with CD46-targeted 225 Ac Alpha Particle Radioimmunotherapy

Radiopharmaceutical therapy is changing the standard of care in prostate cancer and other malignancies. We previously reported high CD46 expression in prostate cancer and developed an antibody–drug conjugate and immunoPET agent based on the YS5 antibody, which targets a tumor-selective CD46 epitope. Here, we present the preparation, preclinical efficacy, and toxicity evaluation of [ 225 Ac]DOTA-YS5, a radioimmunotherapy agent based on the YS5 antibody. [ 225 Ac]DOTA-YS5 was developed, and its therapeutic efficiency was tested on cell-derived (22Rv1, DU145), and patient-derived (LTL-545, LTL484) prostate cancer xenograft models. Biodistribution studies were carried out on 22Rv1 tumor xenograft models to confirm the targeting efficacy. Toxicity analysis of the [ 225 Ac]DOTA-YS5 was carried out on nu/nu mice to study short-term (acute) and long-term (chronic) toxicity. Biodistribution study shows that [ 225 Ac]DOTA-YS5 agent delivers high levels of radiation to the tumor tissue (11.64% ± 1.37%ID/g, 28.58% ± 10.88%ID/g, 29.35% ± 7.76%ID/g, and 31.78% ± 5.89%ID/g at 24, 96, 168, and 408 hours, respectively), compared with the healthy organs. [ 225 Ac]DOTA-YS5 suppressed tumor size and prolonged survival in cell line–derived and patient-derived xenograft models. Toxicity analysis revealed that the 0.5 μCi activity levels showed toxicity to the kidneys, likely due to redistribution of daughter isotope 213 Bi. [ 225 Ac]DOTA-YS5 suppressed the growth of cell-derived and patient-derived xenografts, including prostate-specific membrane antigen–positive and prostate-specific membrane antigen–deficient models. Overall, this preclinical study confirms that [ 225 Ac]DOTA-YS5 is a highly effective treatment and suggests feasibility for clinical translation of CD46-targeted radioligand therapy in prostate cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

A fast Monte Carlo cell-by-cell simulation for radiobiological effects in targeted radionuclide therapy using pre-calculated single-particle track standard DNA damage data

Introduction: We developed a new method that drastically speeds up radiobiological Monte Carlo radiation-track-structure (MC-RTS) calculations on a cell-by-cell basis. Methods: The technique is based on random sampling and superposition of single-particle track (SPT) standard DNA damage (SDD) files from a “pre-calculated” data library, constructed using the RTS code TOPAS-nBio, with “time stamps” manually added to incorporate dose-rate effects. This time-stamped SDD file can then be input into MEDRAS, a mechanistic kinetic model that calculates various radiation-induced biological endpoints, such as DNA double-strand breaks (DSBs), misrepairs and chromosomal aberrations, and cell death. As a benchmark validation of the approach, we calculated the predicted energy-dependent DSB yield and the ratio of direct-to-total DNA damage, both of which agreed with published in vitro experimental data. We subsequently applied the method to perform a superfast cell-by-cell simulation of an experimental in vitro system consisting of neuroendocrine tumor cells uniformly incubated with 177 Lu. Results and discussion: The results for residual DSBs, both at 24 and 48 h post-irradiation, are in line with the published literature values. Our work serves as a proof-of-concept demonstration of the feasibility of a cost-effective “in silico clonogenic cell survival assay” for the computational design and development of radiopharmaceuticals and novel radiotherapy treatments more generally.

62 RADIOLOGY AND NUCLEAR MEDICINE↗