A review of recent advancements in Actinium-225 labeled compounds and biomolecules for therapeutic purposes.

In nuclear medicine, cancers that cannot be cured or can only be treated partially by traditional techniques like surgery or chemotherapy are killed by ionizing radiation as a form of therapeutic treatment. Actinium-225 is an alpha-emitting radionuclide that is highly encouraging as a therapeutic approach and more promising for targeted alpha therapy (TAT). Actinium-225 is the best candidate for tumor cells treatment and has physical characteristics such as high (LET) linear energy transfer (150 keV per µm), half-life (t1/2 = 9.92d), and short ranges (400-100 µm) which prevent the damage of normal healthy tissues. The introduction of various new radiopharmaceuticals and radioisotopes has significantly assisted the advancement of nuclear medicine. Ac-225 radiopharmaceuticals continuously demonstrate their potential as targeted alpha therapeutics. 225 Ac-labeled radiopharmaceuticals have confirmed their importance in medical and clinical areas by introducing [225 Ac]Ac-PSMA-617, [225 Ac]Ac-DOTATOC, [225 Ac]Ac-DOTA-substance-P, reported significantly improved response in patients with prostate cancer, neuroendocrine, and glioma, respectively. The development of these radiopharmaceuticals required a suitable buffer, incubation time, optimal pH, and reaction temperature. There is a growing need to standardize quality control (QC) testing techniques such as radiochemical purity (RCP). This review aims to summarize the development of the Ac-225 labeled compounds and biomolecules. The current state of their reported resulting clinical applications is also summarized as well.

Preclinical Evaluation of 225Ac-Labeled Single-Domain Antibody for the Treatment of HER2pos Cancer.

Human epidermal growth factor receptor type 2 (HER2) is overexpressed in various cancers; thus, HER2-targeting single-domain antibodies (sdAb) could offer a useful platform for radioimmunotherapy. In this study, we optimized the labeling of an anti-HER2-sdAb with the α-particle-emitter 225Ac through a DOTA-derivative. The formed radioconjugate was tested for binding affinity, specificity and internalization properties, whereas cytotoxicity was evaluated by clonogenic and DNA double-strand-breaks assays. Biodistribution studies were performed in mice bearing subcutaneous HER2pos tumors to estimate absorbed doses delivered to organs and tissues. Therapeutic efficacy and potential toxicity were assessed in HER2pos intraperitoneal ovarian cancer model and in healthy C57Bl/6 mice. [225Ac]Ac-DOTA-2Rs15d exhibited specific cell uptake and cell-killing capacity in HER2pos cells (EC50 = 3.9 ± 1.1 kBq/mL). Uptake in HER2pos lesions peaked at 3 hours (9.64 ± 1.69% IA/g), with very low accumulation in other organs (<1% IA/g) except for kidneys (11.69 ± 1.10% IA/g). α-camera imaging presented homogeneous uptake of radioactivity in tumors, although heterogeneous in kidneys, with a higher signal density in cortex versus medulla. In mice with HER2pos disseminated tumors, repeated administration of [225Ac]Ac-DOTA-2Rs15d significantly prolonged survival (143 days) compared to control groups (56 and 61 days) and to the group treated with HER2-targeting mAb trastuzumab (100 days). Histopathologic evaluation revealed signs of kidney toxicity after repeated administration of [225Ac]Ac-DOTA-2Rs15d. [225Ac]Ac-DOTA-2Rs15d efficiently targeted HER2pos cells and was effective in treatment of intraperitoneal disseminated tumors, both alone and as an add-on combination with trastuzumab, albeit with substantial signs of inflammation in kidneys. This study warrants further development of [225Ac]Ac-DOTA-2Rs15d.

H2BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy.

Actinium-225 (225Ac) is one of the most promising radionuclides for targeted alpha therapy (TAT). With a half-life of 9.92 days and a decay chain that emits four high-energy α particles, 225Ac is well-suited for TAT when conjugated to macromolecular targeting vectors that exhibit extended in vivo circulation times. The implementation of 225Ac in these targeted constructs, however, requires a suitable chelator that can bind and retain this radionuclide in vivo. Previous work has demonstrated the suitability of a diaza-18-crown-6 macrocyclic chelator H2macropa for this application. Building upon these prior efforts, in this study, two rigid variants of H2macropa, which contain either one (H2BZmacropa) or two (H2BZ2macropa) benzene rings within the macrocyclic core, were synthesized and investigated for their potential use for 225Ac TAT. The coordination chemistry of these ligands with La3+, used as a nonradioactive model for Ac3+, was carried out. Both NMR spectroscopic and X-ray crystallographic studies of the La3+ complexes of these ligands revealed similar structural features to those found for the related complex of H2macropa. Thermodynamic stability constants of the La3+ complexes, however, were found to be 1 and 2 orders of magnitude lower than those of H2macropa for H2BZmacropa and H2BZ2macropa, respectively. The decrease in thermodynamic stability was rationalized via the use of density functional theory calculations. 225Ac radiolabeling and serum stability studies with H2BZmacropa showed that this chelator compares favorably with H2macropa. Based on these promising results, a bifunctional version of this chelator, H2BZmacropa-NCS, was synthesized and conjugated to the antibody codrituzumab (GC33), which targets the liver cancer biomarker glypican-3 (GPC3). The resulting GC33-BZmacropa conjugate and an analogous GC33-macropa conjugate were evaluated for their 225Ac radiolabeling efficiencies, antigen-binding affinities, and in vivo biodistribution in HepG2 liver cancer tumor-bearing mice. Although both conjugates were comparably effective in their radiolabeling efficiencies, [225Ac]Ac-GC33-BZmacropa showed slightly poorer serum stability and biodistribution than [225Ac]Ac-GC33-macropa. Together, these results establish H2BZmacropa-NCS as a new bifunctional chelator for the preparation of 225Ac radiopharmaceuticals.

FZD10-targeted α-radioimmunotherapy with 225 Ac-labeled OTSA101 achieves complete remission in a synovial sarcoma model.

Synovial sarcomas are rare tumors arising in adolescents and young adults. The prognosis for advanced disease is poor, with an overall survival of 12-18 months. Frizzled homolog 10 (FZD10) is overexpressed in most synovial sarcomas, making it a promising therapeutic target. The results of a phase 1 trial of ß-radioimmunotherapy (RIT) with the 90 Y-labeled anti-FZD10 antibody OTSA101 revealed a need for improved efficacy. The present study evaluated the potential of α-RIT with OTSA101 labeled with the α-emitter 225 Ac. Competitive inhibition and cell binding assays showed that specific binding of 225 Ac-labeled OTSA101 to SYO-1 synovial sarcoma cells was comparable to that of the imaging agent 111 In-labeled OTSA101. Biodistribution studies showed high uptake in SYO-1 tumors and low uptake in normal organs, except for blood. Dosimetric studies showed that the biologically effective dose (BED) of 225 Ac-labeled OTSA101 for tumors was 7.8 Bd higher than that of 90 Y-labeled OTSA101. 90 Y- and 225 Ac-labeled OTSA101 decreased tumor volume and prolonged survival. 225 Ac-labeled OTSA101 achieved a complete response in 60% of mice, and no recurrence was observed. 225 Ac-labeled OTSA101 induced a larger amount of necrosis and apoptosis than 90 Y-labeled OTSA101, although the cell proliferation decrease was comparable. The BED for normal organs and tissues was tolerable; no treatment-related mortality or obvious toxicity, except for temporary body weight loss, was observed. 225 Ac-labeled OTSA101 provided a high BED for tumors and achieved a 60% complete response in the synovial sarcoma mouse model SYO-1. RIT with 225 Ac-labeled OTSA101 is a promising therapeutic option for synovial sarcoma.

Detailed Chemistry Studies of 225Actinium Labeled Radiopharmaceuticals.

BACKGROUND: The synthesis of 225Actinium derivatives was afforded by using PSMA- 617, DOTATATE peptides, and EDTMP ligand. Detailed experiments, quality control (QC), and stability studies were also well described. The radiolabelling reactions were performed in mild conditions with desirable radiochemical yields and high radiochemical purities. METHODS: PSMA-617, DOTATATE were radiolabelled with 225Actinium in 0.1 M HCl in the presence of ascorbate buffer solution and passed through the C-18 light cartridge for purification and the product was eluted by ethanol-water solution. EDTMP was also radiolabelled with 225Actinium without using any stabilizer and purification step. All products were well analyzed by R-TLC and R-HPLC. The stability of those compounds was also studied within the validity period of time. RESULTS: 225Ac-DOTATATE and 225Ac-PSMA-617 were obtained at the same condition. The radiochemical yield of 225Ac-DOTATATE was less than225Ac-PSMA 617. The stability experiments indicating decay daughters of 225Actinium appeared after T0 +1 h due to the recoil effect radiolysis. On the other hand, 225Ac-EDTMP was more stable than DOTA-peptide radiolabelled compounds. 225Ac-EDTMP was produced with more than 95% radiochemical yield and 99% radiochemical purity. CONCLUSION: A detailed chemistry study was presented for the synthesis of 225Actinium derivatives in mild conditions with absolute radiochemical purities and high yields. The experimental results showed that 225Ac-EDTMP could be a suitable radiopharmaceutical alternative for bone metastases arising from primer tumors as a cocktail therapy.

Radiotheranostics Using a Novel 225Ac-Labeled Radioligand with Improved Pharmacokinetics Targeting Prostate-Specific Membrane Antigen.

225Ac-based radiotheranostics targeting prostate-specific membrane antigen (PSMA) has induced impressive responses in patients with metastatic castration-resistant prostate cancer. To enhance the therapeutic effects of radioligands labeled with 225Ac (half-life: 10 days), a radioligand that shows longer tumor retention would be useful. Here, we designed and synthesized a straight-chain PSMA-targeting radioligand, PSMA-DA1, which includes an (iodophenyl)butyric acid derivative as an albumin binder (ALB). We performed preclinical evaluations of PSMA-DA1 as a tool for PSMA-targeting radiotheranostics using 111In, 90Y, and 225Ac. [111In]In-PSMA-DA1 demonstrated significantly greater tumor uptake and retention than a corresponding non-ALB-conjugated compound. In mice, single-photon emission computed tomography performed with [111In]In-PSMA-DA1 produced clear tumor images, and the administration of [90Y]Y-PSMA-DA1 or [225Ac]Ac-PSMA-DA1 inhibited tumor growth. [225Ac]Ac-PSMA-DA1 had antitumor effects in mice at a lower radioactivity level than [225Ac]Ac-PSMA-617, which has been reported to be clinically useful. These results indicate that PSMA-DA1 may be a useful PSMA-targeting radiotheranostic agent.

Measurement of 227Ac impurity in 225Ac using decay energy spectroscopy.

225Ac is a valuable medical radionuclide for targeted α therapy, but 227Ac is an undesirable byproduct of an accelerator-based synthesis method under investigation. Sufficient detector sensitivity is critical for quantifying the trace impurity of 227Ac, with the 227Ac/225Ac activity ratio predicted to be approximately 0.15% by end-of-bombardment (EOB). Superconducting transition edge sensor (TES) microcalorimeters offer high resolution energy spectroscopy using the normal-to-superconducting phase transition to measure small changes in temperature. By embedding 225Ac production samples in a gold foil thermally coupled to a TES microcalorimeter we can measure the decay energies of the radionuclides embedded with high resolution and 100% detection efficiency. This technique, known as decay energy spectroscopy (DES), collapses several peaks from α decays into single Q-value peaks. In practice there are more complex factors in the interpretation of data using DES, which we will discuss herein. Using this technique we measured the EOB 227Ac impurity to be (0.142 ± 0.005)% for a single production sample. This demonstration has shown that DES is a useful tool for quantitative measurements of complicated spectra.

225Ac-H4py4pa for Targeted Alpha Therapy.

Herein, we present the syntheses and characterization of a new undecadendate chelator, H4py4pa, and its bifunctional analog H4py4pa-phenyl-NCS, conjugated to the monoclonal antibody, Trastuzumab, which targets the HER2+ cancer. H4py4pa possesses excellent affinity for 225Ac (α, t1/2 = 9.92 d) for targeted alpha therapy (TAT), where quantitative radiolabeling yield was achieved at ambient temperature, pH = 7, in 30 min at 10-6 M chelator concentration, leading to a complex highly stable in mouse serum for at least 9 d. To investigate the chelation of H4py4pa with large metal ions, lanthanum (La3+), which is the largest nonradioactive metal of the lanthanide series, was adopted as a surrogate for 225Ac to enable a series of nonradioactive chemical studies. In line with the 1H NMR spectrum, the DFT (density functional theory)-calculated structure of the [La(py4pa)]- anion possessed a high degree of symmetry, and the La3+ ion was secured by two distinct pairs of picolinate arms. Furthermore, the [La(py4pa)]- complex also demonstrated a superb thermodynamic stability (log K[La(py4pa)]- ∼ 20.33, pLa = 21.0) compared to those of DOTA (log K[La(DOTA)]- ∼ 24.25, pLa = 19.2) or H2macropa (log K[La(macropa)]- = 14.99, pLa ∼ 8.5). Moreover, the functional versatility offered by the bifunctional py4pa precursor permits facile incorporation of various linkers for bioconjugation through direct nucleophilic substitution. In this work, a short phenyl-NCS linker was incorporated to tether H4py4pa to Trastuzumab. Radiolabeling studies, in vitro serum stability, and animal studies were performed in parallel with the DOTA-benzyl-Trastuzumab. Both displayed excellent in vivo stability and tumor specificity.

Computer-Assisted Design of Macrocyclic Chelators for Actinium-225 Radiotherapeutics.

Actinium-225 (225Ac) is an excellent candidate for targeted radiotherapeutic applications for treating cancer, because of its 10-day half-life and emission of four high-energy α2+ particles. To harness and direct the energetic potential of actinium, strongly binding chelators that remain stable in vivo during biological targeting must be developed. Unfortunately, controlling chelation for actinium remains challenging. Actinium is the largest +3 cation on the periodic table and has a 6d05f0 electronic configuration, and its chemistry is relatively unexplored. Herein, we present theoretical work focused on improving the understanding of actinium bonding with macrocyclic chelating agents as a function of (1) macrocycle ring size, (2) the number and identity of metal binding functional groups, and (3) the length of the tether linking the metal binding functional group to the macrocyclic backbone. Actinium binding by these chelators is presented within the context of complexation with DOTA4-, the most relevant Ac3+ binding agent for contemporary radiopharmaceutical applications. The results enabled us to develop a new strategy for actinium chelator design. The approach is rooted in our identification that Ac3+-chelation chemistry is dominated by ionic bonding interactions and relies on (1) maximizing electrostatic interactions between the metal binding functional group and the Ac3+ cation and (2) minimizing electronic repulsion between negatively charged actinium binding functional groups. This insight will provide a foundation for future innovation in developing the next generation of multifunctional actinium chelators.

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models.

PURPOSE: Despite the availability of new drugs, many patients with acute myeloid leukemia (AML) do not achieve remission and outcomes remain poor. Venetoclax is a promising new therapy approved for use in combination with a hypomethylating agent or with low-dose cytarabine for the treatment of newly diagnosed older AML patients or those ineligible for intensive chemotherapy. 225 Actinium-lintuzumab (225 Ac-lintuzumab) is a clinical stage radioimmunotherapy targeting CD33 that has shown evidence of single-agent activity in relapsed/refractory AML. Increased expression of MCL-1 is a mediator of resistance to venetoclax in cancer. EXPERIMENTAL DESIGN: Here we investigated the potential for 225 Ac-lintuzumab-directed DNA damage to suppress MCL-1 levels as a possible mechanism of reversing resistance to venetoclax in two preclinical in vivo models of AML. RESULTS: We demonstrated that 225 Ac-lintuzumab in combination with venetoclax induced a synergistic increase in tumor cell killing compared to treatment with either drug alone in venetoclax-resistant AML cell lines through both an induction of double-stranded DNA breaks (DSBs) and depletion of MCL-1 protein levels. Further, this combination led to significant tumor growth control and prolonged survival benefit in venetoclax-resistant in vivo AML models. CONCLUSIONS: There results suggest that the combination of 225 Ac-lintuzumab with venetoclax is a promising therapeutic strategy for the treatment of patients with venetoclax-resistant AML. Clinical trial of this combination therapy (NCT03867682) is currently ongoing.

Engineering Mesoporous Silica Nanoparticles for Targeted Alpha Therapy against Breast Cancer.

Targeted alpha therapy, where highly cytotoxic doses are delivered to tumor cells while sparing surrounding healthy tissue, has emerged as a promising treatment against cancer. Radionuclide conjugation with targeting vectors and dose confinement, however, are still limiting factors for the widespread application of this therapy. In the current study, we developed multifunctional silica nanoconstructs for targeted alpha therapy that show targeting capabilities against breast cancer cells, cytotoxic responses at therapeutic dosages, and enhanced clearance. The silica nanoparticles were conjugated to transferrin, which promoted particle accumulation in cancerous cells, and 3,4,3-LI(1,2-HOPO), a chelator with high selectivity and binding affinity for f-block elements. High cytotoxic effects were observed when the nanoparticles were loaded with 225Ac, a clinically relevant radioisotope. Lastly, in vivo studies in mice showed that the administration of radionuclides with nanoparticles enhanced their excretion and minimized their deposition in bones. These results highlight the potential of multifunctional silica nanoparticles as delivery systems for targeted alpha therapy and offer insight into design rules for the development of new nanotherapeutic agents.

Construction of a thorium/actinium generator at the Canadian Nuclear Laboratories.

Targeted Alpha Therapy (TAT) has demonstrated considerable promise in the treatment of a range of cancers in both preclinical and, more recently clinical research. In particular, work with the alpha-emitting radionuclide 225Ac has been effectively employed due to the relatively rapid decay cascade that leads to 4 alpha and 2 beta emissions. One limitation for TAT has been caused by access to the vital radionuclide. Traditionally, 225Ac has been sourced from thorium/actinium generators based on the alpha decay of stockpiles of 229Th. 229Th is itself the alpha-decay product from 233U. Due to proliferation issues associated with 233U, only three thorium/actinium generators have been reported in the literature, capable of supporting clinical research. This paper describes the construction and operation of a thorium/actinium radionuclide generator at the Canadian Nuclear Laboratories, capable of supporting preclinical and limited clinical research in the area of TAT. Thorium was recovered and purified by a combination of anion exchange and extraction chromatography from aged 233U stockpiles. A separation scheme for 225Ra and 225Ac has been developed, based upon the chemical composition of the thorium material to allow for regular, routine milkings capable of supplying up to 3.7 GBq (100 mCi) of radiochemically pure 225Ac annually. This routine separation is accomplished using a combination of anion exchange chromatography to separate Ac and Ra isotopes from Th and extraction chromatography employing TEVA and DGA-N resins to separate actinium from radium and breakthrough thorium.

Preclinical evaluation of an 111In/225Ac theranostic targeting transformed MUC1 for triple negative breast cancer.

Rationale: Transformed MUC1 (tMUC1) is a cancer-associated antigen that is overexpressed in >90% of triple-negative breast cancers (TNBC), a highly metastatic and aggressive subtype of breast cancer. TAB004, a murine antibody targeting tMUC1, has shown efficacy for the targeted delivery of therapeutics to cancer cells. Our aim was to evaluate humanized TAB004 (hTAB004) as a potential theranostic for TNBC. Methods: The internalization of hTAB004 in tMUC1 expressing HCC70 cells was assessed via fluorescent microscopy. hTAB004 was DOTA-conjugated and radiolabeled with Indium-111 or Actinium-225 and tested for stability and tMUC1 binding (ELISA, flow cytometry). Lastly, in vivo biodistribution (SPECT-CT), dosimetry, and efficacy of hTAB004 were evaluated using a TNBC orthotopic mouse model. Results: hTAB004 was shown to bind and internalize into tMUC1-expressing cells. A production method of 225Ac-DOTA-hTAB004 (yield>97%, RCP>97% SA=5 kBq/µg) and 111In-DOTA-hTAB004 (yield>70%, RCP>99%, SA=884 kBq/µg) was developed. The labeled molecules retained their affinity to tMUC1 and were stable in formulation and mouse serum. In NSG female mice bearing orthotopic HCC70 xenografts, the in vivo tumor concentration of 111In-DOTA-hTAB004 was 65 ± 15 %ID/g (120 h post injection). A single 225Ac-DOTA-hTAB004 dose (18.5 kBq) caused a significant reduction in tumor volume (P<0.001, day 22) and increased survival compared to controls (P<0.007). The human dosimetry results were comparable to other clinically used agents. Conclusion: The results obtained with hTAB004 suggest that the 111In/225Ac-DOTA-hTAB004 combination has significant potential as a theranostic strategy in TNBC and merits further development toward clinical translation.

225Ac- and 213Bi-Substance P Analogues for Glioma Therapy.

Within the last decades, there has been no major improvement in treatment of patients with glioma, especially with glioblastoma multiforme (GBM) which is related to specific features of this tumor type, such as heterogeneity at the macroscopic, microscopic and genetic level, the infiltrative nature of tumors and the obstacle of the brain-blood barrier which limits the accessability of most drugs. The current standard of care is surgical resection, followed by radio- and chemotherapy. After first-line treatment of the primary lesion, tumor recurrence is diagnosed in virtually all GBM patients. Treatment of tumor recurrence represents a challenging clinical task. Surgical resection to relief symptoms of mass effect and/or salvage chemotherapy are often considered as last therapeutic option. A new treatment option is urgently needed. Targeted alpha therapy with an intratumoral injection of 213Bi-DOTA-Substance P (SP) or 225Ac-DOTAGA-Substance P has been introduced into the therapeutic armamentarium of recurrent GBM. There are many advantages of using SP such as very high prevalence of increased NK-1 expression in GBM cells, regardless of the degree of malignancy, and expression of the NK-1 receptor system not only on the membrane of cancer cells but also strong expression of NK1 receptors within the tumor neovasculature suggesting concomitant targeting of vascular and neoplastic structures. Radioisotopes with different physical properties, mainly beta-emitting metallic radionuclides, were implemented for brain tumor treatment. Based on their radiophysical properties, however, alpha emitters exhibit more promising properties. In investigator-initiated phase I and II studies, targeted alpha therapy using Bi-213/Ac-225 radiolabeled Substance P for malignant gliomas compare favorably with standard therapy, with the limitation that no large controlled series have so far been generated. Further development should focus on the improvement of the biological and chemical properties of the compound and the application by dedicated catheter systems to improve the intratumoral distribution of the radiopharmaceutical within growth and infiltrative zone of these glial neoplasms.

Trastuzumab Conjugated Superparamagnetic Iron Oxide Nanoparticles Labeled with 225Ac as a Perspective Tool for Combined α-Radioimmunotherapy and Magnetic Hyperthermia of HER2-Positive Breast Cancer.

It has been proven and confirmed in numerous repeated tests, that the use of a combination of several therapeutic methods gives much better treatment results than in the case of separate therapies. Particularly promising is the combination of ionizing radiation and magnetic hyperthermia in one drug. To achieve this objective, magnetite nanoparticles have been modified in their core with α emitter 225Ac, in an amount affecting only slightly their magnetic properties. By 3-phosphonopropionic acid (CEPA) linker nanoparticles were conjugated covalently with trastuzumab (Herceptin®), a monoclonal antibody that recognizes ovarian and breast cancer cells overexpressing the HER2 receptors. The synthesized bioconjugates were characterized by transmission electron microscopy (TEM), Dynamic Light Scattering (DLS) measurement, thermogravimetric analysis (TGA) and application of 131I-labeled trastuzumab for quantification of the bound biomolecule. The obtained results show that one 225Ac@Fe3O4-CEPA-trastuzumab bioconjugate contains an average of 8-11 molecules of trastuzumab. The labeled nanoparticles almost quantitatively retain 225Ac (>98%) in phosphate-buffered saline (PBS) and physiological salt, and more than 90% of 221Fr and 213Bi over 10 days. In human serum after 10 days, the fraction of 225Ac released from 225Ac@Fe3O4 was still less than 2%, but the retention of 221Fr and 213Bi decreased to 70%. The synthesized 225Ac@Fe3O4-CEPA-trastuzumab bioconjugates have shown a high cytotoxic effect toward SKOV-3 ovarian cancer cells expressing HER2 receptor in-vitro. The in-vivo studies indicate that this bioconjugate exhibits properties suitable for the treatment of cancer cells by intratumoral or post-resection injection. The intravenous injection of the 225Ac@Fe3O4-CEPA-trastuzumab radiobioconjugate is excluded due to its high accumulation in the liver, lungs and spleen. Additionally, the high value of a specific absorption rate (SAR) allows its use in a new very perspective combination of α radionuclide therapy with magnetic hyperthermia.

Advancing Chelation Chemistry for Actinium and Other +3 f-Elements, Am, Cm, and La.

A major chemical challenge facing implementation of 225Ac in targeted alpha therapy-an emerging technology that has potential for treatment of disease-is identifying an 225Ac chelator that is compatible with in vivo applications. It is unclear how to tailor a chelator for Ac binding because Ac coordination chemistry is poorly defined. Most Ac chemistry is inferred from radiochemical experiments carried out on microscopic scales. Of the few Ac compounds that have been characterized spectroscopically, success has only been reported for simple inorganic ligands. Toward advancing understanding in Ac chelation chemistry, we have developed a method for characterizing Ac complexes that contain highly complex chelating agents using small quantities (µg) of 227Ac. We successfully characterized the chelation of Ac3+ by DOTP8- using EXAFS, NMR, and DFT techniques. To develop confidence and credibility in the Ac results, comparisons with +3 cations (Am, Cm, and La) that could be handled on the mg scale were carried out. We discovered that all M3+ cations (M = Ac, Am, Cm, La) were completely encapsulated within the binding pocket of the DOTP8- macrocycle. The computational results highlighted the stability of the M(DOTP)5- complexes.

111In- and 225Ac-Labeled Cixutumumab for Imaging and α-Particle Radiotherapy of IGF-1R Positive Triple-Negative Breast Cancer.

Insulin growth factor receptor (IGF-1R) is overexpressed in many cancers of epithelial origin, where it confers enhanced proliferation and resistance to therapies targeted at other receptors. Anti-IGF-1R monoclonal antibodies have not demonstrated significant improvements in patient outcomes in clinical trials. Humanized monoclonal antibody cixutumumab (IMC-A12) binds to IGF-1R with low nM affinity. In this study, cixutumumab was conjugated with p-SCN-Bn-DOTA and radiolabeled with 111In or 225Ac for imaging or radiotherapy using a triple-negative breast cancer (TNBC) model SUM149PT. The antibody conjugate showed low nM affinity to IGF-1R, which was not affected by conjugation and radiolabeling procedures. Cixutumumab immunoconjugates were effectively internalized in SUM149PT and were cytotoxic to the cells with an EC50 of 225Ac-cixutumumab (0.02 nM) that was almost 5000-fold less than that of unlabeled cixutumumab (95.2 nM). MicroSPECT imaging of the SUM149PT xenograft showed the highest tumor uptake occurred at 48 h post injection and was 9.9 ± 0.5% injected activity per gram (%IA/cc). In radiotherapy studies, we evaluated the effect of the specific activity of 225Ac-cixutumumab on efficacy following a tail vein injection of two doses (days 0 and 10) of the investigation agent or controls. Cixutumumab (2.5 mg/kg) prolonged the survival of the SUM149PT tumor-bearing mice with a median survival of 87 days compared to the PBS control group (median survival of 62 days). Median survival of high specific activity 225Ac-cixutumumab (8 kBq/µg, 225 nCi, 0.05 mg/kg) was 103.5 days compared to 122 days for low specific activity 225Ac-cixutumumab (0.15 kBq/µg, 225 nCi, 2.5 mg/kg). Additionally, low specific activity radioimmunoconjugate led to complete tumor remission in 2/6 mice. The data suggest that the efficacy of cixutumumab can be enhanced by radiolabeling with 225Ac at a low specific activity.

Targeted alpha therapy with bismuth-213 and actinium-225: Meeting future demand.

Targeted alpha therapy (TAT) is a promising approach for the treatment of cancer. The use of alpha emitters for cancer therapy has two distinct advantages over conventional therapies. The short range of alpha radiation in human tissue (less than 0.1 mm), corresponding to only a few cell diameters, allows selective killing of targeted cancer cells while sparing surrounding healthy tissue. At the same time, the high energy (several MeV) of alpha radiation and its associated high linear energy transfer leads to highly effective cell kill. Consequently, alpha radiation can destroy cells which otherwise exhibit resistance to treatment with beta or gamma irradiation or chemotherapeutic drugs, and can thus offer a therapeutic option for tumors resistant to conventional therapies. Recent results demonstrating the remarkable therapeutic efficacy of alpha emitters to treat various cancers have underlined the clinical potential of TAT. This paper describes the recent clinical experience with 213 Bi and 225 Ac. In view of the enormous benefit of targeted cancer treatment with alpha emitters, their production will have to be considerably increased beyond current supply capabilities. Alternative production methods based on the irradiation of uranium, thorium, or radium targets at reactors or accelerator facilities have the potential to meet future demand.

Optimization of Cation Exchange for the Separation of Actinium-225 from Radioactive Thorium, Radium-223 and Other Metals.

Actinium-225 (225Ac) can be produced with a linear accelerator by proton irradiation of a thorium (Th) target, but the Th also underdoes fission and produces 400 other radioisotopes. No research exists on optimization of the cation step for the purification. The research herein examines the optimization of the cation exchange step for the purification of 225Ac. The following variables were tested: pH of load solution (1.5-4.6); rinse steps with various concentrations of HCl, HNO3, H2SO4, and combinations of HCl and HNO3; various thorium chelators to block retention; MP50 and AG50 resins; and retention of 20-45 elements with different rinse sequences. The research indicated that HCl removes more isotopes earlier than HNO3, but that some elements, such as barium and radium, could be eluted with ≥2.5 M HNO3. The optimal pH of the load solution was 1.5-2.0, and the optimized rinse sequence was five bed volumes (BV) of 1 M citric acid pH 2.0, 3 BV of water, 3 BV of 2 M HNO3, 6 BV of 2.5 M HNO3 and 20 BV of 6 M HNO3. The sequence recovered >90% of 225Ac with minimal 223Ra and thorium present.

Defining Processing Times for Accelerator Produced 225Ac and Other Isotopes from Proton Irradiated Thorium.

During the purification of radioisotopes, decay periods or time dependent purification steps may be required to achieve a certain level of radiopurity in the final product. Actinum-225 (Ac-225), Silver-111 (Ag-111), Astatine-211 (At-211), Ruthenium-105 (Ru-105), and Rhodium-105 (Rh-105) are produced in a high energy proton irradiated thorium target. Experimentally measured cross sections, along with MCNP6-generated cross sections, were used to determine the quantities of Ac-225, Ag-111, At-211, Ru-105, Rh-105, and other co-produced radioactive impurities produced in a proton irradiated thorium target at Brookhaven Linac Isotope Producer (BLIP). Ac-225 and Ag-111 can be produced with high radiopurity by the proton irradiation of a thorium target at BLIP.