In vitro and in vivo study of Fr and Bi progeny release from the Ac-labelled TiO nanoparticles.

Background: Targeted alpha therapy (TAT) is an effective option for cancer treatment. To maximize its efficacy and minimize side effects, carriers must deliver radionuclides to target tissues. Most of the nuclides used in TAT decay via the alpha cascade, producing several radioactive daughter nuclei with sufficient energy to escape from the original carrier.

Survival impact of [Ac]Ac-DOTATOC alpha-therapy in a preclinical model of pancreatic neuroendocrine tumor liver micrometastases.

Unlabelled: Although peptide radionuclide therapy (PRRT) using a somatostatin analog (SSA) radiolabeled with a beta- emitter: [Lu]Lu-DOTATATE has shown a good clinical efficacy in neuroendocrine tumors (NETs), most of the patients only achieved tumoral stabilization and rare but severe long-term hematological toxicities have been reported. One of the promising options to improve PRRT is targeted alpha therapy. It is therefore essential to propose animal models that can mimic systemic spread disease, especially microscopic disease such as early stage of NET liver metastases to explore targeted alpha therapy.

Design of Ac-PSMA for targeted alpha therapy in prostate cancer.

The first alpha emitting radiopharmaceutical, RaCl, radium dichloride, was approved 10 years ago into the clinical armament of treating bone metastases in metastatic castration-resistant prostate cancer (mCRPC). In addition to this, the first beta-emitting radionuclide Lu-177 chelated with a prostate-specific membrane antigen (PSMA) compound, got last year its marketing approval for the third line treatment of mCRPC. Therefore, there is great excitement about combining alpha-emitters and prostate cancer targeting PSMA compounds.

Deescalated Ac-PSMA-617 Versus Lu/Ac-PSMA-617 Cocktail Therapy: A Single-Center Retrospective Analysis of 233 Patients.

The aim of this work is to evaluate our clinical real-world data obtained with Ac-PSMA-617 (AcPSMA), which were acquired under compassionate care regulations in patients with advanced-stage prostate cancer. The objective parameters that could be derived from this evaluation are compared with previous literature about AcPSMA and Lu-PSMA-617 (LuPSMA). The medical files of all patients who had received AcPSMA on an individual patient basis at the Heidelberg University Hospital since January 2014 were analyzed retrospectively.

Quantitative SPECT/CT imaging of actinium-225 for targeted alpha therapy of glioblastomas.

Background: A new, alternative option for patients with recurrent glioblastoma is targeted alpha therapy (TAT), in the form of a local administration of substance P (neurokinin type 1 receptor ligand, NK-1) labelled with Ac. The purpose of the study was to confirm the feasibility of quantitative SPECT imaging of Ac, in a model reproducing specific conditions of TAT. In particular, to present the SPECT calibration methodology used, as well as the results of validation measurements and their accuracy.

Development of Ac/Bi generator based on α-ZrP-PAN composite for targeted alpha therapy.

Background: Radioligand therapy using alpha emitters has gained more and more prominence in the last decade. Despite continued efforts to identify new appropriate radionuclides, the combination of Ac/Bi remains among the most promising. Bismuth-213 has been employed in clinical trials in combination with appropriate vectors to treat patients with various forms of cancer, such as leukaemia, bladder cancer, neuroendocrine tumours, melanomas, gliomas, or lymphomas.

Evaluation of the tolerability and safety of [Ac]Ac-PSMA-I&T in patients with metastatic prostate cancer: a phase I dose escalation study.

Background: Life expectancy of patients with metastatic castration-resistant prostate cancer (mCRPC) is still limited despite several systemic treatments. Within five years after diagnosis of primary prostate cancer, 10-20% of the patients have mCRPC and curation is not an option. Radionuclide therapy (RNT) targeted against prostate-specific membrane antigen (PSMA) emerged as a new treatment option and showed effective results in patients with mCRPC.

Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): a multicentre, retrospective study.

Background: Actinium-225 (Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC). We aimed to report the safety and antitumour activity of Ac-PSMA RLT of mCRPC in a large cohort of patients treated at multiple centres across the world.

Methods: This retrospective study included patients treated at seven centres in Australia, India, Germany, and South Africa.

Comparative Analysis of Morphological and Functional Effects of Ac- and Lu-PSMA Radioligand Therapies (RLTs) on Salivary Glands.

Most Prostate Specific Membrane Antigens (PSMAs) targeting small molecules accumulate in the salivary glands (SGs), raising concerns about SG toxicity, especially after repeated therapies or therapy with Ac-labeled ligands. SG toxicity is assessed clinically by the severity of patient-reported xerostomia, but this parameter can be challenging to objectively quantify. Therefore, we explored the feasibility of using SG volume as a biomarker for toxicity.

Long-Term Tumor Control Following Targeted Alpha Therapy (TAT) of Low-Grade Gliomas (LGGs): A New Treatment Paradigm?

The median survival time has been reported to vary between 5 and 8 years in low-grade (WHO grade 2) astrocytoma, and between 10 and 15 years for grade 2 oligodendroglioma. Targeted alpha therapy (TAT), using the modified peptide vector [Bi]Bi/[Ac]Ac-DOTA-substance P, has been developed to treat glioblastoma (GBM), a prevalent malignant brain tumor. In order to assess the risk of late neurotoxicity, assuming that reduced tumor cell proliferation and invasion should directly translate into good responses in low-grade gliomas (LGGs), a limited number of patients with diffuse invasive astrocytoma (n = 8) and oligodendroglioma (n = 3) were offered TAT.

α-Zirconium(IV) Phosphate: Static Study of Ac Sorption in an Acidic Environment and Its Kinetic Sorption Study Using Eu as a Model System for Ac.

Zirconium phosphate (ZrP), especially its alpha allotropic modification, appears to be a very promising sorbent material for the sorption and separation of various radionuclides due to its properties such as an extremely high ion exchange capacity and good radiation stability. Actinium-225 and its daughter nuclide Bi are alpha emitting radioisotopes of high interest for application in targeted alpha therapy of cancer. Thus, the main aim of this paper is to study the sorption of Ac on the α-ZrP surface and its kinetics, while the kinetics of the sorption is studied using Eu as a non-radioactive homologue of Ac.

First preclinical evaluation of [Ac]Ac-DOTA-JR11 and comparison with [Lu]Lu-DOTA-JR11, alpha versus beta radionuclide therapy of NETs.

Background: The [Lu]Lu-DOTA-TATE mediated peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) is sometimes leading to treatment resistance and disease recurrence. An interesting alternative could be the somatostatin antagonist, [Lu]Lu-DOTA-JR11, that demonstrated better biodistribution profile and higher tumor uptake than [Lu]Lu-DOTA-TATE. Furthermore, treatment with alpha emitters showed improvement of the therapeutic index of PRRT due to the high LET offered by the alpha particles compared to beta emitters.

Targeted α-Therapy Using Ac Radiolabeled Single-Domain Antibodies Induces Antigen-Specific Immune Responses and Instills Immunomodulation Both Systemically and at the Tumor Microenvironment.

Targeted radionuclide therapy (TRT) using targeting moieties labeled with α-particle-emitting radionuclides (α-TRT) is an intensely investigated treatment approach as the short range of α-particles allows effective treatment of local lesions and micrometastases. However, profound assessment of the immunomodulatory effect of α-TRT is lacking in literature. Using flow cytometry of tumors, splenocyte restimulation, and multiplex analysis of blood serum, we studied immunologic responses ensuing from TRT with an antihuman CD20 single-domain antibody radiolabeled with Ac in a human CD20 and ovalbumin expressing B16-melanoma model.

In Vivo evaluation of newly synthesized Bi-conjugated alpha-melanocyte stimulating hormone (α-MSH) peptide analogues in melanocortin-1 receptor (MC1-R) positive experimental melanoma model.

Given the rising pervasiveness of melanocortin-1 receptor (MC1-R) positive melanoma malignum (MM) and pertinent metastases, radiolabelled receptor-affine alpha-melanocyte stimulating hormone-analogue (α-MSH analogue) imaging probes would be of crucial importance in timely tumor diagnostic assessment. Herein we aimed at investigating the biodistribution and the MM targeting potential of newly synthesized Bi-conjugated MC1-R specific peptide-based radioligands with the establishment of MC1-R overexpressing MM preclinical model. DOTA-conjugated NAP, -HOLD, -FOLD, -and MARSamide were labelled with Bi.

Ac-PSMA-617 radioligand therapy of de novo metastatic hormone-sensitive prostate carcinoma (mHSPC): preliminary clinical findings.

Purpose: Ac-PSMA-617 has demonstrated good anti-tumor effect as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) patients. No study has previously assessed treatment outcome and survival following Ac-PSMA-617 treatment of de novo metastatic hormone-sensitive prostate carcinoma (mHSPC) patients. Based on the potential side effects that are known and explained to the patients by the oncologist, some of the patients refused the standard treatment and are seeking alternative therapies.

Locoregional Treatment of Glioblastoma With Targeted α Therapy: [ 213 Bi]Bi-DOTA-Substance P Versus [ 225 Ac]Ac-DOTA-Substance P-Analysis of Influence Parameters.

Background: Glioblastoma (GB) is the most malignant primary brain tumor. Therefore, introduction of new treatment options is critically important. The aim of this study was to assess local treatment with α emitters [ 213 Bi]Bi-DOTA-substance P (SP) and [ 225 Ac]Ac-DOTA-SP.

Therapeutic Performance Evaluation of Bi-Labelled Aminopeptidase N (APN/CD13)-Affine NGR-Motif ([Bi]Bi-DOTAGA-cKNGRE) in Experimental Tumour Model: A Treasured Tailor for Oncology.

Since NGR-tripeptides (asparagine-glycine-arginine) selectively target neoangiogenesis-associated Aminopeptidase N (APN/CD13) on cancer cells, we aimed to evaluate the in vivo tumour targeting capability of radiolabelled, NGR-containing, ANP/CD13-selective [Bi]Bi-DOTAGA-cKNGRE in CD13pos. HT1080 fibrosarcoma-bearing severe combined immunodeficient CB17 mice. 10 ± 1 days after cancer cell inoculation, positron emission tomography (PET) was performed applying [Ga]Ga-DOTAGA-cKNGRE for tumour verification.

Resonant laser ionization and mass separation of Ac.

[Formula: see text]Ac is a radio-isotope that can be linked to biological vector molecules to treat certain distributed cancers using targeted alpha therapy. However, developing [Formula: see text]Ac-labelled radiopharmaceuticals remains a challenge due to the supply shortage of pure [Formula: see text]Ac itself. Several techniques to obtain pure [Formula: see text]Ac are being investigated, amongst which is the high-energy proton spallation of thorium or uranium combined with resonant laser ionization and mass separation.

Targeted alpha therapy for glioblastoma.

According to the 2021 World Health Organization Classification of Tumors of the Central Nervous System, glioblastoma (GB) is a primary brain tumor and presents with the worst prognosis. Due to its infiltrating characteristic, molecular heterogeneity, and only partly preserved function of the blood-brain barrier, the median overall survival time is short (9-15 months), regardless of comprehensive treatment including surgery, radiotherapy, and chemotherapy. Several novel treatment strategies are under investigation.

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.

Cubosomal Lipid Formulation for Combination Cancer Treatment: Delivery of a Chemotherapeutic Agent and Complexed α-Particle Emitter Bi.

Here, we propose tailored lipid liquid-crystalline carriers (cubosomes), which incorporate an anticancer drug (doxorubicin) and complexed short-lived α-emitter (bismuth-213), as a strategy to obtain more effective action toward the cancer cells. Cubosomes were formulated with doxorubicin (DOX) and an amphiphilic ligand (DOTAGA-OA), which forms stable complexes with Bi radionuclide. The behavior of DOX incorporated into the carrier together with the chelating agent was investigated, and the drug liberation profile was determined.

Carbonic Anhydrase IX-Targeted α-Radionuclide Therapy with 225Ac Inhibits Tumor Growth in a Renal Cell Carcinoma Model.

In this study, we compared the tumor-targeting properties, therapeutic efficacy, and tolerability of the humanized anti-CAIX antibody (hG250) labeled with either the α-emitter actinium-225 (225Ac) or the β--emitter lutetium-177 (177Lu) in mice. BALB/c nude mice were grafted with human renal cell carcinoma SK-RC-52 cells and intravenously injected with 30 µg [225Ac] Ac-DOTA-hG250 (225Ac-hG250) or 30 µg [177Lu] Lu-DOTA-hG250 (177Lu-hG250), followed by ex vivo biodistribution studies. Therapeutic efficacy was evaluated in mice receiving 5, 15, and 25 kBq of 225Ac-hG250; 13 MBq of 177Lu-hG250; or no treatment.

Hematologic toxicity profile and efficacy of [Ac]Ac-PSMA-617 α-radioligand therapy of patients with extensive skeletal metastases of castration-resistant prostate cancer.

Purpose: Actinium-225-labeled prostate-specific membrane antigen ([Ac]Ac-PSMA-617) is safe and effective in the treatment of metastatic castration-resistant prostate cancer (mCRPC). No study has specifically assessed its safety in patients with extensive skeletal metastases of mCRPC. We aimed to investigate the hematologic toxicity and efficacy of [Ac]Ac-PSMA-617 therapy in patients with extensive skeletal metastases of mCRPC.