Α-particle Emitters Research Articles

Transport cocktails for cancer therapeutics

Beyond biological cell heterogeneity, evidenced by different resistances to therapeutics, “delivery heterogeneity” crucially limits treatment efficacy for advanced solid tumors: variations in therapeutic drug delivery to different tumor areas (perivascular, perinecrotic) leading to nonuniform drug concentrations/doses and to unsuccessful treatment (cancer cell kill). Short-range (40–80 µm), high energy (1–5 MeV) α particles successfully address the biological heterogeneity: the double-strand DNA breaks they cause make them impervious to cell resistance mechanisms. Multiresponsive nanocarriers and/or engineered antibody-drug-conjugates are elegant approaches to delivering such α-particle emitters. Delivery heterogeneity, however, remains a challenge in established (i.e., large, vascularized) tumors. Remarkably, delivery properties enabling efficacy at the cell scale (targeting selectivity, affinity, cell drug uptake) may act against spatial delivery uniformity at the tumor scale (binding-site barrier effect). We have previously demonstrated, in different mouse models, that spatial delivery uniformity, key to the effective killing of solid tumors, can be achieved utilizing combinations of different, distinct delivery carriers of the same emitter, but with different, complementary delivery properties, “leaving no cancer cell behind.” We build first principles reaction-transport models (quantitatively informed by experiments) that explain the “geographically complementary” behaviors of such carrier cocktails, and help optimally design these cocktails and their delivery protocols. Published by the American Physical Society 2024

Abstract 6030: Optimizing the therapeutic index of targeted α-particle radioimmuotherapy (TART) of HER2-positive breast cancer tumors in NRG mice with 225Ac-labeled trastuzumab

Abstract Introduction: Our aim was to optimize the therapeutic index of TART of HER2-positive BC in NRG mice by studying the effectiveness and normal tissue toxicity of trastuzumab IgG, F(ab’)2 or Fab modified with DOTA for complexing the α-particle emitter, 225Ac. Methods: The toxicity of [225Ac]Ac-DOTA-trastuzumab IgG, F(ab’)2 and Fab were assessed in NRG mice (n=5) injected i.v. with 2 and 4 kBq (total 80 μg) separated by 8 d. Body weight was monitored and complete blood cell (CBC) counts and alanine aminotransferase (ALT) and creatinine (CRE) were measured at 14 d post-injection (p.i.). TART was performed in NRG mice (n=7) with s.c. HER2-positive 164/8-1B/H2N.luc+ xenografts injected i.v. with 2 and 4 kBq (total 80 μg) separated by 8 d of [225Ac]Ac-DOTA-trastuzumab IgG, F(ab’)2 or Fab. Control mice received irrelevant [225Ac]Ac-DOTA-IgG, trastuzumab or saline. The tumor growth index (TGI=tumor volume/initial tumor volume) was measured and Kaplan-Meier median survival estimated. Tumor and normal tissue uptake (%ID/g) of [225Ac]Ac-DOTA-trastuzumab IgG, F(ab’)2 and Fab (4 kBq) in tumor-bearing NRG mice were measured up to 14 d p.i.. Results: [225Ac]Ac-DOTA-trastuzumab F(ab’)2 and Fab caused no decrease in CBC, while [225Ac]Ac-DOTA-trastuzumab IgG decreased white blood cells by 4.5-fold, platelets by 7.5-fold, red blood cells by 1.2-fold and hematocrit by 1.2-fold compared to saline-treated mice. [225Ac]Ac-trastuzumab F(ab’)2 or Fab caused no increase in ALT or CRE. Body weight was not decreased in all groups of mice. [225Ac]Ac-DOTA-trastuzumab IgG, F(ab’)2 or Fab inhibited tumor growth (TGI at 15 d = 2.5, 1.8, and 1.9, respectively) vs. saline or trastuzumab (TGI= 6.3 and 5.2; P=0.0047 and 0.0028). Median survival was increased to 46 d for mice treated with [225Ac]Ac-DOTA-trastuzumab F(ab’)2 vs. 29 d for Fab (P=0.008), 22 d for IgG (P=0.0005) and 15 d for saline (P=0.0005). Median survival for mice treated with [225Ac]Ac-DOTA-IgG was 20 d and for trastuzumab was 22 d. Tumor uptake of [225Ac]Ac-DOTA-trastuzumab IgG and F(ab’)2 at 48 h p.i. were 10.6 ± 0.6 and 8.7 ± 0.8, respectively, while uptake of [225Ac]Ac-DOTA-trastuzumab Fab at 18 h p.i. was 3.1 ± 0.5 %ID/g. Elimination from the blood was slowest for [225Ac]Ac-DOTA-trastuzumab IgG followed by F(ab’)2 then Fab. Spleen and liver uptake were greatest for [225Ac]Ac-DOTA-trastuzumab IgG but much lower for F(ab’)2 and Fab. Kidney uptake was highest for [225Ac]Ac-DOTA-trastuzumab Fab. Conclusion: [225Ac]Ac-DOTA-trastuzumab F(ab’)2 provided the highest therapeutic index, inhibiting tumor growth and improving survival while minimizing toxicity. TART with [225Ac]Ac-DOTA-trastuzumab F(ab’)2 is a promising new treatment for HER2-positive BC that could be more effective than trastuzumab. Citation Format: Misaki Kondo, Zhongli Cai, Conrad Chan, Raymond M. Reilly. Optimizing the therapeutic index of targeted α-particle radioimmuotherapy (TART) of HER2-positive breast cancer tumors in NRG mice with 225Ac-labeled trastuzumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6030.

Towards Effective Targeted Alpha Therapy for Neuroendocrine Tumours: A Review.

This review article explores the evolving landscape of Molecular Radiotherapy (MRT), emphasizing Peptide Receptor Radionuclide Therapy (PRRT) for neuroendocrine tumours (NETs). The primary focus is on the transition from β-emitting radiopharmaceuticals to α-emitting agents in PRRT, offering a critical analysis of the radiobiological basis, clinical applications, and ongoing developments in Targeted Alpha Therapy (TAT). Through an extensive literature review, the article delves into the mechanisms and effectiveness of PRRT in targeting somatostatin subtype 2 receptors, highlighting both its successes and limitations. The discussion extends to the emerging paradigm of TAT, underlining its higher potency and specificity with α-particle emissions, which promise enhanced therapeutic efficacy and reduced toxicity. The review critically evaluates preclinical and clinical data, emphasizing the need for standardised dosimetry and a deeper understanding of the dose-response relationship in TAT. The review concludes by underscoring the significant potential of TAT in treating SSTR2-overexpressing cancers, especially in patients refractory to β-PRRT, while also acknowledging the current challenges and the necessity for further research to optimize treatment protocols.

Beyond Average: α-Particle Distribution and Dose Heterogeneity in Bone Metastatic Prostate Cancer.

α-particle emitters are emerging as a potent modality for disseminated cancer therapy because of their high linear energy transfer and localized absorbed dose profile. Despite great interest and pharmaceutical development, there is scant information on the distribution of these agents at the scale of the α-particle pathlength. We sought to determine the distribution of clinically approved [223Ra]RaCl2 in bone metastatic castration-resistant prostate cancer at this resolution, for the first time to our knowledge, to inform activity distribution and dose at the near-cell scale. Methods: Biopsy specimens and blood were collected from 7 patients 24 h after administration. 223Ra activity in each sample was recorded, and the microstructure of biopsy specimens was analyzed by micro-CT. Quantitative autoradiography and histopathology were segmented and registered with an automated procedure. Activity distributions by tissue compartment and dosimetry calculations based on the MIRD formalism were performed. Results: We revealed the activity distribution differences across and within patient samples at the macro- and microscopic scales. Microdistribution analysis confirmed localized high-activity regions in a background of low-activity tissue. We evaluated heterogeneous α-particle emission distribution concentrated at bone-tissue interfaces and calculated spatially nonuniform absorbed-dose profiles. Conclusion: Primary patient data of radiopharmaceutical therapy distribution at the small scale revealed that 223Ra uptake is nonuniform. Dose estimates present both opportunities and challenges to enhance patient outcomes and are a first step toward personalized treatment approaches and improved understanding of α-particle radiopharmaceutical therapies.

Targeted Alpha Therapy: All We Need to Know about 225Ac's Physical Characteristics and Production as a Potential Theranostic Radionuclide.

The high energy of α emitters, and the strong linear energy transfer that goes along with it, lead to very efficient cell killing through DNA damage. Moreover, the degree of oxygenation and the cell cycle state have no impact on these effects. Therefore, α radioisotopes can offer a treatment choice to individuals who are not responding to β- or gamma-radiation therapy or chemotherapy drugs. Only a few α-particle emitters are suitable for targeted alpha therapy (TAT) and clinical applications. The majority of available clinical research involves 225Ac and its daughter nuclide 213Bi. Additionally, the 225Ac disintegration cascade generates γ decays that can be used in single-photon emission computed tomography (SPECT) imaging, expanding the potential theranostic applications in nuclear medicine. Despite the growing interest in applying 225Ac, the restricted global accessibility of this radioisotope makes it difficult to conduct extensive clinical trials for many radiopharmaceutical candidates. To boost the availability of 225Ac, along with its clinical and potential theranostic applications, this review attempts to highlight the fundamental physical properties of this α-particle-emitting isotope, as well as its existing and possible production methods.

Surface and decay properties of newly synthesized 207,208Th isotopes for various α-decay chains

Considering various initial deformations, the ground, first excited, and second excited states binding energies are calculated using the effective field theory motivated relativistic mean-field based IOPB-I force parameter. The alpha decay chains for both the 207Th and 208Th are examined. As observed for both nuclei, it takes four subsequent α-particle emissions to reach the stable Pb nucleus. The half-lives determined by two widely used Viola-Seaborg and modified universal decay law formulas are compared with the available experimental data. The surface property-like symmetry energy is also predicted for these nuclei in the framework of the coherent density fluctuation model and establishes a connection between the decay behavior and the symmetry energy.

Exploring a Nuclear-Selective Radioisotope Delivery System for Efficient Targeted Alpha Therapy.

Targeted alpha therapy (TAT) has garnered significant interest as an innovative cancer therapy. Owing to their high energy and short range, achieving selective α-particle accumulation in target tumor cells is crucial for obtaining high potency without adverse effects. To meet this demand, we fabricated an innovative radiolabeled antibody, specifically designed to selectively deliver 211At (α-particle emitter) to the nuclei of cancer cells. The developed 211At-labeled antibody exhibited a superior effect compared to its conventional counterparts. This study paves the way for organelle-selective drug delivery.

Effective therapy with Bismuth-212 labeled macroaggregated albumin in orthotopic mouse breast tumor models.

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 4h 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 4421: Targeting myeloid-derived suppressor cells with actinium-225 lintuzumab, a CD33 antibody radioconjugate to enhance antitumor immunity

Abstract Introduction: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid lineage cells with potent immunosuppressive activity found enriched in cancer patients. Crosstalk between MDSCs and the tumor microenvironment can promote tumor immune evasion and thus there is growing interest in developing therapeutic approaches to intervene in the MDSC suppressive function. Both monocytic-MDSC (M-MDSC) and granulocytic-MDSC (G-MDSC) subpopulations express the cell surface CD33 myeloid marker. For well-defined cell surface markers like CD33, there is considerable interest in the use of radionuclides as therapeutic payloads, particularly α-particle emitters such as actinium-225 (225Ac) since they deliver substantially higher decay energies over a much shorter distance than β-emitters, rendering them more suitable for precise, potent, and efficient target cell killing while minimizing toxicity to surrounding bystander cells. Actimab A, the anti-CD33 antibody lintuzumab armed with the 225Ac radioisotope (CD33 ARC), is currently being evaluated in R/R AML and has demonstrated significant anti-leukemic activity in Phase 1/2 clinical trials. We therefore hypothesized that MDSCs can be directly targeted by the CD33 ARC. Hence, we evaluated the therapeutic potential of the CD33 ARC to deplete MDSCs through preclinical studies in vitro and in vivo with humanized mouse model. Methods: CD33 ARC was generated by conjugating lintuzumab with p-SCN-Bn-DOTA and subsequently radiolabeled with 225Ac. Primary MDSCs were isolated from cancer patient peripheral blood or healthy donor PBMCs. The specific binding of CD33 ARC to CD33 positive MDSCs and the decreased viability of MDSCs in response to treatment in vitro was characterized by immunophenotyping using flow cytometry. The therapeutic efficacy of CD33 ARC to deplete MDSC in vivo was evaluated in human CD34 reconstituted humanized NOG-EXL mice. Results: CD33 positive MDSCs (M-MDSCs and G-MDSCs) were identified in human cancer peripheral blood samples, including colorectal and lung. Significantly more MDSCs were found in the peripheral blood of cancer patients in comparison to healthy donors. CD33 ARC treatment of human cancer MDSCs induced a potent dose-dependent reduction in MDSC viability leading to increased depletion of MDSCs. Furthermore, in the humanized NOG-EXL mouse model, CD33 ARC therapy demonstrated in vivo activity of CD33 ARC to deplete human MDSCs. Conclusions: In this study, we demonstrate CD33 ARC alpha targeted radiotherapy depletes human CD33 positive immune suppressing MDSCs present in multiple cancer types, to enhance antitumor immunity. These findings present a translatable strategy that supports further evaluation of 225Ac lintuzumab as a MDSC targeting agent to improve the efficacy of antitumor therapies. Citation Format: Amanda Chin, Mary Chen, Jason Li, Megan McCloskey, Caroline Jennings, Le-Cun Xu, Monideepa Roy, Denis Beckford, Helen Kotanides. Targeting myeloid-derived suppressor cells with actinium-225 lintuzumab, a CD33 antibody radioconjugate to enhance antitumor immunity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4421.

Intra-Arterial Delivery of Radiopharmaceuticals in Oncology: Current Trends and the Future of Alpha-Particle Therapeutics.

A paradigm shift is underway in cancer diagnosis and therapy using radioactivity-based agents called radiopharmaceuticals. In the new strategy, diagnostic imaging measures the tumor uptake of radioactive agent "X" in a patient's specific cancer, and if uptake metrics are realized, the patient can be selected for therapy with radioactive agent "Y". The X and Y represent different radioisotopes that are optimized for each application. X-Y pairs are known as radiotheranostics, with the currently approved route of therapy being intravenous administration. The field is now evaluating the potential of intra-arterial dosing of radiotheranostics. In this manner, a higher initial concentration can be achieved at the cancer site, which could potentially enhance tumor-to-background targeting and lead to improved imaging and therapy. Numerous clinical trials are underway to evaluate these new therapeutic approaches that can be performed via interventional radiology. Of further interest is changing the therapeutic radioisotope that provides radiation therapy by β- emission to radioisotopes that also decay by α-particle emissions. Alpha (α)-particle emissions provide high energy transfer to the tumors and have distinct advantages. This review discusses the current landscape of intra-arterially delivered radiopharmaceuticals and the future of α-particle therapy with short-lived radioisotopes.

Signaling Network Response to α-Particle-Targeted Therapy with the 225Ac-Labeled Minigastrin Analog 225Ac-PP-F11N Reveals the Radiosensitizing Potential of Histone Deacetylase Inhibitors.

α-particle emitters have recently been explored as valuable therapeutic radionuclides. Yet, toxicity to healthy organs and cancer radioresistance limit the efficacy of targeted α-particle therapy (TAT). Identification of the radiation-activated mechanisms that drive cancer cell survival provides opportunities to develop new points for therapeutic interference to improve the efficacy and safety of TAT. Methods: Quantitative phosphoproteomics and matching proteomics followed by the bioinformatics analysis were used to identify alterations in the signaling networks in response to TAT with the 225Ac-labeled minigastrin analog 225Ac-PP-F11N (DOTA-(dGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe) in A431 cells, which overexpress cholecystokinin B receptor (CCKBR). Western blot analysis and microscopy verified the activation of the selected signaling pathways. Small-molecule inhibitors were used to validate the potential of the radiosensitizing combinatory treatments both invitro and in A431/CCKBR tumor-bearing nude mice. Results: TAT-induced alterations were involved in DNA damage response, cell cycle regulation, and signal transduction, as well as RNA transcription and processing, cell morphology, and transport. Western blot analysis and microscopy confirmed increased phosphorylations of the key proteins involved in DNA damage response and carcinogenesis, including p53, p53 binding protein 1 (p53BP1), histone deacetylases (HDACs), and H2AX. Inhibition of HDAC class II, ataxia-telangiectasia mutated (ATM), and p38 kinases by TMP269, AZD1390, and SB202190, respectively, sensitized A431/CCKBR cells to 225Ac-PP-F11N. As compared with the control and monotherapies, the combination of 225Ac-PP-F11N with the HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) significantly reduced the viability and increased the DNA damage of A431/CCKBR cells, led to the most pronounced tumor growth inhibition, and extended the mean survival of A431/CCKBR xenografted nude mice. Conclusion: Our study revealed the cellular responses to TAT and demonstrated the radiosensitizing potential of HDAC inhibitors to 225Ac-PP-F11N in CCKBR-positive tumors. This proof-of-concept study recommends development of novel radiosensitizing strategies by targeting TAT-activated and survival-promoting signaling pathways.

Quantitative SPECT/CT imaging of lead-212: a phantom study

BackgroundLead-212 (212Pb) is a promising radionuclide for targeted therapy, as it decays to α-particle emitter bismuth-212 (212Bi) via β-particle emission. This extends the problematic short half-life of 212Bi. In preparation for upcoming clinical trials with 212Pb, the feasibility of quantitative single photon-emission computed tomography/computed tomography (SPECT/CT) imaging of 212Pb was studied, with the purpose to explore the possibility of individualised patient dosimetric estimation.ResultsBoth acquisition parameters (combining two different energy windows and two different collimators) and iterative reconstruction parameters (varying the iterations x subsets between 10 × 1, 15 × 1, 30 × 1, 30 × 2, 30 × 3, 30 × 4, and 30 × 30) were investigated to evaluate visual quality and quantitative uncertainties based on phantom images. Calibration factors were determined using a homogeneous phantom and were stable when the total activity imaged exceeded 1 MBq for all the imaging protocols studied, but they increased sharply as the activity decayed below 1 MBq. Both a 20% window centred on 239 keV and a 40% window on 79 keV, with dual scatter windows of 5% and 20%, respectively, could be used. Visual quality at the lowest activity concentrations was improved with the High Energy collimator and the 79 keV energy window. Fractional uncertainty in the activity quantitation, including uncertainties from calibration factors and small volume effects, in spheres of 2.6 ml in the NEMA phantom was 16–21% for all protocols with the 30 × 4 filtered reconstruction except the High Energy collimator with the 239 keV energy window. Quantitative analysis was possible both with and without filters, but the visual quality of the images improved with a filter.ConclusionsOnly minor differences were observed between the imaging protocols which were all determined suitable for quantitative imaging of 212Pb. As uncertainties generally decreased with increasing iterative updates in the reconstruction and recovery curves did not converge with few iterations, a high number of reconstruction updates are recommended for quantitative imaging.

Abstract 213: Assessing the role of X-ray radiation in combination with a DNA-PK inhibitor on cellular activity and adhesion using an in vitro HER2-positive breast cancer model

Abstract Introduction: Breast cancer (BC) is the most common cancer for women regardless of ethnicity, and the leading cause of cancer-related deaths in women. Radiation therapy (XRT) plays a vital role in multidisciplinary treatment approaches. Although XRT has been found to reduce breast cancer recurrence and mortality rate, like all other therapeutics, XRT contains some risks. Radiation can increase the mortality rate due to the risk of ischemic heart diseases. As part of an overall effort to understand the interaction between different types of radiations (e.g., radiopharmaceutical therapy (RPT) with β or α-particle emitters) and DNA double-strand break repair (DSB) repair pathways, we observed that impairment of DNA DSB by DNA-PKcs inhibitor (NU7441) fragmented HER2-positive BC spheroids in the presence of XRT. This could be possibly due to the modulation of cellular adhesion protein mediated by DNA-PK inhibition. In this study, we aim to assess the spheroids fragmentations and also measure the cell viability and levels of a cell adhesion protein, β1-integrin in irradiated HER2-positive monolayer cells, to get a mechanistic view for XRT and NU7441 combinatorial action so as to compare with β- or α-emitter RPT. Methods: In brief, NT2.5 BC spheroids were formed in agarose-coated 96-well plates. For both spheroids and monolayer cells, half of the media was replaced with fresh media containing 1 nM-5μM of NU7441 every other day. A colorimetric cell viability kit was used to measure cell viability and western blot analysis was performed to measure the β1-integrin level, which was normalized against β-actin. Results: Microscopic analysis suggested that XRT increased spheroid fragmentations in the presence of NU7441 compared to the XRT alone. Interaction between XRT and NU7441 (6.68% of the total variation, P<0.0001) was found for the cell viability data, where XRT (74.07% of the total variation, P<0.0001) and NU7441 (5.07% of the total variation, P<0.0001) both regulated cell viability on their own. Western blot data suggest that β1-integrin level was reduced for 8 Gy XRT and 5 μM NU7441 combination compared to the no XRT and vehicle combination. Moreover, 2-way ANOVA analysis revealed that XRT plays a role to regulate the β1-integrin level in NT2.5 monolayer cells (57.61% of the total variation, P<0.0001). Conclusion: XRT increased BC spheroids fragmentations when DNA damage was inhibited by a small molecule inhibitor. XRT and NU7441 both regulated NT2.5 cell viability with an interaction between them. Furthermore, XRT reduced β1-integrin level in monolayer NT2.5 cells. The XRT and NU7441 combination may induce fragmentations by decreasing cell viability and adhesion proteins. Future studies assessing the mechanisms of XRT and DNA PK inhibitor in BC spheroids and in vivo are warranted to confirm these results. Citation Format: Mahmud Hasan, Ioanna Liatsou, George Sgouros. Assessing the role of X-ray radiation in combination with a DNA-PK inhibitor on cellular activity and adhesion using an in vitro HER2-positive breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 213.

Utility of PET to Appropriately Select Patients for PSMA-Targeted Theranostics.

The majority of aggressive prostate cancers overexpress the transmembrane protein prostate-specific membrane antigen (PSMA). PSMA is, therefore, an attractive target for drug development. Over the last decade, numerous PSMA-targeted radiopharmaceuticals for imaging and therapy have been developed and investigated in theranostic combination. PSMA-targeted radiopharmaceuticals for imaging have been primarily developed for PET. PSMA PET provides whole-body evaluation of the degree of PSMA expression on tumors and potentially provides a method to better select patients for PSMA-targeted therapy. Numerous PSMA-targeted therapeutic agents using β- or α-particle emitters are under study in clinical trials. In particular, the β-particle-emitting radioisotope 177Lu bound to PSMA-targeted small molecules have ongoing and completed late-stage clinical trials in metastatic castration-resistant prostate cancer. To define the most appropriate patient group for PSMA-targeted therapeutics, multiple studies have investigated PSMA and FDG PET/CT to establish PET parameters as predictive and prognostic biomarkers. This article discusses recent clinical trials that examine the optimal use of PET for the selection of patients for PSMA-targeted therapeutics and provides an integrative overview of choice of PET tracer(s), targeting molecule, therapeutic radioisotope, nonradioactive therapy, and cancer type (prostate or nonprostate).

Therapeutic efficacy of heterogeneously distributed radiolabelled peptides: Influence of radionuclide choice

PurposeTo model dose-response relationships for in vivo experiments with radiolabelled peptides enabling maximum therapeutic efficacy while limiting toxicity to kidney and bone marrow. MethodsA multiregional murine kidney phantom, with a kinetic model for cortex and outer medulla distribution, were used to predict renal toxicity.Maximum tolerated activities to avoid nephrotoxicity (at 40 Gy Biological Effective Dose BED) and hematologic toxicity (at 2 Gy) were compared.The therapeutic efficacy of 90Y, 161Tb, 177Lu and 213Bi was assessed at their respective maximum tolerated activities based on cellular-level dosimetry accounting for activity and tumor heterogeneity. These results were compared with average tumor-dosimetry-based predictions. ResultsThe kidney was found to be the dose-limiting organ for all radionuclides, limiting the administered activity to 44 MBq 177Lu, 34 MBq 161Tb, 19 MBq 90Y and 13 MBq 213Bi , respectively.The average S-values for the initial heterogeneous activity distribution in the tumor volume are not significantly different from the homogeneous ones. The in vivo tumor cell survivals predicted by assuming uniform dose rate-distributions are not significantly different from those for heterogeneous dose rate-based predictions.The lowest in vivo survival was found for 213Bi (2%) followed by 161Tb (30%), 177Lu (37%) and 90Y (60%). The minimal effective dose rate for cell kill is 13–14 mGy/h for β-emitters and 2.2 mGy/h for the α-particle emitter 213Bi, below these values proliferation takes over. ConclusionsRadionuclides emitting α-particles have the highest potential for improving therapeutic efficacy in tumors and metastases with uniform receptor expression, after careful evaluation of their burden to the healthy organs.

Radiation dosimetry and efficacy of an 89Zr/225Ac-labeled humanized anti-MUC5AC antibody

IntroductionTheranostic applications are currently difficult to achieve owing to the limited evaluation of suitable chelators for therapeutic nuclides, such as 225Ac and 227Th. With a focus on targeted α therapy and theranostics using human IgG as a drug-delivery system (i.e., combining highly cytotoxic α-particle emitter radiation with efficient tumor targeting), we developed a recombinant humanized Nd2 (hNd2) as an anti-MUC5AC antibody since MUC5AC is highly expressed in patients with pancreatic cancer. Therefore, we aimed to evaluate the performance of 89Zr- (for diagnosis) and 225Ac- (for therapy) labeling of these antibodies using well-controlled radioisotope (RI)-labeling technology in pancreatic cancer mouse models. Methods89Zr-labeled hNd2 (NMK89) and 225Ac-labeled hNd2 (NMT25) were manufactured by chemical conjugation using affinity peptides. A binding assay and the evaluation of plasma stability were performed in vitro to confirm the properties of NMK89 and NMT25. In vivo, we evaluated biodistribution, positron emission tomography (PET)/computed tomography (CT) imaging, antitumor effects, and toxicity. Moreover, the exposure dose in humans was estimated based on the biodistribution evaluation in normal mice. ResultsNMK89 and NMT25 showed binding specificity to MUC5AC and stability with radiochemical purity ≥90% in mice and human plasma following incubation for 168 h. NMK89 showed high accumulation in tumors and low non-specific accumulation in normal tissues. The antitumor effect of NMT25 was dose-dependent and significantly suppressed tumor growth in the NMT25 treatment groups compared with the control group (p < 0.05). NMK89 and NMT25 showed similar pharmacokinetics and biodistribution characteristics. Additionally, the human estimated exposure dose of NMK89 and NMT25 was confirmed, and the effective dose of NMK89 and NMT25 was 0.33 mSv/MBq and 177.5 mSv/MBq, respectively. ConclusionNMK89 showed specific accumulation in the MUC5AC-expressing tumors, while NMT25 showed strong antitumor effects. These results suggest NMK89 and NMT25 as promising theranostic agents for pancreatic cancer.

Two diverse carriers are better than one: A case study in α-particle therapy for prostate specific membrane antigen-expressing prostate cancers.

Partial and/or heterogeneous irradiation of established (i.e., large, vascularized) tumors by α‐particles that exhibit only a 4–5 cell‐diameter range in tissue, limits the therapeutic effect, since regions not being hit by the high energy α‐particles are likely not to be killed. This study aims to mechanistically understand a delivery strategy to uniformly distribute α‐particles within established solid tumors by simultaneously delivering the same α‐particle emitter by two diverse carriers, each killing a different region of the tumor: (1) the cancer‐agnostic, but also tumor‐responsive, liposomes engineered to best irradiate tumor regions far from the vasculature, and (2) a separately administered, antibody, targeting any cancer‐cell's surface marker, to best irradiate the tumor perivascular regions. We demonstrate that on a prostate specific membrane antigen (PSMA)‐expressing prostate cancer xenograft mouse model, for the same total injected radioactivity of the α‐particle emitter Actinium‐225, any radioactivity split ratio between the two carriers resulted in better tumor growth inhibition compared to the tumor inhibition when the total radioactivity was delivered by any of the two carriers alone. This finding was due to more uniform tumor irradiation for the same total injected radioactivity. The killing efficacy was improved even though the tumor‐absorbed dose delivered by the combined carriers was lower than the tumor‐absorbed dose delivered by the antibody alone. Studies on spheroids with different receptor‐expression, used as surrogates of the tumors' avascular regions, demonstrated that our delivery strategy is valid even for as low as 1+ (ImmunoHistoChemistry score) PSMA‐levels. The findings presented herein may hold clinical promise for those established tumors not being effectively eradicated by current α‐particle radiotherapies.

The Road to Personalized Myeloma Medicine: Patient-specific Single-domain Antibodies for Anti-idiotypic Radionuclide Therapy.

To this day, multiple myeloma remains an incurable cancer. For many patients, recurrence is unavoidably a result of lacking treatment options in the minimal residual disease stage. This is due to residual and treatment-resistant myeloma cells that can cause disease relapse. However, patient-specific membrane-expressed paraproteins could hold the key to target these residual cells responsible for disease recurrence. Here, we describe the therapeutic potential of radiolabeled, anti-idiotypic camelid single-domain antibody fragments (sdAbs) as tumor-restrictive vehicles against a membrane-bound paraprotein in the syngeneic mouse 5T33 myeloma model and analogously assess the feasibility of sdAb-based personalized medicine for patients with multiple myeloma. Llamas were immunized using extracts containing paraprotein from either murine or human sera, and selective sdAbs were retrieved using competitive phage display selections of immune libraries. An anti-5T33 idiotype sdAb was selected for targeted radionuclide therapy with the β--particle emitter 177Lu and the α-particle emitter 225Ac. sdAb-based radionuclide therapy in syngeneic mice with a low 5T33 myeloma lesion load significantly delayed tumor progression. In five of seven patients with newly diagnosed myeloma, membrane expression of the paraprotein was confirmed. Starting from serum-isolated paraprotein, for two of three selected patients anti-idiotype sdAbs were successfully generated.

Surface Adsorption of the Alpha-Emitter Astatine-211 to Gold Nanoparticles Is Stable In Vivo and Potentially Useful in Radionuclide Therapy

Targeted α-therapy (TAT) can eradicate tumor metastases while limiting overall toxicity. One of the most promising α-particle emitters is astatine-211 (211At). However, 211At-carbon bonds are notoriously unstable in vivo and no chelators are available. This hampers its adoption in TAT. In this study, the stability of 211At on the surface of gold nanoparticles (AuNPs) was investigated. The employed AuNPs had sizes in the 25–50 nm range. Radiolabeling by non-specific surface-adsorption in &gt;99% radiochemical yield was achieved by mixing 211At and AuNPs both before and after polyethylene glycol (PEG) coating. The resulting 211At-AuNPs were first challenged by harsh oxidation with sodium hypochlorite, removing roughly 50% of the attached 211At. Second, incubation in mouse serum followed by a customized stability test, showed a stability of &gt;95% after 4 h in serum. This high stability was further confirmed in an in vivo study, with comparison to a control group of free 211At. The AuNP-associated 211At showed low uptake in stomach and thyroid, which are hallmark organs of uptake of free 211At, combined with long circulation and high liver and spleen uptake, consistent with nanoparticle biodistribution. These results support that gold surface-adsorbed 211At has high biological stability and is a potentially useful delivery system in TAT.

Obstacles and Recommendations for Clinical Translation of Nanoparticle System-Based Targeted Alpha-Particle Therapy.

The rationale for application of nanotechnology in targeted alpha therapy (TAT) is sound. However, the translational strategy requires attention. Formulation of TAT in nanoparticulate drug delivery systems has the potential to resolve many of the issues currently experienced. As α-particle emitters are more cytotoxic compared to beta-minus-emitting agents, the results of poor biodistribution are more dangerous. Formulation in nanotechnology is also suggested to be the ideal solution for containing the recoil daughters emitted by actinium-225, radium-223, and thorium-227. Nanoparticle-based TAT is likely to increase stability, enhance radiation dosimetry profiles, and increase therapeutic efficacy. Unfortunately, nanoparticles have their own unique barriers towards clinical translation. A major obstacle is accumulation in critical organs such as the spleen, liver, and lungs. Furthermore, inflammation, necrosis, reactive oxidative species, and apoptosis are key mechanisms through which nanoparticle-mediated toxicity takes place. It is important at this stage of the technology’s readiness level that focus is shifted to clinical translation. The relative scarcity of α-particle emitters also contributes to slow-moving research in the field of TAT nanotechnology. This review describes approaches and solutions which may overcome obstacles impeding nanoparticle-based TAT and enhance clinical translation. In addition, an in-depth discussion of relevant issues and a view on technical and regulatory barriers are presented.