Targeted alpha-particle therapy using radionuclides with alpha emission is a rapidly developing area in modern cancer treatment. To selectively deliver alpha-emitting isotopes to tumors, targeting vectors, including monoclonal antibodies, peptides, small molecule inhibitors, or other biomolecules, are attached to them, which ensures specific binding to tumor-related antigens and cell surface receptors. Although earlier studies have already demonstrated the anti-tumor potential of alpha-emitting radium (Ra) isotopes—Radium-223 and Radium-224 (^223/224Ra)—in the treatment of skeletal metastases, their inability to complex with target-specific moieties hindered application beyond bone targeting. To exploit the therapeutic gains of Ra across a wider spectrum of cancers, nanoparticles have recently been embraced as carriers to ensure the linkage of ^223/224Ra to target-affine vectors. Exemplified by prior findings, Ra was successfully bound to several nano/microparticles, including lanthanum phosphate, nanozeolites, barium sulfate, hydroxyapatite, calcium carbonate, gypsum, celestine, or liposomes. Despite the lengthened tumor retention and the related improvement in the radiotherapeutic effect of ^223/224Ra coupled to nanoparticles, the in vivo assessment of the radiolabeled nanoprobes is a prerequisite prior to clinical usage. For this purpose, experimental xenotransplant models of different cancers provide a well-suited scenario. Herein, we summarize the latest achievements with ^223/224Ra-doped nanoparticles and related advances in targeted alpha radiotherapy.

Among humanized monoclonal antibodies, bevacizumab specifically binds to vascular endothelial growth factor A (VEGF-A). VEGF-A is an overexpressed biomarker in cervix carcinoma and is involved in the development and maintenance of tumor-associated neo-angiogenesis. The non-invasive positron emission tomography using radiolabeled target-specific antibodies (immuno-PET) provides the longitudinal and quantitative assessment of tumor target expression. Due to antibodies having a long-circulating time, radioactive metal ions (e.g., ⁵²Mn) with longer half-lives are the best candidates for isotope conjugation. The aim of our preclinical study was to assess the biodistribution and tumor-targeting potential of ⁵²Mn-labeled DOTAGA-bevacizumab. The VEGF-A targeting potential of the new immuno-PET ligand was assessed by using the VEGF-A expressing KB-3-1 (human cervix carcinoma) tumor-bearing CB17 SCID mouse model and in vivo PET/MRI imaging. Due to the high and specific accumulation found in the subcutaneously located experimental cervix carcinoma tumors, [⁵²Mn]Mn-DOTAGA-bevacizumab is a promising PET probe for the detection of VEGF-A positive gynecological tumors, for patient selection, and monitoring the efficacy of therapies targeting angiogenesis.

Osteosarcoma is a frequent and extremely aggressive type of pediatric cancer. New therapeutic approaches are needed to improve the overall survival of osteosarcoma patients. Our previous results suggest that NMNAT1, a key enzyme in nuclear NAD⁺ synthesis, facilitates the survival of cisplatin-treated osteosarcoma cells. A high-throughput cytotoxicity screening was performed to identify novel pathways or compounds linked to the cancer-promoting role of NMNAT1. Nine compounds caused higher toxicity in the NMNAT1 KO U2OS cells compared to their wild type counterparts, and actinomycin D (ActD) was the most potent. ActD-treatment of NMNAT1 KO cells increased caspase activity and secondary necrosis. The reduced NAD⁺ content in NMNAT1 KO cells was further decreased by ActD, which partially inhibited NAD⁺-dependent enzymes, including the DNA nick sensor enzyme PARP1 and the NAD⁺-dependent deacetylase SIRT1. Impaired PARP1 activity increased DNA damage in ActD-treated NMNAT1 knockout cells, while SIRT1 impairment increased acetylation of the p53 protein, causing the upregulation of pro-apoptotic proteins (NOXA, BAX). Proliferation was decreased through both PARP- and SIRT-dependent pathways. On the one hand, PARP inhibitors sensitized wild type but not NMNAT1 KO cells to ActD-induced anti-clonogenic effects; on the other hand, over-acetylated p53 induced the expression of the anti-proliferative p21 protein leading to cell cycle arrest. Based on our results, NMNAT1 acts as a survival factor in ActD-treated osteosarcoma cells. By inhibiting both PARP1- and SIRT1-dependent cellular pathways, NMNAT1 inhibition can be a promising new tool in osteosarcoma chemotherapy.

The cornerstone of ovarian cancer treatment is complete surgical cytoreduction. The gold-standard option in the absence of extra-abdominal metastases and intra-abdominal inoperable circumstances is primary cytoreductive surgery (CRS). However, achieving complete cytoreduction is challenging, and only possible in a selected patient population. Preoperative imaging modalities such as [¹⁸F]FDG PET/CT could be useful in patient selection for cytoreductive surgery. In our systematic review and meta-analysis, we aimed to evaluate the role of preoperative [¹⁸F]FDG PET/CT in predicting complete cytoreduction in primary and secondary debulking surgeries. Publications were pooled from two databases (PubMed, Mendeley) with predefined keywords “(ovarian cancer) AND (FDG OR PET) AND (cytoreductive surgery)”. The quality of the included studies was assessed with the Prediction model Risk Of Bias Assessment Tool (PROBAST). During statistical analysis, MetaDiSc 1.4 software and the DerSimonian–Laird method (random effects models) were used. Primary and secondary cytoreductive surgeries were evaluated. Pooled sensitivities, specificities, positive predictive values (PPVs), and negative predictive values (NPVs) were calculated and statistically analyzed. Results were presented in forest plot diagrams and summary receiver operating characteristic (SROC) curves. Overall, eight publications were included in our meta-analysis. Four publications presented results of primary, three presented results of secondary cytoreductions, and two presented data related to both primary and secondary surgery. Pooled sensitivities, specificities, and positive and negative predictive values were the following: in the case of primary surgeries: 0.65 (95% CI 0.60–0.71), 0.73 (95% CI 0.66–0.80), 0.82 (95% CI 0.77–0.87), 0.52 (95% CI 0.46–0.59); and in the case of secondary surgeries: 0.91 (95% CI 0.84–0.95), 0.48 (95% CI 0.30–0.67), 0.88 (95% CI 0.81–0.93), 0.56 (95% CI 0.35–0.75), respectively. The PPVs of [¹⁸F]FDG PET/CT proved to be higher in cases of secondary debulking surgeries; therefore, it can be a valuable predictor of complete successful secondary cytoreduction.

Background/Objectives: Artificial intelligence (AI) is a promising tool for the enhancement of physician workflow and serves to further improve the efficiency of their diagnostic evaluations. This study aimed to assess the performance of an AI-based bone scan noise-reduction filter on noisy, low-count images in a routine clinical environment. Methods: The performance of the AI bone-scan filter (BS-AI filter) in question was retrospectively evaluated on 47 different patients’ ^99mTc-MDP bone scintigraphy image pairs (anterior- and posterior-view images), which were obtained in such a manner as to represent the diverse characteristics of the general patient population. The BS-AI filter was tested on artificially degraded noisy images—75, 50, and 25% of total counts—which were generated by binominal sampling. The AI-filtered and unfiltered images were concurrently appraised for image quality and contrast by three nuclear medicine physicians. It was also determined whether there was any difference between the lesions seen on the unfiltered and filtered images. For quantitative analysis, an automatic lesion detector (BS-AI annotator) was utilized as a segmentation algorithm. The total number of lesions and their locations as detected by the BS-AI annotator in the BS-AI-filtered low-count images was compared to the total-count filtered images. The total number of pixels labeled as lesions in the filtered low-count images in relation to the number of pixels in the total-count filtered images was also compared to ensure the filtering process did not change lesion sizes significantly. The comparison of pixel numbers was performed using the reduced-count filtered images that contained only those lesions that were detected in the total-count images. Results: Based on visual assessment, observers agreed that image contrast and quality were better in the BS-AI-filtered images, increasing their diagnostic confidence. Similarities in lesion numbers and sites detected by the BS-AI annotator compared to filtered total-count images were 89%, 83%, and 75% for images degraded to counts of 75%, 50%, and 25%, respectively. No significant difference was found in the number of annotated pixels between filtered images with different counts (p > 0.05). Conclusions: Our findings indicate that the BS-AI noise-reduction filter enhances image quality and contrast without loss of vital information. The implementation of this filter in routine diagnostic procedures reliably improves diagnostic confidence in low-count images and elicits a reduction in the administered dose or acquisition time by a minimum of 50% relative to the original dose or acquisition time.

Melanocortin-1 receptor (MC1-R) targeting alpha-melanocyte stimulating hormone-analogue (α-MSH) biomolecules labelled with α-emitting radiometal seem to be valuable in the targeted radionuclide therapy of MC1-R positive melanoma malignum (MM). Herein is reported the anti-tumor in vivo therapeutic evaluation of MC1-R-affine [²¹³Bi]Bi-DOTA-NAPamide and HOLDamide treatment in MC1-R positive B16-F10 melanoma tumor-bearing C57BL/6J mice. On the 6^th, 8^th and 10^th days post tumor cell inoculation; the treated groups of mice were intravenously injected with approximately 5 MBq of both amide derivatives. Beyond body weight and tumor volume assessment, [⁶⁸Ga]Ga-DOTA-HOLDamide and NAPamide-based PET/MRI scans, and ex vivo biodistribution studies were executed 30,- and 90 minutes postinjection. In the PET/MRI imaging studies the B16-F10 tumors were clearly visualized with both ⁶⁸Ga-labelled tracers, however, significantly lower tumor-to-muscle (T/M) ratios were observed by using [⁶⁸Ga]Ga-DOTA-HOLDamide. After alpha-radiotherapy treatment the tumor size of the control group was larger relative to both treated cohorts, while the smallest tumor volumes were observed in the NAPamide-treated subclass on the 10^th day. Relatively higher [²¹³Bi]Bi-DOTA-NAPamide accumulation in the B16-F10 tumors (%ID/g: 2.71±0.15) with discrete background activity led to excellent T/M ratios, particularly 90 minutes postinjection. Overall, the therapeutic application of receptor selective [²¹³Bi]Bi-DOTA-NAPamide seems to be feasible in MC1-R positive MM management.