Biology subjects

de Vries, E. F. J.

Publications and source records attributed to de Vries, E. F. J..

3 recordsLinked to original sources

bioRxiv2026

Italia: A PARP-Directed Auger Electron-Emitting Agent for Targeted Radionuclide Therapy of Cancer

Poly(ADP-ribose) polymerase 1 (PARP1) is a central mediator of DNA damage repair and an established therapeutic target in homologous recombination-deficient cancers. Radiolabelled PARP inhibitors provide a strategy to deliver cytotoxic radiation directly to tumour DNA by exploiting PARP overexpression and trapping at sites of DNA damage. Here, we describe the design, radiosynthesis, and in vitro evaluation of [123I]Italia, a talazoparib-derived Auger electron-emitting agent for PARP-targeted radionuclide therapy. Stereochemically pure [123I]Italia, (8S,9R)-5-fluoro-8-(4-(iodo-123I)phenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one was synthesised in one step via copper-mediated iodo-deboronation, achieving activity yields >80% and molar activities >6.2 {+/-} 3.1 GBq/{micro}mol (n=8). UPLC analysis confirmed radiochemical purity >97%. Italia exhibited potent PARP1 inhibition (IC50 0.48 nM) and in silico predicted binding affinity comparable to talazoparib. In a panel of PARP-expressing cancer cell lines, [123I]Italia demonstrated highest uptake at 60 min, PARP-selective uptake, predominant nuclear localisation (up to 60% of added activity) and chromatin association consistent with PARP trapping (up to 15% of total activity recorded). Uptake was reduced more than 50-fold by addition of an excess of any PARP inhibitor (e.g. olaparib, talazoparib, and rucaparib) and in PARP1 knockout cells, confirming target specificity. Clonogenic assays showed a marked, added activity-dependent reduction in survival of PARP-expressing cells following a brief one-hour exposure, whereas PARP1-deficient cells were resistant. Collectively, these findings identify [123I]Italia as a promising PARP-targeted Auger electron-emitting theranostic candidate that warrants further in vivo evaluation.

cancer biology↗

bioRxiv2025

Apomorphine susceptibility and prenatal infection alter neurodevelopment, synaptic density and anticipatory behavior in rats

Schizophrenia is a complex psychiatric disorder, driven by genetic and environmental factors. While individual risk genes have limited impact, polygenic susceptibility increases the likelihood of schizophrenia and heightens sensitivity to environmental stressors, such as prenatal immune activation. Yet, preclinical studies often focused on single-gene mutations, leaving polygenic influences largely unexplored. Using the apomorphine-susceptible (APO-SUS) rat model, which exhibits schizophrenia-like features, we investigated how polygenic susceptibility influences early neurodevelopment, synaptic density, and behavior, and how these effects are modulated by prenatal immune activation. APO-SUS rats demonstrated early neurodevelopmental abnormalities, including a reduced number and duration of separation-induced ultrasonic vocalizations (USVs), increased principal frequency of USVs, and reduced heart rate variability (HRV), indicative of heightened sympathetic dominance commonly seen in psychiatric disorders. These effects were particularly pronounced in females. Male APO-SUS rats exhibited elevated synaptophysin levels, a presynaptic marker for synaptic density, in the frontal cortex during adolescence and in the hippocampus during adulthood. Interestingly, prenatal immune activation counteracted some of these changes, preventing HRV reduction and normalizing synaptophysin levels. Male and female APO-SUS rats, as well as Wistar male rats exposed to prenatal immune activation, showed anticipatory behavior during adolescence, but not in adulthood. Our results suggest that polygenic susceptibility induces early neurodevelopmental changes and that genetic and environmental risk factors do not always act synergistically; sometimes counterbalancing each other. Future studies should explore how early neurodevelopmental changes, such as alterations in USVs and HRV, influence later behavioral outcomes in polygenic models of schizophrenia. HighlightsO_LIApomorphine-susceptible rats show altered vocalizations and heart rate variability C_LIO_LIApomorphine susceptibility increases synaptophysin in frontal cortex and hippocampus C_LIO_LIPrenatal immune activation reduces synaptophysin in the adult frontal cortex C_LIO_LIPrenatal immune activation prevents apomorphine-susceptible brain and behavior changes C_LI

animal behavior and cognition↗

bioRxiv2024

Head-to-head comparison of nuclear imaging approaches to quantify tumor CD8+ T-cell infiltration

Many immunotherapies focus on (re)invigorating CD8+ T cell anti-cancer responses and different nuclear imaging techniques have been developed to measure CD8+ T cell distributions. In vivo labeling approaches using radiotracers primarily show CD8+ T cell distributions, while ex vivo labeled CD8+ T cells can show CD8+ T cell migration patterns, homing, and tumor infiltration. Currently, a comprehensive head-to-head comparison of in vivo and ex-vivo cell labeling with respect to their tumor and normal tissue targeting properties and correlation to the presence of CD8+ T cells is lacking, yet essential for correct interpretation of clinical CD8+ imaging applications. Therefore, we performed a head-to-head comparison of three different CD8+ T cell imaging approaches: 1) 89Zr-labeled DFO-conjugated Fc-silent anti-CD8 antibody ([89Zr]Zr-anti-CD8-IgG2asilent), 2) ex vivo 89Zr-oxine labeled ovalbumin-specific CD8+ T cells ([89Zr]Zr-OT-I cells), and 3) 18F-labeled IL2 ([18F]AlF-RESCA-IL2). MethodsB16F10/OVA tumor-bearing C57BL/6 mice (n=10/group) received intravenously one of the three radiopharmaceuticals. PET/CT images were acquired starting 72 h ([89Zr]Zr-anti-CD8-IgG2asilent), 24 and 48 h ([89Zr]Zr-OT-I cells), and 10 min ([18F]AlF-RESCA-IL2) post injection. Subsequently, ex vivo biodistribution analysis of the radiopharmaceuticals was performed followed by flow cytometric analysis to evaluate the number of intratumoral CD8+ T cells. Additionally, the intratumoral radiolabel distributions was assessed by autoradiography and immunohistochemistry (IHC) on tumor slices. Results[89Zr]Zr-anti-CD8-IgG2asilent, [89Zr]Zr-OT-I cells, and [18F]AlF-RESCA-IL2 showed uptake in CD8-rich tissues, with preferential targeting to the spleen. Biodistribution analysis showed tumor uptake above blood level for all radiopharmaceuticals, except [18F]AlF-RESCA-IL2. For all three approaches, the uptake in the tumor-draining lymph node was significantly higher compared with the contralateral axial lymph node, suggesting that all approaches allow evaluation of immune responses involving CD8+ T cells. Tumor uptake of [89Zr]Zr-anti-CD8-IgG2asilent (R2=0.65, p<0.01) and [89Zr]Zr-OT-I cells (R2=0.74, p<0.01) correlated to the number of intratumoral CD8+ T cells (flow cytometry). The intratumoral distribution pattern of the radiosignal was different for ex vivo and in vivo radiolabeling techniques. The short half-life of 18F precluded autoradiography assessment of [18F]AlF-RESCA-IL2. ConclusionWe show that [89Zr]Zr-anti-CD8-IgG2asilent and [89Zr]Zr-OT-I cells PET/CT imaging can be used to evaluate intratumoral CD8+ T cells, even though their normal tissues and intratumoral distribution patterns are significantly different. Based on their characteristics, [89Zr]Zr-anti-CD8-IgG2asilent might be most useful to immunophenotyping the TME, while the ex vivo cell labeling approach visualizes CD8+ T cell migrations patterns and the permissiveness of tumors for invasion, whereas [18F]AlF-RESCA-IL2 allows for rapid recurrent imaging and might prove useful for tracking rapid changes in CD8+ T cell distributions. In conclusion, our head-to-head comparison of the three prototype CD8+ T cell labeling approaches provides new insights which can aid in correct interpretation of clinical CD8 imaging and may guide in the selection of the optimal imaging approach for the research question of interest.

immunology↗