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Purpose: Targeted radionuclide therapy (TRT) is a cancer treatment with relative therapeutic efficacy across various cancer types. We studied the therapeutic potential of TRT using fibroblast activation protein-α (FAP) targeting sdAbs (4AH29) labelled with 225 Ac or 131 I in immunocompetent mice in a human FAP (hFAP) expressing lung cancer mouse model. We further explored the combination of TRT with programmed cell death ligand 1 (PD-L1) immune checkpoint blockade (ICB)., Methods: We studied the biodistribution and tumour uptake of [ 131 I]I-GMIB-4AH29 and [ 225 Ac]Ac-DOTA-4AH29 by ex vivo γ-counting. Therapeutic efficacy of [ 131 I]I-GMIB-4AH29 and [ 225 Ac]Ac-DOTA-4AH29 was evaluated in an immunocompetent mouse model. Flow cytometry analysis of tumours from [ 225 Ac]Ac-DOTA-4AH29 treated mice was performed. Treatment with [ 225 Ac]Ac-DOTA-4AH29 was repeated in combination with PD-L1 ICB., Results: The biodistribution showed high tumour uptake of [ 131 I]I-GMIB-4AH29 with 3.5 ± 0.5% IA/g 1 h post-injection (p.i.) decreasing to 0.9 ± 0.1% IA/g after 24 h. Tumour uptake of [ 225 Ac]Ac-DOTA-4AH29 was also relevant with 2.1 ± 0.5% IA/g 1 h p.i. with a less steep decrease to 1.7 ± 0.2% IA/g after 24 h. Survival was significantly improved after treatment with low and high doses [ 131 I]I-GMIB-4AH29 or [ 225 Ac]Ac-DOTA-4AH29 compared to vehicle solution. Moreover, we observed significantly higher PD-L1 expression in tumours of mice treated with [ 225 Ac]Ac-DOTA-4AH29 compared to vehicle solution. Therefore, we combined high dose [ 225 Ac]Ac-DOTA-4AH29 with PD-L1 ICB showing therapeutic synergy., Conclusion: [ 225 Ac]Ac-DOTA-4AH29 and [ 131 I]I-GMIB-4AH29 exhibit high and persistent tumour targeting, translating into prolonged survival in mice bearing aggressive tumours. Moreover, we demonstrate that the combination of PD-L1 ICB with [ 225 Ac]Ac-DOTA-4AH29 TRT enhances its therapeutic efficacy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Fibroblast activation protein α (FAP) is highly expressed on cancer-associated fibroblasts of epithelial-derived cancers. Breast, colon, and pancreatic tumors often show strong desmoplastic reactions, which result in a dominant presence of stromal cells. FAP has gained interest as a target for molecular imaging and targeted therapies. Single-domain antibodies (sdAbs) are the smallest antibody-derived fragments with beneficial pharmacokinetic properties for molecular imaging and targeted therapy. Methods: We describe the generation, selection, and characterization of a sdAb against FAP. In mice, we assessed its imaging and therapeutic potential after radiolabeling with tracer-dose 131 I and 68 Ga for SPECT and PET imaging, respectively, and with 131 I and 225 Ac for targeted radionuclide therapy. Results: The lead sdAb, 4AH29, exhibiting picomolar affinity for a distinct FAP epitope, recognized both purified and membrane-bound FAP protein. Radiolabeled versions, including [ 68 Ga]Ga-DOTA-4AH29, [ 225 Ac]Ac-DOTA-4AH29, and [ 131 I]I-guanidinomethyl iodobenzoate (GMIB)-4AH29, displayed radiochemical purities exceeding 95% and effectively bound to recombinant human FAP protein and FAP-positive GM05389 human fibroblasts. These radiolabeled compounds exhibited rapid and specific accumulation in human FAP-positive U87-MG glioblastoma tumors, with low but specific uptake in lymph nodes, uterus, bone, and skin (∼2-3 percentage injected activity per gram of tissue [%IA/g]). Kidney clearance of unbound [ 131 I]I-GMIB-4AH29 was fast (<1 %IA/g after 24 h), whereas [ 225 Ac]Ac-DOTA-4AH29 exhibited slower clearance (8.07 ± 1.39 %IA/g after 24 h and 2.47 ± 0.18 %IA/g after 96 h). Mice treated with [ 225 Ac]Ac-DOTA-4AH29 and [ 131 I]I-GMIB-4AH29 demonstrated prolonged survival compared with those receiving vehicle solution. Conclusion: [ 68 Ga]Ga-DOTA-4AH29 and [ 131 I]I-GMIB-4AH29 enable precise FAP-positive tumor detection in mice. Therapeutic [ 225 Ac]Ac-DOTA-4AH29 and [ 131 I]I-GMIB-4AH29 exhibit strong and sustained tumor targeting, resulting in dose-dependent therapeutic effects in FAP-positive tumor-bearing mice, albeit with kidney toxicity observed later for [ 225 Ac]Ac-DOTA-4AH29. This study confirms the potential of radiolabeled sdAb 4AH29 as a radiotheranostic agent for FAP-positive cancers, warranting clinical evaluation., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Despite the growing interest in radioiodine and 211 At-labeled radiopharmaceuticals, the search for radiolabeling reactions has been somewhat neglected, resulting in a limited number of available radiosynthetic strategies. Herein we report a comparative study of nucleophilic 125 I and 211 At-labeling of aryliodonium ylides. Whereas radioiodination efficiency was low, 211 At-labeling performed efficiently on a broad scope of precursors. The most activated aryliodonium ylides led rapidly to quantitative reactions at room temperature in acetonitrile. For deactivated precursors, heating up to 90 °C in glyme and addition of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as radical scavenger appeared essential to avoid precursor degradation and to achieve high radiochemical yields and molar activity. The approach was applied successfully to the preparation of 4-[ 211 At]astatophenylalanine (4-APA), an amino acid derivative increasingly studied as radiotherapeutic drug for cancers. This validated aryliodonium ylides as a valuable tool for nucleophilic 211 At-labeling and will complement the short but now growing list of available astatination reactions., (© 2021 Wiley-VCH GmbH.)

Administration of diethylenetriaminepentaacetic acid (DTPA) is the treatment approach used to promote the decorporation of internalized plutonium. Here we evaluated the efficacy of PEGylated liposomes coated with DTPA, primarily designed to prevent enhanced plutonium accumulation in bones, compared to marketed nonliposomal DTPA and liposomes encapsulating DTPA. The comparative effects were examined in terms of reduction of activity in tissues of plutonium-injected rats. The prompt treatment with DTPA-coated liposomes elicited an even greater efficacy than that with liposome-encapsulated DTPA in limiting skeletal plutonium. This advantage, undoubtedly due to the anchorage of DTPA to the outer layer of liposomes, is discussed, as well as the reason for the loss of this superiority at delayed times after contamination. Plutonium complexed with DTPA-coated liposomes in extracellular compartments was partly diverted into the liver and the spleen. These complexes and those directly formed inside hepatic and splenic cells appeared to be degraded, then released from cells at extremely slow rates. This transitory accumulation of activity, which could not be counteracted by combining both liposomal forms, entailed an underestimation of the efficacy of DTPA-coated liposomes on soft tissue plutonium until total elimination probably more than one month after treatment. DTPA-coated liposomes may provide the best delivery vehicle of DTPA for preventing plutonium deposition in tissues, especially in bone where nuclides become nearly impossible to remove once fixed. Additional development efforts are needed to limit the diversion or to accelerate cell release of plutonium bound to DTPA-coated liposomes, using a labile bond for DTPA attachment., (©2021 by Radiation Research Society. All rights of reproduction in any form reserved.)

Easy access to radioiodinated and 211 At-labelled bio(macro)molecules is essential to develop new strategies in nuclear imaging and targeted radionuclide therapy of cancers. Yet, the labelling of complex molecules with heavy radiohalogens is often poorly effective due to the multiple steps and intermediate purifications needed. Herein, we investigate the potential of arylboron chemistry as an alternative approach for the late stage labelling of antibodies. The reactivity of a model precursor, 4-chlorobenzeneboronic acid ( 1 ) with nucleophilic iodine-125 and astatine-211 was at first investigated in aqueous conditions. In the presence of a copper(ii) catalyst and 1,10-phenanthroline, quantitative radiochemical yields (RCYs) were achieved within 30 minutes at room temperature. The optimum conditions were then applied to a CD138 targeting monoclonal antibody (mAb) that has previously been validated for imaging and therapy in a preclinical model of multiple myeloma. RCYs remained high (>80% for 125 I-labelling and >95% for 211 At-labelling), and the whole procedure led to increased specific activities within less time in comparison with previously reported methods. Biodistribution study in mice indicated that targeting properties of the radiolabelled mAb were well preserved, leading to a high tumour uptake in a CD138 expressing tumour model. The possibility of divergent synthesis from a common modified carrier protein demonstrated herein opens facilitated perspectives in radiotheranostic applications with the radioiodine/ 211 At pairs. Overall, the possibility to develop radiolabelling kits offered by this procedure should facilitate its translation to clinical applications., Competing Interests: The authors declare the following competing financial interest: M. B., A. F.-C., J.-F. G. and F. G. have filed a provisional patent application relating to this work., (This journal is © The Royal Society of Chemistry.)

The contribution of genetic variation to phenotypes is a central factor in whether and how populations respond to selection. The most common approach to estimating these influences is via the calculation of heritabilities, which summarize the contribution of genetic variation to phenotypic variation. Heritabilities also indicate the relative effect of genetic variation on phenotypes versus that of environmental sources of variation. For labile traits like behavioral responses, life history traits, and physiological responses, estimation of heritabilities is important as these traits are strongly influenced by the environment. Thus, knowing whether or not genetic variation is present within populations is necessary to understand whether or not these populations can evolve in response to selection. Here we report the results of a meta-analysis summarizing what we currently know about the heritability of behavior. Using phylogenetically controlled methods we assessed the average heritability of behavior (0.235)-which is similar to that reported in previous analyses of physiological and life history traits-and examined differences among taxa, behavioral classifications, and other biologically relevant factors. We found that there was considerable variation among behaviors as to how heritable they were, with migratory behaviors being the most heritable. Interestingly, we found no effect of phylogeny on estimates of heritability. These results suggest, first, that behavior may not be particularly unique in the degree to which it is influenced by factors other than genetics and, second, that those factors influencing whether a behavioral trait will have low or high heritability require further consideration., (© The American Genetic Association 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

125 I- and 211 At-labeled azide and tetrazine based prosthetic groups for bioorthogonal conjugation were designed and tested in a comparative study of five bioorthogonal systems. All five bioconjugation reactions conducted on a model clickable peptide led to quantitative yields within less than a minute to several hours depending on the system used. Transferability to the labeling of an IgG was demonstrated with one of the bioorthogonal system. This study provides several new alternatives to the conventional and suboptimal approach currently in use for radioiodination and astatination of biomolecules and should accelerate the development of new probes with these radionuclides for applications in nuclear imaging and targeted alpha-therapy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Impaired wound healing is a frequent problem in diabetes. Hyperglycemia may be an operative mechanism, but a link between glycemic control and wound healing has never been established. Wounds in db/db mice have been extensively studied. This study was undertaken to see if plasma glucose was a predictor of wound healing. An excisional wound was made (149 db/db mice). Wound closure was studied versus metabolic variables. The animals were 11.8 ± 0.2 weeks (mean ± standard error of the mean), obese (38.1 ± 0.5 g), and hyperglycemic (fasting plasma glucose 21.0 ± 0.7 mmol/L). Wound closure at day 13 was 30.1 ± 1.6%. In linear mixed model analyses neither fasting plasma glucose nor its change from start to end of experiment was a significant predictor of wound closure (β = 0.15, P = 0.07, 95% CI: -0.01 to 0.31 and β = 0.06, P = 0.5, 95% CI: -0.11 to 0.23, resp.). However, increase in body weight significantly and independently predicted wound closure (for weight change, β = 0.22, P = 0.008, 95% CI: 0.06 to 0.38). This study strongly suggests that wound healing in db/db mice is independent of prevailing glycemia but dependent on anabolic changes such as weight gain over time.

Inflammatory responses are common in diabetes and are operative in angiopathy, neuropathy, and wound healing. There are indications of incomplete macrophage activation in diabetes and reduced expression of growth factors. We have previously found that up to 15 topical applications of the macrophage-stimulant, aminated β-1,3-D-glucan (AG), improved wound healing in db/db mice. The present open-label study was undertaken to examine dose-dependent effects of AG over 40 days in db/db mice. AG was given as a single dose (group 1), one dose every 10th day (group 2), five initial doses on consecutive days (group 3), and ≥15 doses (group 4). Controls were db/db mice receiving platelet-derived growth factor + insulin-like growth factor-1 (group 5), topical placebo (NaCl 9 mg/mL) and insulin (group 6), placebo (group 7), and a nondiabetic group receiving placebo (group 8). Seven to 14 animals were allocated to each group. Percentage wound closure 17 days after surgery in groups 1 and 2 were (mean ± standard error of the mean) 25.5 ± 5.3 and 32.2 ± 6.3, respectively. Corresponding closure in groups 3, 4, and 5 was 55.7 ± 5.0, 57.3 ± 5.0, and 55.6 ± 4.8, respectively (p < 0.05 vs. groups 1 and 2). Groups 6, 7, and 8 closed 32.0 ± 4.5, 38.2 ± 5.3, and 98.5 ± 0.4%, respectively. Significant association between the number of AG-dosages and wound closure indicates dose-related effects in db/db mice., (© 2011 by the Wound Healing Society.)