Intratumoral injection of holmium-166 microspheres as neoadjuvant therapy of soft tissue sarcomas in dogs

Morsink, N.C.; Nijsen, J. Frank W.; Grinwis, Guillaume Cornelis Maria; Hesselink, Jan Willem; Kirpensteijn, Jolle; Nimwegen, S.A. van

doi:10.3389/fvets.2022.1015248

Cited by 2 publications

(1 citation statement)

References 48 publications

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“…Mice are too small to use IA delivery of drugs into tumor vasculature, so direct IT injection was needed for delivery of radioembolics into tumor tissue. It is well known that large particles can be retained in solid tumors after injection ( Rosemurgy et al, 2008 ; Bakker et al, 2017 ; Morsink et al, 2022 ). Mice with orthotopic EO771 tumor were injected IT and imaged 2 h later.…”

Section: Resultsmentioning

confidence: 99%

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

Kauffman

Singh

Morrison³

et al. 2023

Front. Chem.

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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 4 h 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.

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Section: Resultsmentioning

confidence: 99%

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

Kauffman

Singh

Morrison³

et al. 2023

Front. Chem.

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Quantitative CT imaging and radiation-absorbed dose estimations of 166Ho microspheres: paving the way for clinical application

Morsink,

Klaassen,

van de Maat

et al. 2024

Eur Radiol Exp

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Background Microbrachytherapy enables high local tumor doses sparing surrounding tissues by intratumoral injection of radioactive holmium-166 microspheres (166Ho-MS). Magnetic resonance imaging (MRI) cannot properly detect high local Ho-MS concentrations and single-photon emission computed tomography has insufficient resolution. Computed tomography (CT) is quicker and cheaper with high resolution and previously enabled Ho quantification. We aimed to optimize Ho quantification on CT and to implement corresponding dosimetry. Methods Two scanners were calibrated for Ho detection using phantoms and multiple settings. Quantification was evaluated in five phantoms and seven canine patients using subtraction and thresholding including influences of the target tissue, injected amounts, acquisition parameters, and quantification volumes. Radiation-absorbed dose estimation was implemented using a three-dimensional 166Ho specific dose point kernel generated with Monte Carlo simulations. Results CT calibration showed a near-perfect linear relation between radiodensity (HU) and Ho concentrations for all conditions, with differences between scanners. Ho detection during calibration was higher using lower tube voltages, soft-tissue kernels, and without a scanner detection limit. The most accurate Ho recovery in phantoms was 102 ± 11% using a threshold of mean tissue HU + (2 × standard deviation) and in patients 98 ± 31% using a 100 HU threshold. Thresholding allowed better recovery with less variation and dependency on the volume of interest compared to the subtraction of a single HU reference value. Corresponding doses and histograms were successfully generated. Conclusion CT quantification and dosimetry of 166Ho should be considered for further clinical application with on-site validation using radioactive measurements and intra-operative Ho-MS and dose visualizations. Relevance statement Image-guided holmium-166 microbrachytherapy currently lacks reliable quantification and dosimetry on CT to ensure treatment safety and efficacy, while it is the only imaging modality capable of quantifying high in vivo holmium concentrations. Key Points Local injection of 166Ho-MS enables high local tumor doses while sparing surrounding tissue. CT enables imaging-based quantification and radiation-absorbed dose estimation of concentrated Ho in vivo, essential for treatment safety and efficacy. Two different CT scanners and multiple acquisition and reconstruction parameters showed near-perfect linearity between radiodensity and Ho concentration. The most accurate Ho recoveries on CT were 102 ± 11% in five phantoms and 98 ± 31% in seven canine patients using thresholding methods. Dose estimations and volume histograms were successfully implemented for clinical application using a dose point kernel based on Monte Carlo simulations. Graphical Abstract

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Intratumoral injection of holmium-166 microspheres as neoadjuvant therapy of soft tissue sarcomas in dogs

Cited by 2 publications

References 48 publications

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

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

Quantitative CT imaging and radiation-absorbed dose estimations of 166Ho microspheres: paving the way for clinical application

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