Radioactive Holmium Acetylacetonate Microspheres for Interstitial Microbrachytherapy: An In Vitro and In Vivo Stability Study

Purpose The clinical application of holmium acetylacetonate microspheres (HoAcAcMS) for the intratumoral radionuclide treatment of solid malignancies requires a thorough understanding of their stability. Therefore, an in vitro and an in vivo stability study with HoAcAcMS was conducted. Methods HoAcAcMS, before and after neutron irradiation, were incubated in a phosphate buffer at 37°C for 6 months. The in vitro release of holmium in this buffer after 6 months was 0.5%. Elemental analysis, scanning electron microscopy, infrared spectroscopy and time of flight secondary ion mass spectrometry were performed on the HoAcAcMS. Results After 4 days in buffer the acetylacetonate ligands were replaced by phosphate, without altering the particle size and surface morphology. HoAcAcMS before and after neutron irradiation were administered intratumorally in VX2 tumor-bearing rabbits. No holmium was detected in the faeces, urine, femur and blood. Histological examination of the tumor revealed clusters of intact microspheres amidst necrotic tissue after 30 days. Conclusion HoAcAcMS are stable both in vitro and in vivo and are suitable for intratumoral radionuclide treatment.Radiation, Radionuclides and ReactorsApplied Science

Holmium Nanoparticles: Preparation and In Vitro Characterization of a New Device for Radioablation of Solid Malignancies

# The Author(s) 2010. This article is published with open access at Springerlink.com Purpose The present study introduces the preparation and in vitro characterization of a nanoparticle device comprising holmium acetylacetonate for radioablation of unresectable solid malignancies. Methods HoAcAc nanoparticles were prepared by dissolving holmium acetylacetonate in chloroform, followed by emulsification in an aqueous solution of a surfactant and evaporation of W. Bult: R. Varkevisser: P. R. Luijten: A. D. van het Schip

Long-term toxicity of holmium-loaded poly(L-lactic acid) microspheres in rats

The aim of this study was to get insight into the toxic effects of holmium-166-loaded poly(L-lactic acid) microspheres (Ho-PLLA-MS) which have very interesting features for treatment of liver malignancies. Acute, mid- and long-term effects were studied in healthy Wistar rats by evaluating clinical, biochemical and tissue response. Rats were divided into four treatment groups: sham, decayed neutron-irradiated Ho-PLLA-MS, non-irradiated Ho-PLLA-MS and PLLA-MS. After implantation of the microspheres into the liver of the rats, the animals were monitored (body weight, temperature and liver enzymes) for a period of 14-18 months. Some of the rats that received previously neutron-irradiated Ho-PLLA-MS were periodically scanned with magnetic resonance imaging (MRI) to see if holmium was released from the microspheres. After sacrification, the liver tissue was histologically evaluated. Bone tissue was subjected to neutron-activation analysis in order to examine whether accumulation of released holmium in the bone had occurred. No measurable clinical and biochemical toxic effects were observed in any of the treatment groups. Furthermore, histological analyses of liver tissue samples only showed signs of a slight chronic inflammation and no significant differences in the tissue reaction between rats of the different treatment groups could be observed. The non-irradiated PLLA-MS and Ho-PLLA-MS stayed intact during the study. In contrast, 14 months after administration, the neutron-irradiated Ho-PLLA-MS was not completely spherical anymore, indicating that degradation had started. However, the holmium loading had not been released as was illustrated with MRI and affirmed by neutron-activation analysis of bone tissue. In conclusion, neutron-irradiated Ho-PLLA-MS does not provoke any toxic reaction and can be applied safely in vivo. (c) 2007 Elsevier Ltd. All rights reserved

Intratumoral injection of ¹⁶⁶HoAcAcMS is an effective, minimally invasive procedure in kindney cancer.

<p>(<b>A</b>) Tumor volume at different time points after treatment. The solid line represents the tumor volume of the ¹⁶⁶HoAcAcMS group. The dashed line represents the tumor volume of the saline control group. (<b>B</b>) HE staining of kidney and tumor tissue 2 weeks after ¹⁶⁶HoAcAcMS treatment (n indicates normal kidney, t indicates tumor.) (<b>C</b>) HE staining (20×) of renal parenchyma outside the radiated region 2 weeks following ¹⁶⁶HoAcAcMS administration, showing no glomerular, tubular or vascular alterations. (<b>D</b>) HE staining (20×) of irradiated tumor 1 day following ¹⁶⁶HoAcAcMS administration. HoAcAcMS are present as focal intratumoral deposits (arrows). At the site of injection, tumor necrosis and cell death is visible. (<b>E</b>) HE staining of irradiated tumor (20×) 2 days following ¹⁶⁶HoAcAcMS administration. Inflammatory cells are present at the radiated area. (<b>F</b>) HE staining of irradiated tumor (20×) 1 week after ¹⁶⁶HoAcAcMS administration. Grade 3 radiation damage <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052178#pone.0052178-Forrer1" target="_blank">[27]</a> is only visible in renal parenchyma directly surrounding the tumor.</p