Pharm Res (2012) 29:827–836 DOI 10.1007/s11095-011-0610-7 RESEARCH PAPER R a d i o a c t i v e for Interstitial Stability Study H o l m i u m A c e t y l a c e t o n a t e M i c r o s p h e r e s Microbrachytherapy: An In Vitro and In Vivo Wouter Bult & Hendrik de Leeuw & Olav M. Steinebach & Martijn J. van der Bom & Hubert Th. Wolterbeek & Ron M. A. Heeren & Chris J. G. Bakker & Alfred D. van het Schip & Wim E. Hennink & J. Frank W. Nijsen Received: 23 May 2011 / Accepted: 17 October 2011 / Published online: 9 November 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com ABSTRACT Purpose The clinical application of holmium acetylacetonate microspheres (HoAcAcMS) for the intratumoral radionuclide treatment of solid malignancies requires a thorough under- standing 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. W. Bult : A. D. van het Schip : J. F. W. Nijsen (*) Department of Radiology and Nuclear Medicine, UMC Utrecht Utrecht, The Netherlands e-mail: f.nijsen@umcutrecht.nl H. de Leeuw : M. J. van der Bom : C. J. G. Bakker Image Sciences Institute, UMC Utrecht Utrecht, The Netherlands O. M. Steinebach : H. T. Wolterbeek Department of Radiation, Radionuclides and Reactors Section Radiation & Isotopes for Health, Delft University of Technology Delft, The Netherlands KEY WORDS brachytherapy . holmium . in vivo . microspheres . VX2 carcinoma INTRODUCTION Worldwide, cancer is the second cause of death, after cardiovascular diseases (1), and it is estimated that each year over 20 million new cases are presented (2). The majority (over 90%) of these new cases are solid tumors, and each year over 12 million people die from solid tumors (1,2). Traditionally, surgery has been the preferred treat- ment of solid malignancies, since this treatment can be considered curative (3), but, unfortunately, not all tumors are eligible for curative resection. In the 1990s minimally invasive treatment options were proposed as treatment of inoperable solid malignancies, to offer a potentially curative treatment and to reduce the morbidity associated with surgery. These minimally invasive treatments, which are increasingly applied nowadays, include radiofrequency ablation (4), high intensity focused ultrasound (5) and local administration of radionuclides (6,7). With respect to the R. M. A. Heeren FOM institute for Atomic and Molecular Physics Amsterdam, The Netherlands W. E. Hennink Department of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences Utrecht University Utrecht, The Netherlands