Preclinical safety assessment of holmium-based microspheres for micro-brachytherapy in mice

Abstract

INTRODUCTION: Holmium-166 microspheres are suitable for micro-brachytherapy for various solid tumours, due to their favourable characteristics regarding treatment and imaging. The purpose of this study was to investigate acute- to long-term toxicity, 3 days to 12 months, biodegradation and in vivo holmium release of two types of holmium-based microspheres, containing poly (L-lactic acid) (Ho-PLLA-MS) or hydroxide (Ho-(OH) 3-MS), homogeneously suspended in an injection fluid comprised by colloidal microcrystalline cellulose (MCC) and phosphate buffer in healthy mice. METHODS: 250 mice were included in the study. Non-radioactive holmium-165 microsphere suspensions, were injected subcutaneously on the flank of 150 mice, animals were intensively monitored. CT imaging was performed to visualise the location of the injection site, the distribution of the microspheres and the injection fluid and their possible translocation. Injection site and other relevant tissues were assessed histologically and possible holmium leakage or microsphere migration was examined by analysing the holmium content in the injection site and relevant tissues via inductively coupled plasma analysis (ICP). RESULTS: The injection of holmium-165 microspheres suspended in MCC-based injection fluid caused local inflammation ranging from slight to severe. No relevant deviations in haematological or biochemical parameters indicative for acute or chronic systemic toxicity were observed. ICP analysis and CT imaging showed no signs of microsphere translocation from the injection site to other organs. CONCLUSION: These findings indicate that the injection fluid (MCC in phosphate buffer) in combination with Ho-(OH) 3-MS or Ho-PLLA-MS can potentially be used as administration fluid for controlled localized microsphere delivery. However, prior to clinical application, clinically relevant doses have to be tested in sensitive anatomical regions.