Holmium microparticles for intratumoral radioablation

Abstract

The aim of this dissertation is to describe the preparation and characterization of a holmium-loaded radioablation device: holmium acetylacetonate microspheres (HoAcAcMS). This device is to be injected directly into unresectable, chemorefractory, solid tumors, a technique referred to as (interstitial) brachytherapy. The element holmium is ideally suited for this type of therapy, because it can be visualized in vivo using both nuclear imaging, X-ray computed tomography (CT) and magnetic resonance imaging (MRI). Since the injection volume is limited in solid tumors, the activity per sphere should be as high as possible. The holmium content of the HoAcAc microspheres is 45% by weight, which is considered sufficient for intratumoral radioablation. After incubation for 180 days in phosphate buffer, the release of holmium (3+) from the microspheres was 0.50.2%. Elemental analysis, infrared spectroscopy and time of flight scanning secondary ion mass spectrometry showed that the acetylacetonate in the microspheres was replaced by phosphate within four days, creating a very stable complex. Interestingly, scanning electron microscopy revealed that the particles had retained their size and shape, irrespective of the incubation time, which is an indication that these particles are stable systems. The in vivo stability was assessed after intratumoral administration of 166HoAcAcMS to VX2 carcinoma-bearing rabbits. The holmium content in urine, faeces and blood was below the detection limit, indicating that no holmium had leached from the microspheres. It is concluded that 166HoAcAcMS are highly stable in vivo and can therefore be safely used for radioablation of malignancies. A dose-escalation feasibility study was performed to determine the safety and efficacy of 166HoAcAcMS as a radioablation device in three feline liver cancer patients. Shortly after treatment by intratumoral injections with 166HoAcAcMS, the clinical condition of the cats improved markedly, as did most biochemical and hematological parameters resulting in a meaningful extension of life in all animals. The efficacy of 166HoAcAcMS as a minimally invasive ablation device for renal cell carcinoma was tested in a murine renal cell carcinoma model. The mice of the 166HoAcAcMS group showed an arrest of tumor growth, whereas the tumors in the control group showed an exponential increase in tumor volume. Additionally, the multimodality imaging characteristics were exploited by performing microCT, microSPECT and MR imaging on dedicated animal scanners. All imaging modalities showed a similar distribution of the dose of 166HoAcAcMS. Quantitative analysis of SPECT images, and the possibility to use these images for dosimetry is a fundamental advantage of the 166HoAcAcMS over other ablative techniques. It is concluded that tumor radioablation using 166HoAcAcMS, when injected percutaneously, is feasible and efficacious and not associated with adverse side effects