S.W. Zielhuis

Internal radiation therapy of liver tumors: Qualitative and quantitative magnetic resonance imaging of the biodistribution of holmium-loaded microspheres in animal models

In internal radiation therapy of unresectable liver tumors, microspheres containing a radionuclide are injected in the hepatic artery to achieve a preferential deposition of microspheres in the lesions. In this study, MR imaging techniques for qualitative and quantitative assessment of the biodistribution of holmium‐loaded microspheres (HoMS) were investigated for their use in selective internal radiation therapy of liver tumors. To achieve this goal, the relaxivity of HoMS was first investigated in gel experiments. The resultant calibration curve was subsequently employed to quantify the biodistribution of HoMS administered to 13 excised rabbit livers and to the livers of 3 live rabbits with an implanted tumor. Finally, the feasibility of MR imaging of the biodistribution during treatment of a large animal was investigated by MR imaging of hepatic administration of HoMS to a live pig. Overall, the study showed that MRI can clearly depict the biodistribution of HoMS, but that quantification by means of the gel calibration curve yields an underestimation that increases for higher amounts of HoMS. The observed underestimation is tentatively attributed to accumulations of HoMS in larger liver vessels. The exploratory quantification experiments suggest the feasibility of MR dosimetry. Magn Reson Med 53:76–84, 2005.

Influence of neutron irradiation on holmium acetylacetonate loaded poly(l-lactic acid) microspheres

Holmium-loaded microspheres are useful systems in radio-embolization therapy of liver metastases. For administration to a patient, the holmium-loaded microspheres have to be irradiated in a nuclear reactor to become radioactive. In this paper. the influence of neutron irradiation on poly(L-lactic acid) (PLLA) microspheres and films, with or without holmium acetylacetonate (HoAcAc), is investigated, in particular using differential scanning calorimetry (MDSC), scanning electron microscopy, gel permeation chromatography (GPC), infrared spectroscopy, and X-ray diffraction. After irradiation of the microspheres, only minor surface changes were seen using scanning electron microscopy, and the holmium complex remained immobilized in the polymer matrix as reflected by a relatively small release of this complex. GPC and MDSC measurements showed a decrease in molecular weight and crystallinity of the PLLA, respectively, which can be ascribed to radiation induced chain scission. Irradiation of the HoAcAc loaded PLLA matrices resulted in evaporation of the non-coordinated and one coordinated water molecule of the HoAcAc complex, as evidenced by MDSC and X-ray diffraction analysis. Infrared spectroscopy indicated that some degradation of the acetylacetonate anion occurred after irradiation. Although some radiation induced damage of both the PLLA matrix and the embedded HoAcAc-complex occurs, the microspheres retain their favourable properties (no marginal release of Ho, preservation of the microsphere size), which make these systems interesting candidates for the treatment of tumours by radio-embolization.

Lanthanide bearing microparticulate systems for multi-modality imaging and targeted therapy of cancer.

The rapid developments of high-resolution imaging techniques are offering unique possibilities for the guidance and follow up of recently developed sophisticated anticancer therapies. Advanced biodegradable drug delivery systems, e.g. based on liposomes and polymeric nanoparticles or microparticles, are very effective tools to carry these anticancer agents to their site of action. Elements from the group of lanthanides have very interesting physical characteristics for imaging applications and are the ideal candidates to be co-loaded either in their non-radioactive or radioactive form into these advanced drug delivery systems because of the following reasons: Firstly, they can be used both as magnetic resonance imaging (MRI) and computed tomography (CT) contrast agents and for single photon emission computed tomography (SPECT). Secondly, they can be used for radionuclide therapies which, importantly, can be monitored with SPECT, CT, and MRI. Thirdly, they have a relatively low toxicity, especially when they are complexed to ligands. This review gives a survey of the currently developed lanthanide-loaded microparticulate systems that are under investigation for cancer imaging and/or cancer therapy.