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Unlabelled: (166)Ho-poly(l-lactic acid) microspheres allow for quantitative imaging with MR imaging or SPECT for microsphere biodistribution assessment after radioembolization. The purpose of this study was to evaluate SPECT- and MR imaging-based dosimetry in the first patients treated with (166)Ho radioembolization., Methods: Fifteen patients with unresectable, chemorefractory liver metastases of any origin were enrolled in this phase 1 study and were treated with (166)Ho radioembolization according to a dose escalation protocol (20-80 Gy). The contours of all liver segments and all discernible tumors were manually delineated on T2-weighted posttreatment MR images and registered to the posttreatment SPECT images (n = 9) or SPECT/CT images (n = 6) and MR imaging-based R2* maps (n = 14). Dosimetry was based on SPECT (n = 15) and MR imaging (n = 9) for all volumes of interest, tumor-to-nontumor (T/N) activity concentration ratios were calculated, and correlation and agreement of MR imaging- and SPECT-based measurements were evaluated., Results: The median overall T/N ratio was 1.4 based on SPECT (range, 0.9-2.8) and 1.4 based on MR imaging (range, 1.1-3.1). In 6 of 15 patients (40%), all tumors had received an activity concentration equal to or higher than the normal liver (T/N ratio ≥ 1). Analysis of SPECT and MR imaging measurements for dose to liver segments yielded a high correlation (R(2) = 0.91) and a moderate agreement (mean bias, 3.7 Gy; 95% limits of agreement, -11.2 to 18.7)., Conclusion: With the use of (166)Ho-microspheres, in vivo dosimetry is feasible on the basis of both SPECT and MR imaging, which enables personalized treatment by selective targeting of inadequately treated tumors.

Objectives: To demonstrate the feasibility of MRI-based assessment of the intrahepatic Ho-PLLA-MS biodistribution after radioembolisation in order to estimate the absorbed radiation dose., Methods: Fifteen patients were treated with holmium-166 ((166)Ho) poly(L-lactic acid)-loaded microspheres (Ho-PLLA-MS, mean 484 mg; range 408-593 mg) in a phase I study. Multi-echo gradient-echo MR images were acquired from which R (2) maps were constructed. The amount of Ho-PLLA-MS in the liver was determined by using the relaxivity r (2) of the Ho-PLLA-MS and compared with the administered amount. Quantitative single photon emission computed tomography (SPECT) was used for comparison with MRI regarding the whole liver absorbed radiation dose., Results: R (2) maps visualised the deposition of Ho-PLLA-MS with great detail. The mean total amount of Ho-PLLA-MS detected in the liver based on MRI was 431 mg (range 236-666 mg) or 89 ± 19 % of the delivered amount (correlation coefficient r = 0.7; P < 0.01). A good correlation was found between the whole liver mean absorbed radiation dose as assessed by MRI and SPECT (correlation coefficient r = 0.927; P < 0.001)., Conclusion: MRI-based dosimetry for holmium-166 radioembolisation is feasible. Biodistribution is visualised with great detail and quantitative measurements are possible.

In cancer therapy, a promising treatment option to accomplish a high tumor-to-normal-tissue ratio is endovascular intervention with microsized particles, such as embolotherapy. In this study, alginate microspheres (ams) were prepared with the JetCutter technique, which is based on cutting a sodium alginate solution jet stream into small droplets of uniform size which are then cross-linked with different lanthanides or iron-III, resulting in microspheres of a predefined size which can be visualized by magnetic resonance imaging (MRI). The microspheres were investigated for their size and morphology (light microscopy and scanning electron microscopy analysis), cation content and MRI properties. The lanthanide-ams formulations, with a uniform size of 250 μm and a cation content between 0.72-0.94%, showed promising results for MR imaging. This was further demonstrated for Ho(3+)-cross-linked alginate microspheres (Ho(3+)-ams), the most potent microsphere formulation with respect to MR visualization, allowing single sphere detection and detailed microsphere distribution examination. Intravascular infusion of Ho(3+)-ams by catherization of ex vivo rabbit and porcine liver tissue and assessment of the procedure with MRI clearly showed accumulation and subsequently embolization of the targeted vessels, allowing accurate monitoring of the microsphere biodistribution throughout the tissue. Therefore, the different alginate-lanthanide microsphere formulations developed in this study show great potential for utilization as image-guided embolotherapy agents., (Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: To investigate the potential of magnetic resonance imaging (MRI) for accurate assessment of the three-dimensional (166)Ho activity distribution to estimate radiation-absorbed dose distributions in (166)Ho-loaded poly (L-lactic acid) microsphere ((166)Ho-PLLA-MS) liver radioembolization., Methods and Materials: MRI, computed tomography (CT), and single photon emission CT (SPECT) experiments were conducted on an anthropomorphic gel phantom with tumor-simulating gel samples and on an excised human tumor-bearing liver, both containing known amounts of (166)Ho-PLLA-MS. Three-dimensional radiation-absorbed dose distributions were estimated at the voxel level by convolving the (166)Ho activity distribution, derived from quantitative MRI data, with a (166)Ho dose point-kernel generated by MCNP (Monte Carlo N-Particle transport code) and from Medical Internal Radiation Dose Pamphlet 17. MRI-based radiation-absorbed dose distributions were qualitatively compared with CT and autoradiography images and quantitatively compared with SPECT-based dose distributions. Both MRI- and SPECT-based activity estimations were validated against dose calibrator measurements., Results: Evaluation on an anthropomorphic phantom showed that MRI enables accurate assessment of local (166)Ho-PLLA-MS mass and activity distributions, as supported by a regression coefficient of 1.05 and a correlation coefficient of 0.99, relating local MRI-based mass and activity calculations to reference values obtained with a dose calibrator. Estimated MRI-based radiation-absorbed dose distributions of (166)Ho-PLLA-MS in an ex vivo human liver visually showed high correspondence to SPECT-based radiation-absorbed dose distributions. Quantitative analysis revealed that the differences in local and total amounts of (166)Ho-PLLA-MS estimated by MRI, SPECT, and the dose calibrator were within 10%. Excellent agreement was observed between MRI- and SPECT-based dose-volume histograms., Conclusions: Quantitative MRI was demonstrated to provide accurate three-dimensional (166)Ho-PLLA-MS activity distributions, enabling localized intrahepatic radiation-absorbed dose estimation by convolution with a (166)Ho dose point-kernel for liver radioembolization treatment optimization and evaluation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Cerebral embolization models have been hindered by the fact that delivery is predominantly one-sided and cannot be quantified easily. We have developed a model for bilateral cerebral micro-embolization. By using holmium microspheres, it is possible to quantify intracerebral delivery using MRI., Methods: To validate the quantification of holmium microspheres a phantom study was performed in which concentration of microspheres in solution was compared with the number of holmium-induced artifacts on MRI. After that identical microspheres were administered by unilateral injection in the carotid artery, while the opposite carotid artery was clamped. On post-injection MRI scans, intracerebral delivery and right/left distribution of the microspheres was determined., Results: In the phantom study it was shown that quantification by MRI is possible and that MRI artifacts represent single microspheres. In the rat brain, about one-third of the injected dose was consistently located on the contralateral side. The administration was reproducible regarding distribution and number of microspheres., Conclusions: The use of holmium microspheres enables quantification of delivered dose as single microspheres induce artifacts on MRI. By clamping the contralateral carotid artery, one-third of the dose is diverted to the contralateral hemisphere.

Noninvasive imaging techniques like magnetic resonance imaging (MRI), computed tomography (CT) and single photon emission computed tomography (SPECT) play an increasingly important role in the diagnostic workup and treatment of cancerous disease. In this context, a distinct trend can be observed towards the development of contrast agents and radiopharmaceuticals that open up perspectives on a multimodality imaging approach, involving all three aforementioned techniques. To promote insight into the potentialities of such an approach, we prepared an overview of the strengths and limitations of the various imaging techniques, in particular with regard to their capability to quantify the spatial distribution of a multimodal diagnostic agent. To accomplish this task, we used a two-step approach. In the first step, we examined the situation for a particular therapeutic anti-cancer agent with multimodal imaging opportunities, viz. holmium-loaded microspheres (HoMS). Physical phantom experiments were performed to enable a comparative evaluation of the three modalities assuming the use of standard equipment, standard clinical scan protocols, and signal-known-exactly conditions. These phantom data were then analyzed so as to obtain first order estimates of the sensitivity and detection limits of MRI, CT and SPECT for HoMS. In the second step, the results for HoMS were taken as a starting point for a discussion of the factors affecting the sensitivity and detection limits of MRI, CT and SPECT for multimodal agents in general. In this, emphasis was put on the factors that must be taken into account when extrapolating the findings for HoMS to other diagnostic tasks, other contrast agents, other experimental conditions, and other scan protocols.

Unlabelled: Many advanced molecular imaging agents are currently being investigated preclinically. Especially, liposomes, have proven to be very promising carrier systems for diagnostic agents for use in single-photon emission computed tomography (SPECT) or magnetic resonance imaging (MRI), as well as for therapeutic agents to treat diseases such as cancer. In this study, nanosized liposomes were designed and labeled with the radionuclides, holmium-166 (both a beta- and gamma-emitter and also highly paramagnetic) or technetium-99m, and coloaded with paramagnetic gadolinium allowing multimodality SPECT and MR imaging and radionuclide therapy with one single agent., Methods: Diethylenetriaminepentaacetic acid bisoctadecylamide (an amphiphilic molecule with a chelating group suitable for labeling with radionuclides) and gadoliniumacetylacetonate (GdAcAc) (a small lipophilic paramagnetic molecule) were incorporated in liposomes. The liposomes were characterized by measuring their mean size and size distribution, gadolinium content, and radiochemical stability after incubation in human serum at 37 degrees C. The MRI properties (in vitro) were determined by use of relaxivity measurements at 1.5 and 3.0 Tesla in order to evaluate their potency as imaging agents., Results: The liposomes were successfully labeled with holmium-166, resulting in a high labeling efficiency (95% +/- 1%) and radiochemical stability (> 98% after 48 hours of incubation), and coloaded with GdAcAc. Labeling of liposomes with technetium-99m was somewhat less efficient (85% +/- 2%), although their radiochemical stability was sufficient (95% +/- 1% after 6 hours of incubation). MRI measurements showed that the incorporation of GdAcAc had a strong effect on the MRI relaxivity., Conclusions: The synthesized liposomes allow for multimodality imaging and therapy, which makes these new agents highly attractive for future applications.

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., (Copyright 2004 Wiley-Liss, Inc.)

Purpose: To investigate the use of magnetic resonance (MR) imaging in the administration and biodistribution of holmium-loaded poly(L-lactic acid) microspheres (Ho-PLLA-MS) in liver tumors., Materials and Methods: MR imaging measurements were obtained in phantoms, three ex vivo rabbit livers, and four livers in living rabbits. When applicable, measurements were compared with those on scintigraphic images. The transverse relaxivity R2* of the Ho-PLLA-MS was determined in a phantom study. The in vivo animal experiments were performed by using rabbits with an implanted VX2 tumor. Detection of passing Ho-PLLA-MS to estimate lung shunting was performed in a scaled model of the vena cava., Results: In the ex vivo liver experiments, the feasibility of real-time MR imaging during administration of microspheres was demonstrated. The in vivo rabbit experiments demonstrated that MR imaging can depict radioactive, nonradioactive, and decayed Ho-PLLA-MS after treatment for as long as they remain in the body. Furthermore, this study showed the ability of dynamic MR imaging to detect single doses of passing Ho-PLLA-MS., Conclusion: Ho-PLLA-MS used for internal radionuclide therapy can be imaged clearly in vivo with MR imaging.