Alfred D. van het Schip

University Medical Center Utrecht

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J. Frank W. Nijsen

Radboud University Nijmegen

Bernard A. Zonnenberg

University Medical Center Utrecht

Peter P. van Rijk

University Medical Center Utrecht

Wim E. Hennink

Utrecht University

Chris J.G. Bakker

University Medical Center Utrecht

M. A. D. Vente

Utrecht University

Gerard C. Krijger

University Medical Center Utrecht

Peter R. Seevinck

University Medical Center Utrecht

Jan‐Henry Seppenwoolde

University Medical Center Utrecht

Sander W. Zielhuis

University Medical Center Utrecht

Cooperative Institutions

Utrecht University

University Medical Center Utrecht

University Hospital Heidelberg

Heidelberg University

University of Groningen

University Medical Center

Radboud University Nijmegen

Radboud University Medical Center

Delft University of Technology

University of Amsterdam

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Holmium-166 poly lactic acid microspheres applicable for intra-arterial radionuclide therapy of hepatic malignancies: effects of preparation and neutron activation techniques

European Journal of Nuclear Medicine and Molecular Imaging (1999)

J. Frank W. Nijsen Bernard A. Zonnenberg J. R. W. Woittiez D. W. Rook I. A. Swildens-van Woudenberg

Holmium

Radionuclide therapy

10.1007/s002590050440

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Citations (124)

Phase 1 study of rhenium-186-HEDP in patients with bone metastases originating from breast cancer.

PubMed (1996)

John M. de Klerk Alfred D. van het Schip Bernard A. Zonnenberg Anouk van Dijk J M Quirijnen

Rhenium-186-1,1-hydroxyethylidene diphosphonate (186Re-HEDP) has been used for the palliative treatment of metastatic bone pain. A Phase 1 dosage escalation study was performed using 186Re-HEDP in patients with metastatic breast cancer.Twelve patients with metastatic breast cancer were studied. Each patient had at least four bone metastases and adequate hematological function. Groups of three consecutive patients were treated with dosages starting at 1295 MBq (35 mCi) and increasing to 2960 MBq (80 mCi) (escalated in increments of 555 MBq).A transient increase in pain ("flare" reaction) was observed in six patients. Two patients who received 2960 MBq 186Re-HEDP showed Grades 3 (platelets 25-50 x 10(9)/l) and 4 (platelets < 25 x 10(9)/l) platelet toxicity, which was defined as unacceptable. Prior to treatment, alkaline phosphatase levels were elevated in seven cases. These patients showed a transient decline in alkaline phosphatase levels during the first 4 wk.The maximum tolerated administered activity of 186Re-HEDP in patients with metastatic breast cancer is 2405 MBq (65 mCi). Thrombocytopenia proved to be the dose-limiting toxicity, which could not be predicted adequately by the administered activity. Changes of alkaline phosphatase levels suggest anti-tumor effects of 186Re-HEDP.

Radionuclide therapy

Bone pain

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Microsphere radioembolization of liver malignancies: current developments.

PubMed (2009)

Wouter Bult M. A. D. Vente Bernard A. Zonnenberg Alfred D. van het Schip J. Frank W. Nijsen

The worldwide incidence of hepatic malignancies, both primary and secondary, exceeds 1 000 000 new cases each year. The poor prognosis of patients suffering from hepatic malignancies has lead to the development of a liver directed therapy which consists of intra-arterial administration of radioactive particles through a catheter. Yttrium-90 ((90)Y) microspheres are increasingly applied for this purpose, and up to now nearly all clinical experience with radioembolization has been obtained with these microspheres. The response rate is very promising in both patients with primary and metastatic liver malignancies. Currently, two commercially available (90)Y microsphere devices are in use clinically, both as a first-line treatment and in a salvage setting. Unfortunately, the use of a pure beta-emitter like (90)Y hampers acquisition of high quality nuclear images for pre-treatment work-up and follow-up. This issue was addressed by the development of holmium-166 ((166)Ho) and rhenium-188 ((188)Re) microspheres, which emit both beta-particles for therapeutic purposes and gamma-photons for nuclear imaging. Moreover, since holmium is paramagnetic it allows for magnetic resonance imaging. (166)Ho loaded poly(L-lactic acid) microspheres have been thoroughly investigated in a preclinical setting, and recently the first clinical results for (188)Re microspheres were reported. This review provides an overview of the current status and (pre-)clinical developments of radioactive microspheres for treatment of liver malignancies.

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Sequence homologies within the 5′ end region of the estrogen-controlled vitellogenin gene in Xenopus and chicken.

The EMBO Journal (1983)

Philippe Walker Marianne Brown-Luedi Jacques‐Edouard Germond Walter Wahli Frits Meijlink

Vitellogenin

Vitellogenins

Sequence (biology)

10.1002/j.1460-2075.1983.tb01734.x

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Citations (42)

Advances in Nuclear Oncology: Microspheres for Internal Radionuclide Therapy of Liver Tumours

Current Medicinal Chemistry (2002)

J. Frank W. Nijsen Alfred D. van het Schip Wim E. Hennink Denise Rook P. van Rijk

Liver metastases cause the majority of deaths from colorectal cancer, and response to chemotherapy and external radiotherapy is poor. An alternative is internal radionuclide therapy using 90Y labeled microspheres. These microspheres are very stable and have a proven efficacy in the field of treatment of primary or metastatic hepatic cancer. Whilst these glass spheres showed encouraging results in patients, their high density is a serious drawback. Currently, other materials with lower densities and other radioisotopes are being investigated in order to optimize this promising new therapy. Three major radiolabeled microsphere materials, viz. glass, resin-based and polymer-based, are now available for therapy or are being tested in animals. In this review the preparation, stability and degradation of these spheres are discussed. Keywords: Nuclear Oncology, Radionuclide, Therapy, Microspheres, Resins, Polymers

Radionuclide therapy

Glass microsphere

Liver Cancer

Cancer Therapy

10.2174/0929867023371454

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Citations (80)

Liver Tumors: MR Imaging of Radioactive Holmium Microspheres—Phantom and Rabbit Study

Radiology (2004)

J. Frank W. Nijsen Jan‐Henry Seppenwoolde Thomas Havenith Clemens Bos Chris J.G. Bakker

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.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.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.Ho-PLLA-MS used for internal radionuclide therapy can be imaged clearly in vivo with MR imaging.

Biodistribution

Ex vivo

Holmium

10.1148/radiol.2312030594

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Citations (73)

Administration procedure testing of holmium-166 microspheres for treatment of liver cancer

M. A. D. Vente J. Frank W. Nijsen Tim C. de Wit Peter R. Seevinck Remmert de Roos

Liver Cancer

Holmium

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Neutron activation of holmium poly(L-lactic acid) microspheres for hepatic arterial radioembolization: a validation study

Biomedical Microdevices (2009)

M. A. D. Vente J. Frank W. Nijsen Remmert de Roos Mies J. van Steenbergen C. N. J. Kaaijk

Poly(L-lactic acid) microspheres loaded with holmium-166 acetylacetonate (166Ho-PLLA-MS) are a novel microdevice for intra-arterial radio-embolization in patients with unresectable liver malignancies. The neutron activation in a nuclear reactor, in particular the gamma heating, damages the 166Ho-PLLA-MS. The degree of damage is dependent on the irradiation characteristics and irradiation time in a particular reactor facility. The aim of this study was to standardize and objectively validate the activation procedure in a particular reactor. The methods included light- and scanning electron microscopy (SEM), particle size analysis, differential scanning calorimetry, viscometry, thermal neutron flux measurements and energy deposition calculations. Seven hours-neutron irradiation results in sufficient specific activity of the 166Ho-PLLA-MS while structural integrity is preserved. Neutron flux measurements and energy deposition calculations are required in the screening of other nuclear reactors. For the evaluation of microsphere quality, light microscopy, SEM and particle size analysis are appropriate techniques.

Holmium

Neutron activation

10.1007/s10544-009-9291-y

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Citations (40)

Lanthanide-Loaded Liposomes for Multimodality Imaging and Therapy

Cancer Biotherapy and Radiopharmaceuticals (2006)

Sander W. Zielhuis Jan‐Henry Seppenwoolde Vanessa Mateus Chris J.G. Bakker Gerard C. Krijger

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°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.

Multimodality

10.1089/cbr.2006.21.520

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Citations (55)

Fully MR‐guided hepatic artery catheterization for selective drug delivery: A feasibility study in pigs

Journal of Magnetic Resonance Imaging (2005)

Jan‐Henry Seppenwoolde Lambertus W. Bartels R. van der Weide J. Frank W. Nijsen Alfred D. van het Schip

Abstract Purpose To demonstrate the feasibility of hepatic catheterization for selective delivery of therapeutic agents using a clinical MRI scanner for real‐time image guidance. Materials and Methods Experiments were performed in three domestic pigs (70–80 kg) using a clinical 1.5‐T MR scanner. After abdominal three‐dimensional contrast‐enhanced MR angiography (3D‐CE‐MRA) was performed, endovascular devices with susceptibility markers were tracked with passive tracking techniques. Catheters were maneuvered into the primary and secondary hepatic arteries. Selective catheterization was verified using selective time‐resolved CE angiography. Paramagnetic microspheres were administered to a different region for each liver. The resulting biodistributions were investigated using MR images. Results Successful selective hepatic catheterization was repeatedly demonstrated using passive tracking techniques. 3D‐CE‐MRA significantly aided the interventional procedure by showing the vascular anatomy, and maximum‐intensity projections (MIPs) were used as roadmaps during the interventions. In all cases, microspheres were successfully delivered to the selected regions. The catheters were visualized at a maximum frame rate of five frames per second, allowing a good depiction of the devices and a reliable catheterization of the hepatic arteries. Conclusion Fully MR‐guided real‐time navigation of endovascular devices permits complex procedures such as selective intra‐arterial delivery of therapeutic agents to parts of the liver. J. Magn. Reson. Imaging 2006. © 2005 Wiley‐Liss, Inc.

10.1002/jmri.20479

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Citations (41)