Marc Schwarz

Efficient drug-delivery using magnetic nanoparticles — biodistribution and therapeutic effects in tumour bearing rabbits

UNLABELLED To treat tumours efficiently and spare normal tissues, targeted drug delivery is a promising alternative to conventional, systemic administered chemotherapy. Drug-carrying magnetic nanoparticles can be concentrated in tumours by external magnetic fields, preventing the nanomaterial from being cleared by metabolic burden before reaching the tumour. Therefore in Magnetic Drug Targeting (MDT) the favoured mode of application is believed to be intra-arterial. Here, we show that a simple yet versatile magnetic carrier-system (hydrodynamic particles diameter <200nm) accumulates the chemotherapeutic drug mitoxantrone efficiently in tumours. With MDT we observed the following drug accumulations relative to the recovery from all investigated tissues: tumour region: 57.2%, liver: 14.4%, kidneys: 15.2%. Systemic intra-venous application revealed different results: tumour region: 0.7%, liver: 14.4 % and kidneys: 77.8%. The therapeutic outcome was demonstrated by complete tumour remissions and a survival probability of 26.7% (P=0.0075). These results are confirming former pilot experiments and implying a milestone towards clinical studies. FROM THE CLINICAL EDITOR This team of investigators studied drug carrying nanoparticles for magnetic drug targeting (MDT), demonstrating the importance of intra-arterial administration resulting in improved clinical outcomes in the studied animal model compared with intra-venous.

Cellular characterization of the peritumoral edema zone in malignant brain tumors

Brain edema is a hallmark of human malignant brain tumors and contributes to the clinical course and outcome of brain tumor patients. The so‐called perifocal edema or brain swelling imposes in T2‐weighted MR scans as high intensity areas surrounding the bulk tumor mass. The mechanisms of this increased fluid attraction and the cellular composition of the microenvironment are only partially understood. In this study, we focus on imaging perifocal edema in orthotopically implanted gliomas in rodents and correlate perifocal edema with immunohistochemical markers. We identified that areas of perifocal edema not only include the tumor invasion zone, but also are associated with increased glial fibrillary acidic protein (GFAP) and aquaporin‐4 expression surrounding the bulk tumor mass. Moreover, a high number of activated microglial cells expressing CD11b and macrophage migration inhibitory factor (MIF) accumulate at the tumor border. Thus, the area of perifocal edema is mainly dominated by reactive changes of vital brain tissue. These data corroborate that perifocal edema identified in T2‐weighted MR scans are characterized with alterations in glial cell distribution and marker expression forming an inflammatory tumor microenvironment. (Cancer Sci 2009; 100: 1856–1862)

Magnetic nanoparticles for cancer therapy

Abstract Cancer is one of the biggest challenges facing the medical research in our time. The goals are to improve not only the therapeutic outcome, even in the cases of advanced and metastatic cancer, but also the methods of treatment, which often have considerable adverse effects. In addition, the current developments, such as demographic change, population growth, and increasing healthcare costs, have to be taken into consideration. In all likelihood, nanotechnology and, in particular, the use of magnetic nanoparticles consisting of the elements nickel, cobalt, and iron can make a significant contribution. The greatest potential can be ascribed to the drug delivery systems: magnetic nanoparticles are functionalized by binding them to various substances, including chemotherapeutic agents, radionuclides, nucleic acids, and antibodies. They can then be guided and accumulated using a magnetic field. Hyperthermia can be induced with an alternating magnetic field, providing another therapeutic option. Magnetic nanoparticles may be useful in overcoming cancer drug resistance. They also contribute to realizing a combination of diagnostic investigation and therapy in the field of “theranostics”. The multifaceted and promising results of research in the recent years offer the prospect of a real advance in cancer therapy in the near future.

In vivo micro-CT imaging of rat brain glioma: A comparison with 3 T MRI and histology

The aim of this study was to evaluate the potential of a novel micro-CT system to image in vivo the extent of tumor in a rat model of malignant glioma compared to 3T magnetic resonance imaging (MRI) and histology. Fourteen animals underwent double dose contrast-enhanced imaging with micro-CT and 3T MRI using a clinical machine at day 10 after stereotactic F98 glioma cell implantation. Calculation of the volume of the contrast-uptaking part of the tumor was done by manually outlining the tumor contours by two experienced neuroradiologists. The micro-CT- and MRI-derived tumor volumes were compared to histology as gold standard (hematoxylin and eosin staining and fluorescence staining). There was high interobserver reability regarding the tumor volumes (Crombachs alpha>0.81). Also, there was good correlation of micro-CT- and high-field MRI-derived tumor volumes compared to histology: 72+/-21 mm3 and 69+/-23 mm3 compared to 81+/-14 mm3, respectively (r>0.76). Both the micro-CT- and MRI-derived tumor volumes were not significantly smaller compared to histology (P>0.14). In conclusion, micro-CT allows in vivo imaging of the contrast-enhancing part of experimental gliomas with an accuracy comparable to high-field MRI.

Flat-detector computed tomography with intravenous contrast material application in experimental aneurysms: Comparison with multislice CT and conventional angiography

Background: Despite limited soft tissue resolution flat-detector computed tomography (FD-CT) provides substantial superior spatial resolution in comparison with multislice computed tomography (MS-CT). This may add value in the visualization of small vascular structures if intravenous contrast application leads to substantial opacification and visibility of intracranial vessels or aneurysms. Purpose: To evaluate the feasibility of visualization of vascular structures by FD-CT angiography (FD-CTA) after intravenous contrast injection compared with MS-CTA and intra-arterial digital subtracted angiography (IADSA) in an animal model. Material and Methods: Aneurysms were created in the right common carotid artery in six New Zealand White Rabbits using the elastase technique. Imaging was performed using FD-CTA, MS-CTA (injection of 1 ml/kg body weight) and IADSA. Anonymized volume rendering reconstruction (VRT), maximum intensity projection (MIP), and multiplanar reconstruction (MPR) images were reconstructed and evaluated by two experienced reviewers for aneurysm geometry and vascular structure anatomy using standard tools of a dedicated workstation. Results: Aneurysms could be successfully created in all animals. Measurements of aneurysm geometry (aneurysm height, width, neck width) and vascular structures (brachiocephalic trunk, carotid artery diameter and plane) were nearly identical in all three modalities. Intra- and inter-observer correlations of the different parameters showed high r values between 0.83 and 0.99. Conclusion: Our results show the feasibility of FD-CTA in comparison with MS-CTA and IADSA in an animal model. Despite limited soft tissue resolution, opacification of vascular structures with sufficient contrast to the surrounding structures was possible in all animals. Vascular structures appeared better delineated in FD-CTA than in MS-CTA, probably due to the superior spatial resolution.

Flat-detector computed tomography in the assessment of intracranial stents: comparison with multi detector CT and conventional angiography in a new animal model

ObjectiveCareful follow up is necessary after intracranial stenting because in-stent restenosis (ISR) or residual stenosis (RS) is not rare. A minimally invasive follow-up imaging technique is desirable. The objective was to compare the visualisation of stents in Flat Detector-CT Angiography (FD-CTA) after intravenous contrast medium injection (i.v.) with Multi Detector Computed Tomography Angiography (MD-CTA) and Digital Subtracted Angiography (DSA) in an animal model.MethodsStents were implanted in the carotid artery of 12 rabbits. In 6 a residual stenosis (RS) was surgically created. Imaging was performed using FD-CTA, MD-CTA and DSA. Measurements of the inner and outer diameter and cross-section area of the stents were performed. Stenosis grade was calculated.ResultsIn subjective evaluation FD-CTA was superior to MD-CTA. FD-CTA was more accurate compared with DSA than MD-CTA. Cross-sectional area of the stent lumen was significantly larger (p < 0.05) in FD-CTA in comparison to MD-CTA. Accurate evaluation of stenosis was impossible in MD-CTA. There was no statistically significant difference in the stenosis grade of DSA and FD-CTA.ConclusionOur results show that visualisation of stent and stenosis using intravenous FD-CTA compares favourably with DSA and may replace DSA in the follow-up of patients treated with intracranial stents.

Non-immunogenic dextran-coated superparamagnetic iron oxide nanoparticles: a biocompatible, size-tunable contrast agent for magnetic resonance imaging

Iron oxide-based contrast agents have been in clinical use for magnetic resonance imaging (MRI) of lymph nodes, liver, intestines, and the cardiovascular system. Superparamagnetic iron oxide nanoparticles (SPIONs) have high potential as a contrast agent for MRI, but no intravenous iron oxide-containing agents are currently approved for clinical imaging. The aim of our work was to analyze the hemocompatibility and immuno-safety of a new type of dextran-coated SPIONs (SPIONdex) and to characterize these nanoparticles with ultra-high-field MRI. Key parameters related to nanoparticle hemocompatibility and immuno-safety were investigated in vitro and ex vivo. To address concerns associated with hypersensitivity reactions to injectable nanoparticulate agents, we analyzed complement activation-related pseudoallergy (CARPA) upon intravenous administration of SPIONdex in a pig model. Furthermore, the size-tunability of SPIONdex and the effects of size reduction on their biocompatibility were investigated. In vitro, SPIONdex did not induce hemolysis, complement or platelet activation, plasma coagulation, or leukocyte procoagulant activity, and had no relevant effect on endothelial cell viability or endothelial–monocytic cell interactions. Furthermore, SPIONdex did not induce CARPA even upon intravenous administration of 5 mg Fe/kg in pigs. Upon SPIONdex administration in mice, decreased liver signal intensity was observed after 15 minutes and was still detectable 24 h later. In addition, by changing synthesis parameters, a reduction in particle size <30 nm was achieved, without affecting their hemo- and biocompatibility. Our findings suggest that due to their excellent biocompatibility, safety upon intravenous administration and size-tunability, SPIONdex particles may represent a suitable candidate for a new-generation MRI contrast agent.

Dynamic Contrast Enhancement of Experimental Glioma: An Intra-individual Comparative Study to Assess the Optimal Time Delay

RATIONALE AND OBJECTIVES The aim of this study was to compare tumor signal and contrast media uptake characteristics on contrast-enhanced T1-weighted sequences at 3 Tesla over 30 minutes after double-dose administration of different contrast agents in an animal model of brain glioma. MATERIALS AND METHODS Nine rats underwent magnetic resonance imaging (MRI) after stereotactic F98 glioma cell implantation before and repetitively for 30 minutes after injection of gadobutrol, gadopentetate, and gadobenate, respectively. Signal-to-noise ratio (SNR) and tumor contrast-to-noise ratio (CNR) were evaluated and MRI-derived tumor volumes were compared to histology. RESULTS Postcontrast tumor SNR and CNR peaked at 4 minutes after contrast application. While contrast-enhancement within the tumor was fading, tumor volume increased by continuous contrast-uptake of peripheral parts between 4 minutes (137 + or - 29 mm(3), 126 + or - 16 mm(3), 141 + or - 24 mm(3)) and 20 minutes (182 + or - 35 mm(3), 164 + or - 32 mm(3), 191 + or - 25 mm(3)), respectively. At 8 and 12 minutes, 84% and 91% of the tumor volume were definable, respectively. CONCLUSION Optimal correlation between MRI-derived tumor volume and histology is achieved by imaging up to 20 minutes after contrast application. At 4 minutes (this delay is mostly used in clinical routine), only 75% of the enhancing tumor volume is assessable. A delay of 8 minutes already reveals 84% of the tumor and seems to be a practical clinical compromise.

The impact of dietary isoflavonoids on malignant brain tumors

Poor prognosis and limited therapeutic options render malignant brain tumors one of the most devastating diseases in clinical medicine. Current treatment strategies attempt to expand the therapeutic repertoire through the use of multimodal treatment regimens. It is here that dietary fibers have been recently recognized as a supportive natural therapy in augmenting the bodys response to tumor growth. Here, we investigated the impact of isoflavonoids on primary brain tumor cells. First, we treated glioma cell lines and primary astrocytes with various isoflavonoids and phytoestrogens. Cell viability in a dose‐dependent manner was measured for biochanin A (BCA), genistein (GST), and secoisolariciresinol diglucoside (SDG). Dose–response action for the different isoflavonoids showed that BCA is highly effective on glioma cells and nontoxic for normal differentiated brain tissues. We further investigated BCA in ex vivo and in vivo experimentations. Organotypic brain slice cultures were performed and treated with BCA. For in vivo experiments, BCA was intraperitoneal injected in tumor‐implanted Fisher rats. Tumor size and edema were measured and quantified by magnetic resonance imaging (MRI) scans. In vascular organotypic glioma brain slice cultures (VOGIM) we found that BCA operates antiangiogenic and neuroprotective. In vivo MRI scans demonstrated that administered BCA as a monotherapy was effective in reducing significantly tumor‐induced brain edema and showed a trend for prolonged survival. Our results revealed that dietary isoflavonoids, in particular BCA, execute toxicity toward glioma cells, antiangiogenic, and coevally neuroprotective properties, and therefore augment the range of state‐of‐the‐art multimodal treatment approach.

Imaging modalities using magnetic nanoparticles – overview of the developments in recent years

Abstract The use of nanoparticles in tumor imaging, molecular imaging, and drug delivery has significantly expanded in the last few years. The relatively new field of “theranostics” combines their capacity for drug delivery with their potential as contrast agents. Depending on the imaging modality used, several types of nanoparticles are available, such as gold for optical imaging or superparamagnetic iron oxide for magnetic resonance imaging. This review will give a short overview of the different types of nanoparticles as well as their development and potential application in recent years. Furthermore, it describes the research on classic imaging modalities as well as on new techniques to image nanoparticles in vivo and focuses on magnetic-based imaging modalities.