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• W3149456886 abstract "In this thesis research is described which was aimed to develop lipidic nanoparticles for the investigation and visualization of atherosclerosis and angiogenesis with both magnetic resonance molecular imaging and optical techniques. The underlying rationale for this is that conventional MR imaging techniques are only capable of visualizing physiological and morphological changes, while magnetic resonance molecular imaging aims to depict cellular and molecular processes that are associated with or lie at the basis of pathological processes. This may lead to earlier detection, and improved diagnosis and prognosis of disease processes. Furthermore this technique may be very useful for the evaluation of a given therapy. The introduction of MRI as a molecular imaging modality is hampered by its low sensitivity compared to nuclear methods like PET and SPECT. With recent developments in chemistry and the synthesis of powerful, innovative, specific, and multimodal contrast agents, e.g. by introducing fluorescent properties as well, MRI is becoming increasingly important for molecular imaging. Therefore, the first aim of the research described in this thesis was to develop biocompatible nanoparticles that can be made target specific and can be detected by both MRI and optical techniques to allow the investigation of disease processes with two highly complementary imaging methods. Chapter 1 gives a general introduction in magnetic resonance molecular imaging and its potential use for the investigation of several pathological processes. Furthermore, contrast enhanced MRI based on differences in T1 and T2 relaxation times is explained. Lastly, different classes of contrast agents and their contrast generating properties are described. Amphphilic molecules are widely applied to serve as building blocks for nanoparticles in biomedical applications. In the field of drug targeting for example, liposomes comprised of amphiphilic molecules hold great promise and have been used extensively the last several decades. Furthermore, micelles, microemulsions, and other amphiphilic aggregates are also under investigation to serve as drug carriers. A relatively new application of lipidic nanoparticles is their use as contrast generating materials for MRI. In Chapter 2 the properties of amphiphilic molecules and their assembly in a wide range of aggregated structures are described. This is followed by an overview of different strategies that are employed to conjugate targeting ligand to such lipid based nanoparticles. The emphasis of this chapter is a literature overview of what has been realized in this research field thus far. Chapter 3 describes the physical characterization of novel liposomal contrast agents. The morphology of different formulations was investigated with electron microscopy, which revealed the necessity of incorporating cholesterol in the liposomal bilayer. Furthermore the relaxation properties of these contrast agent were measured as a function of temperature and magnetic field strength. In Chapter 4 a liposomal contrast agent with both fluorescent and magnetic properties is described. The liposomes were made target specific by conjugating multiple E-selectin specific antibodies to the surface of the nanoparticle. Its feasibility to serve as molecular imaging contrast agent for the detection of the inflammation marker E-selectin is demonstrated in vitro. The specific uptake of the liposomes by human endothelial cells stimulated to express E-selectin was visualized by MRI and fluorescence microscopy. Chapter 5 describes a superparamagnetic nanoparticle encapsulated in a micellular shell. Fluorescent properties were introduced to this contrast agent by the incorporation of fluorescent lipids in the lipid layer. The contrast agent has a very high r2/r1 ratio and therefore is especially suitable to be used for T2 (*) enhanced MRI. The nanoparticle can be made target specific by covalently linking targeting ligands distally to the PEG chains of lipids incorporated in the micellular shell via maleimide-sulfhydryl coupling. Specificity for apoptotic cells was realized by conjugating multiple Annexin A5 proteins. The feasibility to use this contrast agent for molecular imaging purposes was demonstrated in vitro on apoptotic Jurkat cells. In Chapter 6 the synthesis and characterization of a novel bimodal nanoparticle based on semiconductor nanocrystals encapsulated within the corona of paramagnetic micelles is described. The CdSe nanoparticle, also referred to as quantum dot, serves as the contrast generating material for fluorescence imaging, while the paramagnetic micellular coating is employed for contrast enhanced MRI. The in vitro association of this nanoparticle with isolated cells by either conjugating multiple avs3-integrin specific RGDpeptides or multiple phosphatidyl serine specific Annexin A5 proteins was demonstrated with both fluorescence microscopy and MRI. The second aim of the research described in this thesis was to apply the novel nanoparticles for the investigation of atherosclerosis and tumor angiogenesis in mouse models with magnetic resonance molecular imaging. Chapter 7 describes the application of non targeted paramagnetic liposomes for the improved and sustained visualization of neointimal lesions induced after placing a constrictive collar around the right carotid artery of apoE-KO mice. Commercially available Gd-DTPA (Magnevist) showed little potential for the detection of such lesion. In Chapter 8 pegylated micelles conjugated with macrophage scavenger receptor (MSR) specific antibodies were employed for improved atherosclerotic plaque detection and characterization. Existing nanoparticulate agents that are used to detect macrophages, such as USPIO or lipophilic micelles, show little specificity. The micelles used for this study have a hydrophilic PEG coating, and therefore show minimal non-specific interaction with plaque, which results in negligible background signal. In case of the MSR micelles a pronounced enhancement of atherosclerotic plaque was observed. Furthermore, the micelles exhibit fluorescent properties by the incorporation of either quantum dots or fluorescent lipids. This allowed the detection of macrophages with optical techniques as well. Chapter 9 and Chapter 10 describe the application of avs3 targeted bimodal liposomes for the visualization of angiogenically activated tumor blood vessels with both MRI in vivo and fluorescence microscopy ex vivo. The specificity of the contrast agent was demonstrated with an MRI competition experiment, while the exclusive association with endothelial cells was demonstrated with fluorescence microscopy. The follow-up study demonstrates the usefulness of contrast enhanced MRI after applying this contrast agent for the evaluation of angiostatic therapies, i.e. using endostatin and anginex, at two time points after onset of therapy. Most importantly, the in vivo MRI data show very good correlation with ex vivo microvessel density determinations. In the last experimental Chapter 11 of this thesis a sophisticated method for the parallel visualization of angiogenic tumor blood vessels with both intravital microscopy (IVM) and MRI is described. The nanoparticulate contrast agent conjugated with avs3-specific RGDpeptides described in Chapter 6 was administrated to tumor bearing mice. IVM allowed the investigation of the disease process at the cellular level, while MRI was used to investigate angiogenesis at the anatomical level. The contrast agent possesses excellent contrast generating properties for these complementary imaging techniques. Widespread angiogenic activity within the rim of the tumor, and up to 1 cm from the tumor boundary could be observed by using both techniques." @default.
• W3149456886 created "2021-04-13" @default.
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• W3149456886 date "2006-01-01" @default.
• W3149456886 modified "2023-09-23" @default.
• W3149456886 title "Lipid-based nanoparticles for magnetic resonance molecular imaging : design, characterization, and application" @default.
• W3149456886 doi "https://doi.org/10.6100/ir609405" @default.
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