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iron oxide nanoparticles for theranostic applications using amine-epoxide polymers. Although theranostic agents such as magnetic nanoparticles have been designed and developed for a few decades, there is still more work that needs to be done with the type of materials that can be used to stabilize or functionalize these particles if they are to be used for applications such as drug delivery, imaging and hyperthermia. For in-vivo applications, it is crucial that organic coatings enclose the nanoparticles in order to prevent aggregation and facilitate efficient removal from the body as well as protect the body from toxic material.
The objective of this thesis is to design polymer coated magnetite nanoparticles with polymers that are biocompatible and can stabilize the iron oxide nanoparticle to help create mono-dispersed particles in solution. It is desirable to also have these nanoparticles possess high magnetic susceptibility in response to an applied magnetic field. The co- precipitation method was selected because it is probably the simplest and most efficient chemical pathway to obtain magnetic nanoparticles.
In literature, cationic polymers such as Polyethylenimine (PEI), which is the industry standard, have been used to stabilize IONPs because they can be used in magnetofections to deliver DNA or RNA. PEI however is known to interact very strongly with proteins and is cytotoxic, so as mentioned previously the Iron Oxide nanoparticles
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(IONPs) synthesized in this study were stabilized with amine-epoxide polymers because of the limitations of PEI.
Four different amine-epoxide polymers which have good water solubility, biodegradability and less toxic than PEI were synthesized and used in the synthesis and stabilization of the magnetic nanoparticles and compared to PEI templated IONPs. These polymer-templated magnetic nanoparticles were also characterized by size, surface charge, Iron oxide content (ICP analysis) and superconducting quantum interference devices (SQUID) analysis to determine the magnetization values. TEM images were also used to determine the shape and size of the nanoparticles. All this was done in an effort to choose two or three leads that could be used in future work for magnetofections or drug delivery research.
The methods developed in this work improve the spatial coverage of whole-brain DSC-MRI by combining a highly efficient 3D spiral k-space trajectory with Generalized Autocalibrating Partial Parallel Acquisition (GRAPPA) parallel imaging without increasing temporal resolution. The proposed method is capable of acquiring 30 slices with a temporal resolution of under 1 second, covering the entire cerebrum with isotropic spatial resolution of 3 mm. Additionally, the acquisition method allows for correction of T1-enhancing leakage effects by virtue of collecting two echoes, which confound DSC perfusion measurements. The proposed DSC-perfusion method results in high quality perfusion parameter maps across a larger volume than is currently available with current clinical standards, improving diagnostic utility of perfusion MRI methods, which ultimately improves patient care.
In the first project, the improvements to post processing are made by proposing a new approach to estimating noise statistics for a single spiral acquisition, and using the estimated noise statistics to generate a mask distinguishing flow regions from background noise and static tissue in an image volume. The mask is applied towards reducing the computation time of phase unwrapping. The proposed noise estimation is shown to have comparable noise statistics as that of a vendor specific noise dynamic scan, with the added advantage of reduced scan time. The sparse flow region subset of the image volume is shown to speed up phase unwrapping for multidirectional velocity encoded 3D PCMRI scans. The second research project explores the extent of bias in cine PCMRI based flow estimates is investigated for CSF flow in the cerebral aqueduct. The dependance of the bias on spatial and temporal velocity gradient components is described. A critical velocity threshold is presented to prospectively determine the extent of bias as a function of scan acquisition parameters.
Phase contrast MR imaging is not sensitive to measure bulk CSF drainage. A dynamic approach using a CSF label is investigated in the third project to detect bulk flow in a ventricular shunt. The proposed approach uses a preparatory pulse to label CSF signal and a variable delay between the preparatory pulse and data acquisition enables tracking of the CSF bulk flow.
The tool allowed surgeons to take an allograft reconstruction and fuse it to a patient’s CT or MR medical image for virtual fit assessment. The allograft is either a reconstruction of the donor’s actual heart (from CT or MR images) or an analogue from a health heart library. The analogue allograft geometry is identified from gross donor parameters using a regression model build herein. The need for the regression model is donor images may not exist or they may not become available within the time-window clinicians have to make a provisional acceptance of an offer.
The tool’s assessment suggested > 20% of upper DRBW listings could have been increased at Phoenix Children’s Hospital (PCH). Upper DRBW listings in the UNOS national database was statistically smaller than at PCH (p-values: < 0.001). Delayed sternal closure and surgeon perceived complication variables had an association (p-value: 0.000016) with 9 of the 11 cases that surgeons had perceived fit-related complications had delayed closures (p-value: 0.034809).
A tool to assess allograft size-match has been developed. Findings warrant future preclinical and clinical prospective studies to further assess the tool’s clinical utility.
In this dissertation, the primary goal was to develop a comprehensive cellular and molecular level understanding of ECM remodeling due to the interaction of breast tumor cells and CAFs. To that end, a novel three-dimensional (3D) high-density tumor-stroma model was fabricated in which breast tumor cells (MDA-MB-231 and MCF7) were spatially organized surrounded by CAF-embedded collagen-I hydrogel (Aim 1). Further the platform was integrated with atomic force microscopy to assess the dynamic changes in ECM composition and stiffness during active tumor invasion. The results established an essential role of crosstalk between breast tumor cells and CAFs in ECM remodeling. The studies were further extended by dissecting the mode of interaction between tumor cells and CAFs followed by characterization of the role of various tumor secreted factors on ECM remodeling (Aim 2). The results for the first time established a critical role of paracrine signaling between breast tumor cells and CAFs in modulating biophysical properties of ECM. More in-depth analysis highlighted the role of tumor secreted cytokines, specifically PDGF-AA/BB, on CAF-induced desmoplasia. In aim 3, the platform was further utilized to test the synergistic influence of anti-fibrotic drug (tranilast) in conjugation with chemotherapeutic drug (Doxorubicin) on desmoplasia and tumor progression in the presence of CAFs. Overall this dissertation provided an in-depth understanding on the impact of breast cancer-stromal cell interaction in modulating biophysical properties of the ECM and identified the crucial role of tumor secreted cytokines including PDGF-AA/BB on desmoplasia.
Background: Magnetic Resonance Spectroscopic Imaging (MRSI) has wide applicability for non-invasive biochemical assessment in clinical and pre-clinical applications but suffers from long scan times. Compressed sensing (CS) has been successfully applied to clinical H-1 MRSI, however a detailed evaluation of CS for conventional chemical shift imaging is lacking. Here we evaluate the performance of CS accelerated MRSI, and specifically apply it to accelerate Na-23-MRSI on mouse hearts in vivo at 9.4 T.
Methods: Synthetic phantom data representing a simplified section across a mouse thorax were used to evaluate the fidelity of the CS reconstruction for varying levels of under-sampling, resolution and signal-to-noise ratios (SNR). The amplitude of signals arising from within a compartment, and signal contamination arising from outside the compartment relative to noise-free Fourier-transformed (FT) data were determined. Simulation results were subsequently verified experimentally in phantoms and in three mouse hearts in vivo.
Results: CS reconstructed MRSI data are scaled linearly relative to absolute signal intensities from the fully-sampled FT reconstructed case (R-2 > 0.8, p-value < 0.001). Higher acceleration factors resulted in a denoising of the reconstructed spectra, but also in an increased blurring of compartment boundaries, particularly at lower spatial resolutions. Increasing resolution and SNR decreased cross-compartment contamination and yielded signal amplitudes closer to the FT data. Proof-of-concept high-resolution, 3-fold accelerated Na-23-amplitude maps of murine myocardium could be obtained within similar to 23 mins.
Conclusions: Relative signal amplitudes (i.e. metabolite ratios) and absolute quantification of metabolite concentrations can be accurately determined with up to 5-fold under-sampled, CS-reconstructed MRSI. Although this work focused on murine cardiac Na-23-MRSI, the results are equally applicable to other nuclei and tissues (e.g. H-1 MRSI in brain). Significant reduction in MRSI scan time will reduce the burden on the subject, increase scanner throughput, and may open new avenues for (pre-) clinical metabolic studies.