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Direct nose-to-brain delivery of targeted polymeric nanoparticles

Description

There is growing interest in intranasal delivery of therapeutics because of direct nose-to-brain pathways which are able to bypass biological barriers, such as the blood-brain barrier (BBB), that have historically limited our ability to effectively deliver drugs to the central

There is growing interest in intranasal delivery of therapeutics because of direct nose-to-brain pathways which are able to bypass biological barriers, such as the blood-brain barrier (BBB), that have historically limited our ability to effectively deliver drugs to the central nervous system (CNS). Since these pathways were first discovered, there has been significant preclinical success in delivering a wide range of therapeutics to the CNS with additional growing efforts to further improve delivery through nanoparticle drug delivery systems. Here we sought to improve intranasal delivery of DiR, a lipophilic small molecule cyanine dye, to the CNS by surface modifying a poly (lactic-co-glycolic acid) (PLGA) nanoparticle with a short peptide derived from the rabies virus glycoprotein (RVG). The specific aims of this thesis were to evaluate administration route-dependent delivery of RVG nanoparticles to the CNS, and to identify anatomical transport pathways by which nanoparticles facilitate transport of small lipophilic molecules. Route-dependent delivery kinetics and distribution were studied by administering DiR loaded nanoparticles to healthy Balb/C mice. Specific tissues were homogenized and the fluorescent intensity of DiR was measured and compared to control tissue spiked with known amounts of dye. While bioavailability of DiR after intranasal administration was near 0% with minimal exposure to peripheral organs, quick and efficient delivery to the CNS was still observed. CNS delivery after intranasal administration was rapid with peak concentrations at 30 minutes post-administration followed by broad clearance by 2 hours. Regional differences of delivery of DiR to the CNS demonstrated engagement of direct nose-to-brain transport pathways with high delivery being observed to the olfactory bulb, brain stem, and trigeminal nerve. RVG modification however presented only modest targeting benefits. In conclusion, the biodistribution of DiR after intranasal administration of DiR loaded nanoparticles showed high potential for the direct nose-to-brain delivery while limiting peripheral exposure of lipophilic small molecule drugs.

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Date Created
2016-05

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Development of a Novel Smart Contrast Agent for Magnetic Resonance Imaging

Description

Smart contrast agents allow for noninvasive study of specific events or tissue conditions inside of a patient's body using Magnetic Resonance Imaging (MRI). This research aims to develop and characterize novel smart contrast agents for MRI that respond to temperature

Smart contrast agents allow for noninvasive study of specific events or tissue conditions inside of a patient's body using Magnetic Resonance Imaging (MRI). This research aims to develop and characterize novel smart contrast agents for MRI that respond to temperature changes in tissue microenvironments. Transmission Electron Microscopy, Nuclear Magnetic Resonance, and cell culture growth assays were used to characterize the physical, magnetic, and cytotoxic properties of candidate nanoprobes. The nanoprobes displayed thermosensitve MR properties with decreasing relaxivity with temperature. Future work will be focused on generating and characterizing photo-active analogues of the nanoprobes that could be used for both treatment of tissues and assessment of therapy.

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2014-05

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Utilization of Nanoparticles for Identifying Fibrin Deposition in Neural Tissue

Description

The main objective of this research is to develop and characterize a targeted contrast agent that will recognize acute neural injury pathology (i.e. fibrin) after traumatic brain injury (TBI). Single chain fragment variable antibodies (scFv) that bind specifically to fibrin

The main objective of this research is to develop and characterize a targeted contrast agent that will recognize acute neural injury pathology (i.e. fibrin) after traumatic brain injury (TBI). Single chain fragment variable antibodies (scFv) that bind specifically to fibrin have been produced and purified. DSPE-PEG micelles have been produced and the scFv has been conjugated to the surface of the micelles; this nanoparticle system will be used to overcome limitations in diagnosing TBI. The binding and imaging properties will be analyzed in the future to determine functionality of the nanoparticle system in vivo.

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2014-05

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A Novel Computing Platform for Accelerated Magnetic Resonance Spectroscopic Cancer Imaging

Description

Compressed sensing magnetic resonance spectroscopic imaging (MRSI) is a noninvasive and in vivo potential diagnostic technique for cancer imaging. This technique undersamples the distribution of specific cancer biomarkers within an MR image as well as changes in the temporal dimension

Compressed sensing magnetic resonance spectroscopic imaging (MRSI) is a noninvasive and in vivo potential diagnostic technique for cancer imaging. This technique undersamples the distribution of specific cancer biomarkers within an MR image as well as changes in the temporal dimension and subsequently reconstructs the missing data. This technique has been shown to retain a high level of fidelity even with an acceleration factor of 5. Currently there exist several different scanner types that each have their separate analytical methods in MATLAB. A graphical user interface (GUI) was created to facilitate a single computing platform for these different scanner types in order to improve the ease and efficiency with which researchers and clinicians interact with this technique. A GUI was successfully created for both prospective and retrospective MRSI data analysis. This GUI retained the original high fidelity of the reconstruction technique and gave the user the ability to load data, load reference images, display intensity maps, display spectra mosaics, generate a mask, display the mask, display kspace and save the corresponding spectra, reconstruction, and mask files. Parallelization of the reconstruction algorithm was explored but implementation was ultimately unsuccessful. Future work could consist of integrating this parallelization method, adding intensity overlay functionality and improving aesthetics.

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2016-05

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Fast, variable system delay correction for spiral MRI

Description

Magnetic Resonance Imaging using spiral trajectories has many advantages in speed, efficiency in data-acquistion and robustness to motion and flow related artifacts. The increase in sampling speed, however, requires high performance of the gradient system. Hardware inaccuracies from system delays

Magnetic Resonance Imaging using spiral trajectories has many advantages in speed, efficiency in data-acquistion and robustness to motion and flow related artifacts. The increase in sampling speed, however, requires high performance of the gradient system. Hardware inaccuracies from system delays and eddy currents can cause spatial and temporal distortions in the encoding gradient waveforms. This causes sampling discrepancies between the actual and the ideal k-space trajectory. Reconstruction assuming an ideal trajectory can result in shading and blurring artifacts in spiral images. Current methods to estimate such hardware errors require many modifications to the pulse sequence, phantom measurements or specialized hardware. This work presents a new method to estimate time-varying system delays for spiral-based trajectories. It requires a minor modification of a conventional stack-of-spirals sequence and analyzes data collected on three orthogonal cylinders. The method is fast, robust to off-resonance effects, requires no phantom measurements or specialized hardware and estimate variable system delays for the three gradient channels over the data-sampling period. The initial results are presented for acquired phantom and in-vivo data, which show a substantial reduction in the artifacts and improvement in the image quality.

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Date Created
2013

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Generation of macromolecule-templated gold nanoparticles by ionizing radiation

Description

Ionizing radiation, such as gamma rays and X-rays, are becoming more widely used. These high-energy forms of electromagnetic radiation are present in nuclear energy, astrophysics, and the medical field. As more and more people have the opportunity to be exposed

Ionizing radiation, such as gamma rays and X-rays, are becoming more widely used. These high-energy forms of electromagnetic radiation are present in nuclear energy, astrophysics, and the medical field. As more and more people have the opportunity to be exposed to ionizing radiation, the necessity for coming up with simple and quick methods of radiation detection is increasing. In this work, two systems were explored for their ability to simply detect ionizing radiation. Gold nanoparticles were formed via radiolysis of water in the presence of Elastin-like polypeptides (ELPs) and also in the presence of cationic polymers. Gold nanoparticle formation is an indicator of the presence of radiation. The system with ELP was split into two subsystems: those samples including isopropyl alcohol (IPA) and acetone, and those without IPA and acetone. The samples were exposed to certain radiation doses and gold nanoparticles were formed. Gold nanoparticle formation was deemed to have occurred when the sample changed color from light yellow to a red or purple color. Nanoparticle formation was also checked by absorbance measurements. In the cationic polymer system, gold nanoparticles were also formed after exposing the experimental system to certain radiation doses. Unique to the polymer system was the ability of some of the cationic polymers to form gold nanoparticles without the samples being irradiated. Future work to be done on this project is further characterization of the gold nanoparticles formed by both systems.

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Date Created
2012

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Synthesis and characterization of polymer-templated manetic nanoparticles

Description

This research reports on the investigation into the synthesis and stabilization of

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

This research reports on the investigation into the synthesis and stabilization of

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

i

(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.

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Date Created
2014

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Poly(amino ether) based Polymeric and Nanoparticle Systems for Nucleic Acid Delivery and Bioimaging

Description

Gold nanoparticles have emerged as promising nanomaterials for biosensing, imaging, photothermal treatment and therapeutic delivery for several diseases, including cancer. We have generated poly(amino ether)-functionalized gold nanorods (PAE-GNRs) using a layer-by-layer deposition approach. Sub-toxic concentrations of PAE-GNRs were employed to

Gold nanoparticles have emerged as promising nanomaterials for biosensing, imaging, photothermal treatment and therapeutic delivery for several diseases, including cancer. We have generated poly(amino ether)-functionalized gold nanorods (PAE-GNRs) using a layer-by-layer deposition approach. Sub-toxic concentrations of PAE-GNRs were employed to deliver plasmid DNA to prostate cancer cells in vitro. PAE-GNRs generated using 1,4C-1,4Bis, a cationic polymer from our laboratory demonstrated significantly higher transgene expression and exhibited lower cytotoxicities when compared to similar assemblies generated using 25 kDa poly(ethylene imine) (PEI25k-GNRs), a current standard for polymer-mediated gene delivery. Additionally, sub-toxic concentrations of 1,4C-1,4Bis-GNR nanoassemblies were employed to deliver expression vectors that express shRNA ('shRNA plasmid') against firefly luciferase gene in order to knock down expression of the protein constitutively expressed in prostate cancer cells. The roles of poly(amino ether) chemistry and zeta-potential in determining transgene expression efficacies of PAE-GNR assemblies were investigated. The theranostic potential of 1,4C-1,4Bis-GNR nanoassemblies was demonstrated using live cell two-photon induced luminescence bioimaging. The PAE class of polymers was also investigated for the one pot synthesis of both gold and silver nanoparticles using a small library poly(amino ethers) derived from linear-like polyamines. Efficient nanoparticle synthesis dependent on concentration of polymers as well as polymer chemical composition is demonstrated. Additionally, the application of poly(amino ether)-gold nanoparticles for transgene delivery is demonstrated in 22Rv1 and MB49 cancer cell lines. Base polymer, 1,4C-1,4Bis and 1,4C-1,4Bis templated and modified gold nanoparticles were compared for transgene delivery efficacies. Differences in morphology and physiochemical properties were investigated as they relate to differences in transgene delivery efficacy. There were found to be minimal differences suggestion that 1,4C-1,4Bis efficacy is not lost following use for nanoparticle modification. These results indicate that poly(amino ether)-gold nanoassemblies are a promising theranostic platform for delivery of therapeutic payloads capable of simultaneous gene silencing and bioimaging.

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Date Created
2014

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Improved spatial coverage of high-temporal resolution dynamic susceptibility contrast-MRI through 3D spiral-based acquisition and parallel imaging

Description

Dynamic susceptibility contrast MRI (DSC-MRI) is a powerful tool used to quantitatively measure parameters related to blood flow and volume in the brain. The technique is known as a “bolus-tracking” method and relies upon very fast scanning to accurately measure

Dynamic susceptibility contrast MRI (DSC-MRI) is a powerful tool used to quantitatively measure parameters related to blood flow and volume in the brain. The technique is known as a “bolus-tracking” method and relies upon very fast scanning to accurately measure the flow of contrast agent into and out of a region of interest. The need for high temporal resolution to measure contrast agent dynamics limits the spatial coverage of perfusion parameter maps which limits the utility of DSC-perfusion studies in pathologies involving the entire brain. Typical clinical DSC-perfusion studies are capable of acquiring 10-15 slices, generally centered on a known lesion or pathology.

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.

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Date Created
2017