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Molecular design of advanced oral protein delivery systems using complexation hydrogelsWood, Kristy Marie, January 1900 (has links) (PDF)
Thesis (Ph. D.)--University of Texas at Austin, 2006. / Vita. Includes bibliographical references.
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Intra-articular Clearance of Silk Microparticles and Macromolecules in Healthy and Arthritic Rat Knee JointsMwangi, Timothy Kariithi January 2015 (has links)
<p>Osteoarthritis (OA) is a degenerative disease of articular joints characterized by progressive deterioration of the cartilage lining, subchondral bone destruction and thickening of the joint capsule. These tissue changes lead to symptomatic joint pain and joint dysfunction, leading to restrictions on daily life activities. Intra-articular injections of corticosteroids or anti-inflammatory compounds are commonly given to relieve symptoms associated with OA; however, rapid clearance of these compounds from the joint space and into draining synovial lymphatics necessitates the use of drug carriers to increase drug residence and efficacy. </p><p>Silk fibroin, a protein polymer from the mulberry silkworm (Bombyx mori) and of slow biodegradation in vivo, has a long history of clinical use. Silk fibroin can be fabricated into nano- and micro-particles capable of entrapping small-molecule drugs to provide for sustained release. For this work, silk microparticles were fabricated entrapping the near-infrared fluorescent dye, Cy7, as a model small-molecule drug. The release kinetics of the Cy7 from the silk microparticles were characterized in vitro and fluorescence in vivo imaging was used to study the clearance of silk microparticles following intra-articular injection in healthy rat knee joints.</p><p>Furthermore, a surgically-induced model of OA was used in rat knee joints to study the effect of OA pathology on intra-articular clearance. Fluorescently-labeled dextrans of varying size (10 and 500 kDa molecular weight) were intra-articularly injected in the knee joints of healthy and OA rats, and fluorescence in vivo imaging was employed to detect changes in the intra-articular clearance. Additionally, a new method to characterize the trans-synovial clearance of the fluorescent dextrans was developed using the confocal microscopy of joint tissue sections from healthy and OA joints.</p> / Dissertation
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Targeted delivery of BMP4-siRNA to hepatic stellate cells for treatment of liver fibrosisOmar, Refaat 22 December 2015 (has links)
Hepatic fibrosis is a serious health problem in many parts of the world. However, its treatment remains severely limited because of inadequate target specificity. HSC are the largest reservoir of vitamin A in the body. They are also the principal players responsible for the pathogenesis of liver fibrosis. Targeting HSC is an effective strategy for treatment of liver fibrosis. The specific association of BMP4 with various liver diseases including liver fibrosis makes it an ideal candidate for targeting HSC cells using siRNA. The objective of this study is to develop and characterize vitamin A (VA)-coupled liposomes for the targeted delivery of BMP4-siRNA to cultured HSC. DOTAP/DOPE liposomes surfaces were prepared by thin film hydration and their surfaces were decorated with VA (1:2 mol/mol). Particle size and zeta potential were determined using ZetaPALS. In addition, the siRNA binding efficiency was determined by ultra-centrifugation and fluorescence assays. The cytotoxicity of VA-conjugated liposomes was evaluated by the WST-1 cytotoxicity assay. Inhibition of BMP4 and α-SMA was determined by real time PCR and ELISA. Their average particle size was in the range of 100-120 nm and they exhibited zeta potential around +45 mV. VA-coated liposomes were mixed with BMP4-siRNA, forming lipoplexes with particle sizes less than 200 nm and zeta potential around +25 mV. The presence of VA did not alter the siRNA binding efficiency, it also had no effect on cytotoxicity, but resulted in enhanced cellular uptake of siRNA as shown by flow cytometry. There was a significant reduction in BMP4 mRNA with VA-coupled liposomes carrying BMP4-siRNA. Moreover, BMP4 gene silencing was accompanied by a significantly reduced the expression of the potent fibrinogenic α-SMA at mRNA and protein levels. In conclusion, VA-coated liposomes were successfully able to target and deliver BMP4-siRNA to HSC. This could offer an interesting perspective for the treatment of liver fibrosis. / February 2016
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Exploiting graphene as a therapeutics platform in biological systemsMccallion, Catriona January 2017 (has links)
Since its isolation in 2004, the research landscape around graphene and other 2D materials has expanded rapidly and now encompasses fields as diverse as electronic engineering and drug delivery. For biomedical applications, one of the most desirable properties of the graphene family of nanomaterials (GFNs) is their 2D geometry; the high surface area to volume ratio that is characteristic of nanomaterials is taken to its extreme in a material that can be viewed as being entirely surface. This particular property alongside the versatility with which they may be functionalised both makes GFNs well positioned to function as the foundation of highly tailored and multifunctional therapeutics platforms. In this project, two GFN types, namely pristine graphene and graphene oxide, were prepared to form suspensions suitable for application to therapeutics delivery. Firstly, experiments using four essential amino acids with pristine graphitic material were undertaken to assess whether graphene flakes could be suitably exfoliated and suspended using sonication in the presence of aqueous solutions of these biocompatible molecules. A positive correlation was found between the hydrophobicity of the amino acid and the presence of one or more aromatic rings in the amino acid, and the efficacy of exfoliation both in terms of concentration achieved in suspension and flake thinness. However, the system itself was found to be highly complex, both with regards to the sonication used to exfoliate the graphitic flakes, and the interactions between the amino acids and the flakes. These considerations limited the wider applicability of this form of graphene preparation for therapeutics delivery applications. Secondly, work was performed on graphene oxide (GO), a GFN far more studied in the literature, but notoriously heterogeneous. Therefore much of the work completed focused on its characterisation. A combination of established and novel fluorescence-based characterisation methods were used to fully characterise three preparations of GO, before preliminary experiments were undertaken to test their interactions with cell components. The work showed that the inherent fluorescence of GO can be exploited to improve suspension characterisation; raster image correlation spectroscopy (RICS) was used to measure the apparent hydrodynamic radii of the flakes and flow cytometry was used to provide insight into the interactions between GO flakes and serum components. Preliminary cellular experiments confirmed that flow cytometry could be also employed to assess particular graphene characteristics in the context of cell culture, demonstrating the relatively low toxicity of PEGylated GO compared to unfunctionalised GO. Finally, as the therapeutics target for this project was leukaemia, a targeting ligand was designed and synthesised that could bind to CXCR4 - a receptor that is overexpressed on CLL B-cells, as well as many other cancer types. The ligand was synthesised such that it could easily be attached to GO, however its molecular structure is flexible enough that it can be attached to a number of different therapeutics materials. It was confirmed using both competition and functional assays that the molecule was antagonistic, and was able to deliver a conjugated fluorescent molecule specifically to the CXCR4 receptors on primary CLL B-cells. The work presented in this thesis illustrates the complexity that affects the use of GFNs in biomedicine, but also confirms the potential for their future development. The field is still young, and therapeutics delivery is likely to benefit from advances in the preparation of pristine graphene, and from methods to minimise the heterogeneity of GO. These steps will support a route towards clinical application. In addition, as the field of 2D materials expands, other materials with enviable surface area to volume ratios may come to the fore. Furthermore, this thesis has shown the value of exploring novel approaches to the characterisation of GFNs, and has identified approaches that may be exploited to improve applications of GFNs in biomedicine. Additionally, the aim of using GFNs as a platform for a multifunctional therapeutics delivery vehicle was developed with regards to the attractive CXCL12/CXCR4 axis, which is relevant in a large number of disease states including over 20 cancers, by demonstrating a flexible targeting ligand that could be used to exploit the CXCR4 receptor as a drug delivery target.
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Structural studies of binding to apo-neocarzinostatinUrbaniak, Michael Daniel January 2001 (has links)
No description available.
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Characterization of polymeric microspheres used in drug delivery via electron microscopyGomez Monico, Jose Carlos A. 29 August 2018 (has links)
Drugs can be made up of nucleic acids, sugars, small organic and inorganic compounds, peptides, and large macromolecules. Drug therapy can be optimized by controlled delivery systems that release an appropriate dose to the site of action, extend the duration of delivery, reduce administration sessions, and can target a precise site of activity. An advanced method of controlled drug delivery is through injectable polymeric biomaterial microparticles that entrap drugs within their matrix for slow release (1-6 months). Surface morphology of polymer microparticles is known to affect drug release; however, it is often reported in qualitative terms only.
In this thesis, a mastery over the controlled fabrication of biodegradable poly (ε-caprolactone) (PCL) microspheres is shown, as well as their characterization using different imaging conditions/techniques of the scanning electron microscope (SEM). Retinoic acid (RA), a morphogenic molecule, is encapsulated to create RA/PCL microspheres that are used to successfully deliver drug to human induced pluripotent stem cell aggregates. Furthermore, this works reports the creation of variable surface morphology PCL microspheres and their characterization via size analysis and stereo-microscopy. A rough morphology candidate is identified and selected for 3D SEM surface model reconstruction via a computer vision technique. Surface studies via SEM have a lot of potential to advance the development of these particles. The 3D model first reported here serves as foundation for quantitative surface morphology measurements. / Graduate
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Structure determination, mechanistic study, and safe delivery of an anti-cancer peptideYu, Jing January 1900 (has links)
Doctor of Philosophy / Department of Chemistry / Stefan H. Bossmann / The therapeutic peptide sequence D-K₆L₉: LKLLKKLLKKLLKLL-NH₂ was developed for treating bacterial infections and solid tumors. It is effective against both conditions, because it is capable of targeting negatively charged surface domains due to its positive charge and the presence of hydrophobic units. Here, the peptide was modified with two extra amino acids (Serine and Alanine) at both, C and N terminals, resulting in SA-D-K₆L₉-AS. The sequence and structure of the modified peptide were determined by means of 2D ¹H-¹H -COSY, NOESY, and TOCSY-NMR spectroscopy. The 3D structure of the peptide in the solution phase was generated by CNS software utilizing data generated by NOE spectroscopy. This peptide was tested on the following mouse cancer cell lines: GL 26 (glioma), 4T1 (metastasizing breast cancer), NSC (neural stem cells), and pig monocytes. The LC50 values of the modified peptide were found to be 5- 10 times more active than of the original D-K₆L₉. To gain insight into its biochemical mode of action, SA-D-K₆L₉-AS tagged with a Rhodamine dye was incubated with GL 26 cancer cells. Sequential confocal imaging (every 30 seconds) revealed that the peptide interacts with cell membranes according to the carpet mechanism, and then becomes internalized into the cytoplasm in less than 5 min. and localizes in the mitochondria. This peptide is found to be toxic to neuronal stem cells and monocytes as well, showing the same mechanisms of interaction. To avoid the non-specific toxicity of the peptide for in-vivo applications, highly mesoporous silica nanoparticles (MSN) were synthesized, which served as a “container” for drug delivery. The peptide was then loaded into the MSN. MSN were further coated with a polysilazane as “gift wrap” (gatekeeper) after loading the peptide. This gatekeeper forms a shell that contains the peptide inside the MSN. While inside the MSN, the peptide shows no toxicity at 24 hours and subsequent slow release of its payload into the cytoplasm within 72 hours. This technology could be very useful for in-vivo cancer therapy by means of targeted delivery to the cancer site with appropriate surface modification of MSNs.
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Investigating controlled release pulmonary drug delivery systemsChia, Leonard Sze Onn January 2018 (has links)
The therapeutic effect of pulmonary drug delivery systems is limited by its rapid clearance from the lungs by robust clearance mechanisms. By controlling the release of drugs, the therapeutic effect of pulmonary drug delivery systems, as well as patient convenience and compliance could be improved by reducing the number of times drugs need to be administered. In this study, two controlled pulmonary drug delivery systems for drugs of different solubilities were investigated and they were characterised for their viability as effective controlled release pulmonary drug delivery systems, particularly in areas of aerosol performance and dissolution profile. A hybrid protein-polymer controlled release pulmonary drug delivery system was developed to sustain the release of a water-soluble anti-asthma drug, cromolyn sodium (CS). Two excipients with complementary characteristics – a protein, bovine serum albumin, and a polymer, polyvinyl alcohol – were formulated together with CS via co-spray drying, with varying protein-polymer ratios and drug loadings. The hybrid particles showed promise in combining the positive attributes of each excipient, with respirable particles shown to sustain the release of CS with a fine particle fraction of 30%. Combining the two excipients was complex, with further optimisation of the hybrid formulations possible. A commercially available polymer, Soluplus® was spray-dried with a poorly-water soluble corticosteroid, beclomethasone dipropionate (BDP). The resultant respirable powders were shown to have potential for use as a controlled release pulmonary drug delivery system with up to 7-fold improvement in the amount of BDP released compared to spray-dried BDP. The spray-dried BDP-Soluplus® powders were found to be amorphous, and physically stable against re-crystallisation for up to 9 months at accelerated stress test conditions with drug loadings of up to 15 % (w/w). Although it provided a platform to compare between formulations, the USP 4 flow-through cell dissolution apparatus was found to be inadequate to accurately study the dissolution profiles of the pulmonary drug delivery systems due to the formation of a gel in the apparatus. Preliminary work on the use of a novel technique to predict the crystallisation of amorphous formulations with terahertz time-domain spectroscopy was also conducted. The system confirmed the re-crystallisation tendencies of several hybrid CS/BSA/PVA formulations. Modification to the experimental setup to probe the formulations at different relative humidities instead of temperatures could yield improved results.
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Simvastatin Encapsulation in Alginate-Based MicrospheresParsian, Ava January 2016 (has links)
Despite the great success of hip implant surgeries, wear particle-induced implant aseptic loosening still limits the implant longevity. Simvastatin, an FDA-approved cholesterol lowering statin, is a promising drug candidate for the treatment of implant aseptic loosening due to its anti-inflammatory properties as well as its ability to stimulate bone growth and inhibit bone resorption. In addition, alginate microspheres have been used extensively in drug delivery applications because of alginate properties, including biocompatibility and gelation in mild conditions. However, the hydrophobicity of simvastatin, as well as the large alginate microsphere pore size leading to the leakage of low molecular weight drugs are limiting factors for their use as a delivery system for simvastatin. Therefore, the objectives of this thesis were twofold: 1. To complex simvastatin with 2-hydroxypropyl-β-cyclodextrin (HP-βCD) in order to increase its solubility; and 2. To increase simvastatin encapsulation efficiency in alginate microspheres by coating the microspheres with chitosan, adding dextran sulfate in the alginate solution, and optimizing the gelation conditions used for the synthesis of the microspheres (e.g., volume of gelation medium, curing time, and addition of simvastatin in the gelation medium). Results showed that simvastatin complexation with HP-βCD increased with HP-βCD to simvastatin molar ratio, to a maximum of 97.6% at the molar ratio of 10. Results also showed that chitosan coating of the alginate microspheres increased simvastatin encapsulation efficiency (up to 10.6%), which was further improved (up to 14.0%) when adding 2.0% (w/v) dextran sulfate to the alginate solution. This increase was likely due to electrostatic interactions between dextran sulfate and chitosan in addition to alginate, resulting in a denser coating. Finally, the addition of simvastatin in the gelation medium was shown to also increase simvastatin encapsulation (up to 22.4%), likely because of a decrease in the diffusion of simvastatin out of the microspheres. Overall, this work completed the initial steps for the development of an alginate-based drug delivery system for simvastatin with the long-term goal of providing a local delivery of simvastatin to modulate implant aseptic loosening.
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Novel Therapeutic Delivery via Cell-Nanoparticle HybridizationCooper, Remy C 01 January 2017 (has links)
The immobilization of surface-modified polyamidoamine (PAMAM) dendrimers on the cell surface introduces a novel approach for efficient and specific cellular uptake of therapeutic-carrying nanoparticles. This cell surface-nanoparticle hybridization event takes place via bioorthogonal copper-free click chemistry between a dibenzocyclooctyne (DBCO) group on the dendrimer surface and azide-capped glycans expressed on the cell membrane through metabolic incorporation of azido sugars. This particular cell-nanoparticle hybridization method can be exploited to deliver a variety of therapeutic, genetic or fluorescent payloads directly into cells. Here, this method was employed to deliver plasmid DNA, siRNA and the hydrophobic anticancer drug Camptothecin (CPT) to enhance transfection and therapeutic efficacy. Native, acetylated, and PEGylated generation 4 (G4) PAMAM dendrimers were conjugated with DBCO. When introduced to azide expressing NIH3T3 fibroblasts and HN12 cancer cells, successful surface hybridization was achieved. The physiochemical properties of PAMAM dendrimers allowed for successful hydrophobic drug encapsulation and electrostatic nucleic acid condensation.
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