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Controlled release and targeted drug delivery using polyelectrolyte microcapsulesDeo, Devendra Inder January 2014 (has links)
Polyelectrolyte microcapsules were first established in 1998 as a potential drug delivery vehicle. Despite being well-established, microcapsules have not yet been thoroughly considered as a viable means of targeted drug delivery. This is largely due to the fact that microcapsules are inherently prone to unspecific binding to cells and proteins. Targeted delivery of drugs to specific diseased sites in the body is an area of research that has attracted many studies, particularly in drug deliveries that utilise microparticles. By achieving targeted delivery of a drug, one can increase the efficacy of the treatment, thus, reducing unwanted side effects. This thesis investigates methods which can modify these microcapsules in order to fine tune the release of the encapsulated drug as well as site-specific delivery of these vesicles i.e. obtain spatiotemporal control. To this end, biodegradable microcapsules of varying constituents are manufactured and their biodegradability is indirectly measured through quantification of the release of an encapsulated fluorescent protein (Rhodamine B-BSA). Fluorometry analysis of the supernatants of these microcapsule suspensions indicated that microcapsules synthesised from poly-L-arginine and poly-L-glutamic acid have the ability to encapsulate bovine serum albumin (BSA) with a high encapsulation efficiency (79.7%). Furthermore, they are able to produce a sustained release of BSA over a period of 5 Days. To complement this controlled-release study, an investigation into self-degradable microcapsules was undertaken. To achieve this, proteinase was encapsulated in both biodegradable and non-biodegradable microcapsules of different thickness. Analysis of the protein release over a period of 24 hours revealed that the release profiles of these microcapsules can be successfully controlled. Biodegradable microcapsules released 87% more protein than their non-biodegradable counterpart after 2 hours of incubation in deionised water. This provides conclusive evidence that the biodegradable microcapsules were, indeed, self-degradable. The latter part of this thesis focuses on achieving specific and exclusive targeted delivery using polyelectrolyte microcapsules, with respect to protein substrates. This is accomplished by creating an antibody-functionalised poly(ethylene glycol) (PEG) assembly within the microcapsule structure. Site-specific adsorption of these microcapsules is tested using protein micropatterns. Results obtained from adsorption assays using anti-collagen type IV-functionalised microcapsules show a 600-fold increase in binding to collagen type IV islands, compared to control proteins (fibronectin and BSA). This proves that significant adsorption was achieved on the target protein, with unspecific adsorptions being heavily suppressed on control proteins. Furthermore, similar results were found when microcapsules were functionalised with anti-fibronectin and exposed to fibronectin, highlighting the versatility of this type of biofunctionalisation.
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Microcapsule internalization by cells in vitro caused by physical and biochemical stimuliLiu, Weizhi January 2014 (has links)
There is a growing interest in micro sized vehicles with the function of storing, targeting and controlled releasing of substances during the past few decades. However, delivering the desired drugs inside micro containers to living cells is a particular challenging topic of material science. Microcapsules made of polyelectrolyte multilayers exhibit low- or non-toxicity, appropriate mechanical stability, variable degradation and can incorporate remotely addressable release mechanisms in responding to stimuli and external triggering, making them well suitable for targeted drug delivery to live cells. This study investigates interactions between microcapsules made of synthetic (i.e. PSS/PAH) or natural (i.e. DS/PArg) polyelectrolyte and cells, with particular focus on the effect of the glycocalyx layer on the intake of microcapsules by human umbilical vein endothelial cells (HUVECs). Neuraminidase cleaves N-acetyl neuraminic acid residues of glycoproteins and targets the sialic acid component of the glycocalyx on the cell membrane. Three-dimensional CLSM images reveal that microcapsules functionalized with neuraminidase can be internalized by endothelial cells, whereas ones without neuraminidase are blocked by the glycocalyx layer. Uptake of the microcapsules is most significant in the first 2 hours. Following their internalization by endothelial cells, biodegradable DS/PArg capsules rupture by day 5, however, there is no obvious change in the shape and integrity of PSS/PAH capsules within the period of observation. Results from the study support our hypothesis that the glycocalyx functions as an endothelium barrier to cross membrane movement of microcapsules. Neuraminidase-loaded microcapsules can enter endothelial cells by cleaving the glycocalyx in their close proximity with minimum disruption of the glycocalyx layer, therefore they have high potential to act as drug delivery carriers to pass through the endothelium barrier of blood vessels into the surrounding tissue.
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Iontophoresis in paediatric medicine : non-invasive delivery and monitoring applicationsDjabri, Asma January 2009 (has links)
This thesis investigated the possible use of transdermal iontophoresis in paediatric care, as an alternative strategy to the oral and intravenous routes. More specifically, the potential for non-invasive delivery of ranitidine, midazolam, and phenobarbital; and the clinical sampling of iohexol through the skin were examined. The feasibility for monitoring kidney function was assessed in vitro and in vivo using the glomerular filtration rate (GFR) marker, iohexol. Sampling of iohexol in vitro was sensitive to the changes in its subdermal concentration, and pharmacokinetic parameters estimated from skin sampling agreed well with reference subdermal values. Similar observations were confirmed in vivo in a pilot study performed in four children undergoing routine iohexol GFR test. Iontophoresis was well tolerated in all subjects and the marker was successfully extracted through the skin. In 3 of 4 subjects, the elimination rate constant estimated from skin sampling data agreed well with blood sampling results. This study demonstrated the potential of transdermal iontophoresis as a non-invasive sampling approach which could significantly improve the quality-of-life of children. Drug delivery by transdermal iontophoresis was examined in vitro for three commonly used paediatric medicaments: ranitidine, midazolam, and phenobarbital. Experiments used both intact and compromised pig skin to model the less resistant skin of premature babies. Iontophoretic delivery across intact skin was superior than passive delivery and optimised conditions were achieved by use of maximal molar fraction of the drug, higher current intensity, and appropriate vehicle pH. Pluronic® F-127 gels were suitable drug matrices for the iontophoretic delivery of ranitidine. Midazolam and phenobarbital transdermal delivery through partially compromised skin barriers was controlled by iontophoresis. Across highly compromised skin, however, passive diffusion increased drastically and iontophoretic control was lost. Overall, it was possible to deliver therapeutically meaningful fluxes of all three drugs with acceptable patch application area.
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Synthesis of imprinted polymers for the detection of tamoxifen or its metabolites and evaluation of their potential as drug carriersFosca, Mirata January 2017 (has links)
Recent advances in the area of nanotechnology have led to interesting applications of nanomaterials in medicine, especially in the areas of imaging and treatment. This thesis presents the development of two molecularly imprinted polymers (MIPs) based on the same fluorescent functional monomer. One MIP, prepared in the bulk format, is investigated for its ability to detect tamoxifen and its metabolites. The other MIP synthesised in the nanogel format, holds the potential to be used as pH-responsive drug delivery system. Four objectives were identified within this project. The first was the design and synthesis of fluorescent functional monomer. Two coumarin derivatives carrying a polymerisable unit, for covalent bonding within the polymer, and a carboxylic moiety, for interaction site with the template, were synthesised and characterised. However, only one of them (the VCC: 6-vynilcoumarin-4-carboxylic acid) showed high fluorescent yield and was selected as functional monomer. The second objective involved the development of a detection system based on bulk MIP containing the VCC fluorescent monomer. This system proved effective in generating a detectable signal upon binding the analytes. The signal was observed as a quenching of the polymer fluorescence and it was proportional to the amount of target molecules detected. The third objective was the preparation of tamoxifen-imprinted nanogels for potential application in the drug delivery field. The optimisation of the procedure gave a set of NIP/MIP with the desired solubility, particle size and fluorescence emission. These nanogels were then employed in the last objective, which involved the toxicity study and evaluation of the drug loading on of transgenic line of zebrafish. The nanogels were non-toxic at the tested concentrations and the presence of tamoxifen was confirmed.
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Cationic polymer brush coated nanoparticles for gene deliveryLi, Danyang January 2018 (has links)
Polymer brushes generated via "grafting-from" approach emerged as an attractive surface modification tool offering chemical stability, synthetic flexibility and unprecedented control over the polymer grafting density, thickness, chemical composition and functionality. They display interesting features to many applications in regenerative medicine including cell culture, tissue engineering and as delivery systems due to exquisite control of physicochemical and biological properties. Cationic polymer brushes are particularly attractive in the field of designing effective vectors for gene delivery as polymer brush allows the design and coating of a variety of particles with well-defined core-shell architecture and chemistry to efficiently condense and deliver nucleic acids. This thesis concentrates on designing safe and efficient gene delivery vectors based on 'graft from' cationic polymer brush and understanding the interaction of nucleic acids with polymer brush. Chapter one presented fundamental knowledge of polymer brush and its biomedical application. The first part of this chapter describes the definition of polymer brush, the preparation strategies, mechanism of atom transfer radical polymerisation and the responsiveness of polymer brush including solvent, pH and ionic strength. The second part discusses the state-of-art applications of polymer brush in regenerative medicine including protein resistant polymer brush for tissue engineering and as drug/gene delivery systems.
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Chemical Targeting of Specific Cell Types in Living Brain TissueNwadibia, Ekeoma C. January 2018 (has links)
This thesis details our early efforts towards the discovery of polymeric and macromolecular platforms for the targeted delivery of sensors and actuators to specific cell types in the living brain tissue. Chapter 1 of this thesis discusses the small molecule tropane tag chosen as a homing ligand and the dopamine transporter (DAT) chosen as a cellular target, as well as the synthesis of new tropane-based molecular tags for evaluation in cultured human DAT (hDAT)-expressing cells and targeting in brain tissue. Chapter 2 discusses the results obtained from evaluation of the new tropane tags in hDAT-expressing and hNET-exressing cells, including early results from the first example of a DAT-specific voltage sensing dye. In Chapter 3, we discuss the principles governing molecular targeting of probes in the living brain tissue. Part I of Chapter 3 gives important background necessary for understanding some of the complexities involved in targeting chemical probes to specific sites in living brain tissue. Part II of Chapter 3 discusses early results obtained from targeting of our tropane tags in living brain tissue. We provide, perhaps, the first example of a binding-site barrier effect in healthy tissue and demonstrate successful delivery of a moderate-sized protein, neutravidin, to dopaminergic axons. Chapter 3 also discusses preliminary results demonstrating the behavior of our small molecule tag and tagged quantum dot construct in the living mouse brain. Studies of our tagged polymers in cultured cells and our work thus far in the brain suggest which polymers may be most effective as delivery platforms for chemical targeting to specific cell types in living brain tissue.
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Delivery of therapeutic aerosols to newborns and young infants.January 1997 (has links)
by Tai Fai Fok. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (p. 211-215). / Microfiche. Ann Arbor, Mich. UMI, 1998. 3 microfiches ; 11 x 15 cm.
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Drug and gene delivery strategies for targeting mechanobiological and biochemical pathways for joint and bone tissue engineeringAtluri, Keerthi 01 May 2019 (has links)
A major challenge in drug development is ensuring that each new candidate drug is delivered to the appropriate location, in a timely manner and at an optimal concentration. Low drug solubility, drug instability, drug degradation, drug toxicity, or rapid clearance from the body can reduce the effectiveness of an otherwise promising drug candidate. Formulations such as nano/microparticles and melt extruded pellets made with synthetic and natural polymers are effective solutions for the advancement of drug delivery technology. These polymeric formulations can provide controlled release of therapeutic agents by delivering constant doses over long periods, cyclic dosages, and tunable release of both hydrophilic and hydrophobic drugs in order to improve the bioavailability and bioactivity of a drug. PLGA-based nanoparticles formed by emulsion or nanoprecipitation techniques can be designed to have a range of degradation times. Particle degradation and drug release kinetics can be controlled by the physiochemical properties of the polymer, such as molecular weight, hydrophobicity, and polydispersity. This study is focused on developing polymeric-based delivery systems for small and large molecules as treatment strategies for arthrofibrosis and bone tissue engineering.
In developing arthrofibrotic treatments, several mechanosignaling and biochemical pathways were targeted using small molecule therapeutics such as blebbistatin (a myosin II ATPase inhibitor), paclitaxel (a microtubule stabilizer), sulfasalazine (a kappa B suppressor), beta-aminopropionitrile (a lysyl oxidase inhibitor) and cis-hydroxyproline (inhibits the formation of stable triple helix structure of collagen). The aforementioned drugs were delivered either via PLGA micro/nanoparticles or via pellets formed by melt extrusion. From the studies performed, it was found that blebbistatin delivered by PLGA nanoparticles could reversibly inhibit fibroblast contractile activity and could significantly inhibit collagen synthesis. These findings lay the foundations for further optimization of drug dosing and potentially enabling a new drug delivery technology for treating arthrofibrosis. Sulfasalazine delivered by melt extruded PLGA pellets significantly inhibited myofibroblast numbers as deduced from α-SMA expression and col1A1 gene expression results and thus can be considered a potential treatment for arthrofibrosis.
For bone tissue engineering, plasmids encoding differentiation promoting factors or growth factors such as BMP-2 (pBMP-2), FGF-2 (pFGF-2), PDGF (pPDGF) and VEGF (pVEGF) were delivered via polyethylenimine (PEI), a cationic carrier that interacts electrostatically with negatively charged DNA. The formed nanoplexes were either tested directly or by coating them onto biocompatible titanium metal implants and cultured with human bone marrow derived mesenchymal stem cells (hBMSCs). We found that the combinatorial delivery of pBMP-2 and pFGF-2 significantly enhanced bone regeneration as deduced from Runx-2, alkaline phosphatase and osteocalcin gene expression results as well as from data yielded from alizarin red staining assays and atomic absorption spectroscopy where calcium ion levels were measured. It was also found that pBMP-2 nanoplex-coated titanium discs could significantly enhance bone regenerative gene expression for osteocalcin, Runx-2, and alkaline phosphatase as well as enhance calcium ion expression in human adipose derived mesenchymal stem cells (hADMSCs). Thus, it can be concluded that pFGF-2 and pBMP-2 nanoplexes have osteogenic potential and our studies demonstrate a new methodology with the potential to modify titanium disc implant surfaces for the purposes of enhancing osseointegration.
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pH sensitive thread-based wound dressing with integrated drug delivery and wireless bluetooth interfaceKarperien, Lucas 08 November 2019 (has links)
Wound treatment is a significant field in healthcare, but one with huge potential and need for advancement. Infection monitoring, in its current state, is a largely primitive affair, relying on visual and olfactory inspection to detect bacteria. As a result, early detection is impossible, and doctors and patients are forced to remove dressings to investigate the wound in a laborious, painful, and unsanitary process. When an infection is detected, the treatment is typically systemic administration of antibiotics. Systemic administration reduces the concentration of antibiotics that can be brought to bear on the infection because it interacts with the entire body and is dissipated by the time it reaches the wound and increases the risk of side effects or antibiotic resistance. Within this thesis, a smart, thread-based wound dressing is presented that addresses these issues by providing a pH-based early detection system accompanied by a topical, on-demand drug delivery system. The device has been tested in vitro and in vivo, on bacterial culture and on an animal model, and demonstrated effectiveness at detecting and eliminating bacteria, and at promoting wound healing. This smart wound dressing has the potential to improve treatment and outcomes for a wide variety of injuries, varying from burns to chronic wounds. / Graduate / 2020-10-10
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Role of stromal SPARC in PDAC tumorigenesis and drug deliveryRamu, Iswarya 10 December 2018 (has links)
No description available.
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