Dissertations / Theses on the topic 'Drug Targeting'
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Abbassi, Ramzi Hussam Suleiman. "Targeting glioblastoma with microtubule-targeting agents and epigenetic modulators." Thesis, The University of Sydney, 2020. https://hdl.handle.net/2123/25072.
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Glioblastoma is one of the most lethal tumours. However, current standard of care therapy is ineffective at eradicating the entire tumour cell population. This fractional killing occurs as glioblastoma cells possess great intertumour (patient-to-patient) and intratumour (cell-to-cell) heterogeneities, leading to tumour recurrence.
Microtubules are required for proliferation and other integral cell processes, thus one proposed therapeutic approach to glioblastoma is the use of microtubule-targeting agents (MTAs). It is postulated that this ‘non-targeted’ approach would kill all tumour cells. However, while classical MTAs such as taxanes and Vinca alkaloids are clinically successful anti-cancer drugs and are effective at killing glioblastoma cells in vitro, the polarity and large molecular mass of these drugs render them useless for the treatment brain tumours, as they cannot cross the blood-brain barrier. Our laboratory has been developing small-molecule MTAs, based on the lead inhibitor CMPD1, which are able to cross the blood-brain barrier and effectively kill glioblastoma cells in vivo. While the drug development of small-molecule MTAs for glioblastoma therapy is commercial-in-confidence, the overarching aim of this PhD candidature was to assess the translational potential of microtubule-targeting agents for glioblastoma therapy.
We first questioned whether microtubule heterogeneity, resulting from numerous tubulin isoforms and their post-translational modifications impacts on sensitivity of glioblastoma cells to MTAs. Using a panel of 12 genetically diverse glioblastoma stem cell lines and per-division growth rate inhibition metrics we established that the total α- and β-tubulin levels impact on MTA sensitivity. The baseline levels of α- and β-tubulin were up to 40% lower in cells that were not effectively killed by MTAs. Further, low α/β-tubulin expression was associated with higher degree of stemness. Importantly, we discovered that in every glioblastoma cell line, regardless of tubulin expression levels and sensitivity to MTA, a small subpopulation of cells survived MTA treatment via reversible non-mutational dormancy.
The cells that survived the treatment, known as drug-tolerant persister (DTP) cells, resumed proliferation in ‘drug holidays’ and displayed the same sensitivity to MTAs as their treatment-naïve parental population. Hence, the drug-tolerant state is a survival mechanism mediated by reversible epigenetic processes, often via changes to the histone H3 subunit of the nucleosome. We used SWATH-MS, a technique emerging as a gold-standard in large-scale proteomics, to assess changes in histone H3 post-translational modifications in DTP cells and compared these to modifications in treatment-naïve parental cells. The analysis revealed that DTP cells exhibit a global decrease in histone lysine acetylation and an increase in histone lysine methylation, which is consistent with a genetically repressive chromatin state. Assessment of transcript levels of histone lysine methyltransferases (KMTs) and demethylases (KDMs) demonstrated more increases in KMT than KDM transcripts in DTP cells relative to their treatment-naïve parental counterparts, supporting SWATH-MS findings.
A screen of a library of epigenetic probes and a series of pharmacological assays using disease-relevant cell models discovered that DTP cell recovery and return to a proliferative state was hampered when treated with CMPD1 in combination with inhibitors targeting KDM4 or KDM6. Taken together, the research presented in this thesis suggests that small-molecule MTA are promising drugs to treat glioblastoma patients. However, in order to achieve complete killing of all glioblastoma cells within a tumour population, MTAs must be combined with drugs targeting DTPs. It is hypothesised that KDM inhibitors prevent the demethylation of methylated lysine residues acquired in drug-tolerant cells, and hence, prevent recovery.
Further, we identified KDM4 as a potential novel target in treatment-naïve glioblastoma cells. Given the lack of orthogonal and cell-permeable KDM4 inhibitors to validate KDM4 as a target, we established a high-throughput AlphaScreen KDM4 inhibition assay to begin the drug discovery process. Using this assay, we screened a small chemical library and identified two hit molecules that offer excellent starting points for future hit-to-lead optimisation and the development of KDM4 inhibitors.
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Wright, J. J. "Targeting of colloidal drug carriers." Thesis, University of Nottingham, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381059.
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Saunders, J. E. "Drug targeting using albumin microspheres." Thesis, University of Nottingham, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381061.
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ORSATO, ALEXANDRE. "Studies on tumor drug targeting." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2011. http://hdl.handle.net/10281/19200.
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Tumor drug targeting is one of the most promising therapeutic strategies in oncology. The aim of this PhD work was the study of the essential features required for the assembly of tumor targeting conjugates.This work was focused on the deveploment of ligands for the GRP receptor that should function as carrier molecules for the targeting of tumor cells overexpressing this receptor. For this purpose, non-peptide GRP mimetics were designed, using a computer-based drug design technique, synthesized and tested. Two analogue compounds based on a bicyclic scaffold exerted an antagonist behaviour on the GRP receptor. Synthetic studies have been performed to optimize their production as well as biological tests to determine their potential as carrier molecules. Apart from the targeting moiety, we also studied the antineoplastic part of tumor targeting conjugates. Akt is a proto-oncogenic kinase that has been associated to cancer development. Therefore, the Akt inhibitory activity of phosphatidylinositol phosphate analogues was exploited. A small library of iminosugar-based phosphatidylinositol phosphate analogues was designed and synthesized. During the biological evaluation, target compounds displayed low to moderate inhibitory activity for Akt, which suggests their feasibility for the development of new and more potent Akt inhibitors.
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Nacev, Aleksandar Nelson. "Magnetic drug targeting| Developing the basics." Thesis, University of Maryland, College Park, 2013. http://pqdtopen.proquest.com/#viewpdf?dispub=3587279.
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Focusing medicine to disease locations is a needed ability to treat a variety of pathologies. During chemotherapy, for example, typically less than 0.1% of the drugs are taken up by tumor cells, with the remaining 99.9% going into healthy tissue. Physicians often select the dosage by how much a patient can physically withstand rather than by how much is needed to kill all the tumor cells. The ability to actively position medicine, to physically direct and focus it to specific locations in the body, would allow better treatment of not only cancer but many other diseases.
Magnetic drug targeting (MDT) harnesses therapeutics attached to magnetizable particles, directing them to disease locations using magnetic fields. Particles injected into the vasculature will circulate throughout the body as the applied magnetic field is used to attempt confinement at target locations. The goal is to use the reservoir of particles in the general circulation and target a specific location by pulling the nanoparticles using magnetic forces.
This dissertation adds three main advancements to development of magnetic drug targeting. Chapter 2 develops a comprehensive ferrofluid transport model within any blood vessel and surrounding tissue under an applied magnetic field. Chapter 3 creates a ferrofluid mobility model to predict ferrofluid and drug concentrations within physiologically relevant tissue architectures established from human autopsy samples. Chapter 4 optimizes the applied magnetic fields within the particle mobility models to predict the best treatment scenarios for two classes of chemotherapies for treating future patients with hepatic metastatic breast cancer microtumors.
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Macadam, Anglea Brenda. "Drug targeting in the gastrointestinal tract." Thesis, University of Brighton, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306400.
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Hyde, Robert. "Drug targeting with phagocytic polymorphonuclear leucocytes." Thesis, Aston University, 1989. http://publications.aston.ac.uk/12577/.
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1. Phagocytic polymorphonuclear leucocytes (PMNLs) or neutrophils have a marked avidity for the uptake of particulate material and are the first cell type to respond to inflammatory stimuli in vivo. 2. By harnessing these pathophysiological characteristics the inherent targeting capacity of the PMNL could be exploited to carry drug loaded particles to these sites. 3. In vitro chemotaxis of PMNLs was studied in response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) in the Blindwell chamber assay. 4. After phagocytosis of 1.1m polystyrene latex (PSL) beads at a range of incubation concentrations (5,10,20, and 30 beads/cell) the migration of the PMNL population was not significantly different from control, without beads. 5. The distribution of the beads within the filter showed that a disproportionately large number of PSL (50%) were associated with the cells on the surface of the filter that had not penetrated the filter. Eighty per cent of the PMNL population migrated and despite containing less PSL beads/cell, 50% of the dose was carried into the filter. Between 5 and 10% of these PSL were carried beyond 60m in the assay. 6. These results suggested heterogeneity of the PMNL population and to achieve efficient targeting with these cells preferential selection of the migratory sub-population would be needed. 7. The air-pouch model was then developed to study the focal accumulation of PMNLs in vivo. The PMNL isolated did not survive long enough in the circulation due to the trauma of the isolation procedure used; an alternative method will have to be employed.
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Zhang, Qian. "Natural Product Drug Discovery Targeting Cancer." Thesis, Griffith University, 2017. http://hdl.handle.net/10072/370435.
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Chemotherapy is one of the most effective approaches for cancer treatment. However, to improve efficacy, the therapeutic targets should be identified and characterised. Moreover, new drugs need to be discovered and developed to target different cancer pathways. Current therapeutics can eliminate most of the cancer cells. However, recurrence and metastasis still remain a major failure of cancer therapy. Emerging evidence demonstrates that multidrug resistance (MDR) and the existence of cancer stem cells (CSCs) are two major contributors for the failure of chemotherapy. MDR is a phenomenon in which cancer cells become resistant to structurally and functionally unrelated anticancer agents. CSCs are a small population of cells within cancer cells with capacity for self-renewal, tumor metastasis and differentiation. CSCs are also believed to be associated with chemoresistance. Thus, MDR and CSCs are the greatest challenges for cancer chemotherapy. Significant effort has been made to search for agents that specifically target MDR cells and CSCs. Consequently, some agents derived from nature have been developed to overcome MDR and CSCs. However, the developed chemotherapeutics cannot be used for all the cancers and some of them display severe cytotoxicity. Hence, there is an urgency to investigate the mechanism of drug resistance and to characterise cancer stem cells to identify potential new therapeutic targets. Natural products lie in the heart of the drug discovery. The developed chemotherapeutic compounds mainly originates from the secondary metabolites of microbes, terrestrial plants and marine organisms. In this study, MDR cancer cells were derived from tissue cultured cancer cells by the treatment the cells with fluorouracil (5-FU) and cisplatin (CDDP). CSCs were developed by treatment in serum-free medium with different factors. Fractions and compounds from Nature Bank (Griffith Institute for Drug Discovery, Griffith University), Compounds Australia (Griffith Institute for Drug Discovery, Griffith University) and Traditional Chinese Medicine (TCM) were screening by high through-put screening (HTS). As a result, one potential anticancer flavonoid was isolated from the Australian plant Cryptocarya (QID025519) which was identified by NMR spectroscopic data, in combination with LC-MS. Extracts, fractions and isolated pure compounds from Bruguiera gymnorrhiza andSchisandraviridis were identified as potential agents for the treatment of tongue cancer and breast cancer. The DCM and MeOH extracts and HPLC fractions of B. gymnorrhiza showed antiproliferation activity against cancer cells in a concentration-dependent manner. Further purification of the active fractions led to the isolation of five flavonoids namely rutin, myricetin 3-rutinoside, methoxyflavone, 5-Methoxyluteolin, and 7,3',4',5'-tetrahydroxy-5- gramrione. All five compounds showed antiproliferation activity against CAL27 and MCF7 and MDR cells in a concentration-dependent manner. Methoxyflavone demonstrated the strongest anticancer potential against CAL27 cells, MCF7 cells, CAL27 MDR cells while 7,3',4',5'-tetrahydroxy-5- gramrione illustrated the highest inhibitory effect on MCF7 MDR cells. Both aqueous and ethanol extracts showed activities against MCF7 and CAL27 cancer cells. Bioassay-guided fractionation and purification of the extracts from S.viridis resulted in six active principles, including five dibenzocyclooctene lignans namely gomisin H (1), schisandrin (2), angeloylgomisin H (3), (+)-gomisin M2 (4) and rubschisandrin (5), and one terpenoid, schisanol (6). Compounds 1-3 showed moderate anticancer activities with an IC50 value ranging from 100-200 μg/mL against MCF7 and CAL27 cell lines. Dioxane containing lignans 4-5 and triterpenoid 6 were 10 times more active with IC50 values of14.5, 13.4, 10.6 μg/mL against MCF7, and 21.2, 17.9, 11.7 μg/mL against CAL27, respectively. In addition, two compounds from Compounds Australia exhibited a potential application prospects for tongue cancer and breast cancer therapy. One compound SN00802961 exhibited significant inhibition on MCF7 cells, but low inhibitory effects on fibroblast cells. Meanwhile, it exhibited moderate inhibition on CAL27 MDR cells, CAL27 cells and CSCs. Compound SN00802961 has potently targeted the MAPK/ERK1/2 signaling pathway to induce cytotoxicity in MCF7 cells. Another agent SN00771077 for breast cancer cells in vitro was investigated. The effects of compound SN00771077 on cell viability in vitro were evaluated by treatment of MCF-7 and T47D cells. An in vitro viability assay demonstrated that compound SN00771077 inhibited the cell growth in a dose-dependent manner. The antiproliferative activity of compound SN00771077 is related to its activity on monomeric actin and the subsequent inhibition of polymerization of G-actin monomers. Exposure to compound SN00771077 induced the inhibition of Raf/MEK/ERK pathway in T47D cells. All the results indicated that compound SN00771077 had a strong cytotoxic effects on cancer cells, and shows potential in the treatment of breast cancer by causing the depolymerizing actin cytoskeleton.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Natural Sciences
Science, Environment, Engineering and Technology
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Govender, Thirumala. "Enhancing drug incorporation into nanoparticulate systems." Thesis, University of Nottingham, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299551.
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Vance, Nicholas Robert. "Targeting dynamic enzymes for drug discovery efforts." Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6517.
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Proteins are dynamic molecules capable of performing complex biological functions necessary for life. The impact of protein dynamics in the development of medicines is often understated. Science is only now beginning to unravel the numerous consequences of protein flexibility on structure and function. This thesis will encompass two case studies in developing small molecule inhibitors targeting flexible enzymes, and provide a thorough evaluation of their inhibitory mechanisms of action.
The first case study focuses on caspases, a family of cysteine proteases responsible for executing the final steps of apoptosis. Consequently, they have been the subject of intense research due to the critical role they play in the pathogenesis of various cardiovascular and neurodegenerative diseases. A fragment-based screening campaign against human caspase-7 resulted in the identification of a novel series of allosteric inhibitors, which were characterized by numerous biophysical methods, including an X-ray co-crystal structure of an inhibitory fragment with caspase-7. The fragments described herein appear to have a significant impact on the substrate binding loop dynamics and the orientation of the catalytic Cys-His dyad, which appears to be the origin of their inhibition. This screening effort serves the dual purpose of laying the foundation for future medicinal chemistry efforts targeting caspase proteins, and for probing the allosteric regulation of this interesting class of hydrolases.
The second case study focuses on glutamate racemase, another dynamic enzyme responsible for the stereoinversion of glutamate, providing the essential function of D-glutamate production for the crosslinking of peptidoglycan in all bacteria. Herein, I present a series of covalent inhibitors of an antimicrobial drug target, glutamate racemase. The application of covalent inhibitors has experienced a renaissance within drug discovery programs in the last decade. To leverage the superior potency and drug target residence time of covalent inhibitors, there have been extensive efforts to develop highly specific covalent modifications to reduce off-target liabilities. A combination of enzyme kinetics, mass spectrometry, and surface-plasmon resonance experiments details a highly specific 1,4-conjugate addition of a small molecule inhibitor with the catalytic Cys74 of glutamate racemase. Molecular dynamics simulations and quantum mechanics-molecular mechanics geometry optimizations reveal, with unprecedented detail, the chemistry of the conjugate addition. Two compounds from this series of inhibitors display antimicrobial potency comparable to β-lactam antibiotics, with significant activity against methicillin-resistant S. aureus strains. This study elucidates a detailed chemical rationale for covalent inhibition and provides a platform for the development of antimicrobials with a novel mechanism of action.
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CORRIAS, FRANCESCO. "Nanocarriers for drug targeting and improved bioavailability." Doctoral thesis, Università degli Studi di Cagliari, 2014. http://hdl.handle.net/11584/266439.
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This PhD thesis debates, mostly, on two main topics:
- Drug delivery to brain
- Nanosuspensions for different applications
The objective of the first topic was the development of liposomes to which anti-TfR-monoclonal antibodies (Ox26) or lactoferrin was bounded to transport the selective NK3 receptor agonist senktide to CNS across the BBB. NK3 receptors are widely expressed in the CNS and their stimulation by senktide (ICV) increase extracellular DA. Liposomes were prepared using the film hydration method. In vivo microdialysis studies were performed to estimate the responsiveness of NAc shell DA to senktide as a consequence of its CNS delivery. Senktide given ICV or loaded into Ox26/lactoferrin-liposome (0.5 μg/kg iv) elicited a significant increase of dialysate DA in the NAc shell of rats whilst senktide given iv (0.1 mg/kg) or loaded in control stealth liposomes did not affect NAc shell DA. Liposomes formulation here described represent an effective way of CNS delivering of senktide following intravenous administration the TfR-transport system. On the other hand, three different types of nanosuspensions were formulated and studied:
- Tretinoin nanosuspensions for topical delivery
- Piroxicam nanosuspensions loaded in oral disintegrating tablet (ODT) for oral delivery
- Quercetin nanosuspensions loaded in fast dissolving films for oral delivery
The aims of the first work were to improve cutaneous targeting and photostability of tretinoin by using nanosuspension formulation. Tretinoin is a drug widely used in the topical treatment of various dermatological diseases. The tretinoin nanosuspension was prepared by precipitation
method and then characterized by photo correlation spectroscopy for mean size and size distribution, and by transmission electron microscopy for morphological studies. An oil in water tretinoin nanoemulsion was also prepared and used as a control. Dermal and transdermal delivery of both tretinoin nanosuspension and nanoemulsion were tested in vitro by using Franz diffusion cells and newborn pig skin. Photodegradation studies were carried out by UV irradiation (1 h, λ=366 nm) of the tretinoin nanosuspension in comparison with the nanoemulsion and a methanolic solution of the drug. During 8 h percutaneous experiments, no permeation of tretinoin through the whole skin thickness was detected but the drug was deposited into the skin layers, mainly in the stratum corneum, similarly to the nanoemulsion. UV irradiation of the nanosuspension showed a great improvement of tretinoin stability in comparison with both controls. Overall results show that nanosuspension might be a useful formulation for improving tretinoin dermal delivery and stability. Piroxicam (PRX) is a non-steroidal anti-inflammatory drug characterized by a poorly water solubility and consequently by a low oral bioavailability. Different nanocrystals orally disintegrating tablets (ODT) were prepared to enhance piroxicam dissolution velocity and saturation solubility. Nanosuspensions were prepared using high pressure homogenization technique. Different ODT formulations were prepared using the same nanosuspension but changing different excipients in order to optimize dissolution properties. PRX nanocrystals size and zeta potential were determined by photon correlation spectroscopy (PCS). Characterization of PRX nanocrystals ODT was carried out by infrared spectroscopy (FTIR), X-ray powder diffractometry (XRPD), differential scanning calorimetry. Dissolution study of PRX ODT was performed in distilled water (pH 5.5) and was compared with PRX coarse suspension ODT, PRX/poloxamer 188 physical mixture, bulk PRX samples and a piroxicam commercial ODT (Feldene). All PRX nanocrystals ODT formulations showed a higher drug dissolution rate than coarse PRX ODT. PRX nanocrystals ODT prepared using gelatin or croscaramellose as excipient showed a higher PRX dissolution rate compared with the commercial formulation and with ODT prepared using xanthan gum. The improvement in PRX dissolution rate is mainly caused by the increased surface-to-volume ratio due to the submicron
dimension of the drug nanocrystal, however, also the presence of the correct excipients (as disgregant) seem to play an essential role. Finally, quercetin nanosuspensions loaded fast dissolving films were formulated and studied. The aim of this work was to investigate the possible use of maltodextrin IT6 (MDX) to prepare fast-dissolving films, loaded by quercetin nanocrystals. Quercetin nanosuspensions were prepared using an high pressure homogenizer, meanwhile drug loaded films were obtained drying in a siliconized polyester sheet quercetin nanosuspensions with the others compounds in a oven at 60 °C. Films were finally cut and packed within sealed aluminium pouches. Quercetin nanocrystals were characterized by photo correlation spectroscopy for mean size and size distribution and by transmission electron microscopy for morphological studies. On the other hand, quercetin nanosuspensions loaded films were characterized in term of flexibility, tensile strength and thickness. Finally, dissolution studies in distilled water were performed, comparing release profiles of quercetin loaded films, quercetin raw material and quercetin nanosuspensions.
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Redhead, Helen Margaret. "Drug loading of biodegradable nanoparticles for site specific drug delivery." Thesis, University of Nottingham, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338495.
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Dunn, Susan Elizabeth. "Biodegradable nanosphere systems for drug targeting : with emphasis on systems for bone marrow targeting." Thesis, University of Nottingham, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294260.
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Ward, Richard. "Targeting inositol monophosphatase in structure-based drug design." Thesis, University of Birmingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289291.
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Moshiri, Houtan. "Targeting the editosome - from drug discovery to function." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=117029.
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Trypanosomatid pathogens cause devastating diseases in humans and animals and continue to pose a major challenge in the drug development. Mitochondrial gene expression in trypanosomatid pathogens requires extensive post transcriptional modification, known as RNA editing which generates translatable transcripts for essential components of parasite respiratory complex. RNA editing is catalyzed by a multiprotein complex called editosome. Most of the editosome proteins are essential for parasite survival, thereby making editosome a suitable target for drug discovery. However, how editosome proteins are assembled and perform RNA editing is not fully understood. We hypothesized that identification of novel compounds targeting and perturbing this unique process will not only help to determine the function and assembly of the editosome proteins but may also be used as compounds against all three major trypanosomatid pathogens. In the first part of the thesis, I present developing and testing of a fluorescence resonance energy transfer (FRET)-based high throughput screening assay for identification of compounds that inhibit editosome function. Furthermore, we use our assay to confirm inhibiting effect of known inhibitors of an essential editosome protein, T. brucei RNA editing ligase 1(TbREL1). Using our assay, we also show that these inhibitors are able to inhibit RNA editing in the context of partially purified editosome.The second part of thesis describes a pilot screen of a small set of compounds that were identified via virtual screening of a chemical library against TbREL1. Using secondary biochemical assays we confirmed the specificity of inhibition and showed that these compounds find other targets in addition to the intended TbREL1 target. We showed for the first time that the inhibitory compounds interfere with the interaction of editosome with substrate RNA and consequently lead to the loss of all activities associated with the functional editosome. Moreover, we show that this inhibition is able to interfere with the assembly of the editosome proteins and propose a model to describe possible mode of inhibition by these compounds. In the third part of thesis, I present a study that compares the mechanism of action of inhibitory compounds in the context of recombinant versus native TbREL1 in the editosome. We show that these compounds interfere with RNA substrate binding activities of the editosome accessory factors MRP1&MRP2 (mitochondrial RNA binding proteins 1&2) which result in perturbing other editing activities. We show that these compounds can only inhibit TbREL1 function when the accessory factors are not present. Furthermore, we performed alanine mutagenesis of the amino acid residues of TbREL1 that are predicted to bind inhibitors. We provide a detailed map of the structure of enzyme-inhibitor complex with an opportunity for future design of more potent inhibitors of TbREL1. These studies have led to identification and characterization of novel inhibitors that result in inactivation of editosome function. Moreover, elucidation of the mechanism of RNA editing inhibition provides a basis for future selection of more efficient and potent inhibitors against the editosome proteins. Therefore, this work contributes to both the functional studies of an essential gene expression mechanism and to an exciting possibility for future drug development against three related trypanosomatid pathogens.Pathogènes des trypanosomatides sont responsable de maladies dévastatrices chez les humains et les animaux et continuent de poser un défi majeur dans le développement de médicaments. L'expression du gène mitochondrial chez les agents pathogènes de la famille des trypanosomatides nécessite une modification post transcriptionnelle vaste, connue sous le nom d'édition de l'ARN, qui génère des transcrits traduisibles pour les composants essentiels du complexe respiratoire du parasite. L'édition de l'ARN est catalysée par un complexe multiprotéique appelé éditosome, dont la plupart des protéines sont essentiels pour la survie du parasite, ce qui fait de l'éditosome une cible appropriée pour la découverte de médicaments. Cependant, la façon dont les protéines de l'éditosome sont assemblés et effectue l'édition de l'ARN n'est pas entièrement comprise. Nous émettons l'hypothèse que l'identification de nouveaux composés ciblant et perturbant ce processus unique permettra non seulement de déterminer la fonction et l'assemblage des protéines de l'éditosome mais également d'être utilisé en tant que composés contre les trois principaux pathogènes de la famille des trypanosomatides. Dans la première partie de la thèse, je présente l'élaboration et l'essai basé sur la fluorescence avec un criblage à haut débit pour l'identification de composés qui inhibent la fonction de l'éditosome. En outre, nous avons utilisé notre test pour confirmer l'effet inhibiteur des inhibiteurs connus d'une protéine essentielle de l'éditosome, T. brucei RNA editing ligase 1(TbREL1). Grâce à notre test, nous avons montré également que ces inhibiteurs sont capables d'inhiber la fonction d'édition de l'ARN dans le contexte de l'éditosome partiellement purifié. La deuxième partie de la thèse décrit un essai pilote d'un petit ensemble de composés qui ont été identifiés par criblage virtuel contre TbREL1. En utilisant des tests secondaires, nous avons confirmé la spécificité de l'inhibition et montré que ces composés ont trouvé d'autres cibles en plus de celle de TbREL1. Nous avons montré pour la première fois que les composés inhibiteurs interférent avec l'interaction de l'éditosome à l'ARN substrat et par conséquent entraîne la perte de toutes les activités liées à la fonction de l'éditosome. De plus, nous avons montré que cette inhibition est capable d'interférer avec l'assemblage des protéines de l'éditosome et avons proposé un modèle pour décrire le mécanisme possible d'inhibition par ces composés. Dans la troisième partie de la thèse, je présente une étude qui compare le mécanisme d'action des composés inhibiteurs dans le contexte de TbREL1 recombinant ou natif dans l'éditosome. Nous avons montré que ces composés interfèrent avec les activités de liaison à l'ARN des facteurs accessoires de l'éditosome MRP1 et MRP2 (protéines liant les ARN mitochondriaux 1 & 2) qui aboutissent à la perturbation d'autres activités d'édition. Nous avons montré que ces composés peuvent seulement inhiber la fonction de TbREL1 en l'absence des facteurs accessoires. En outre, nous avons effectué une mutagenèse d'alanine des résidus d'acides aminés de TbREL1 qui sont prévus dans la liaison aux inhibiteurs. Nous fournissons une carte détaillée de la structure du complexe enzyme-inhibiteur avec une opportunité de conception future de plus puissants inhibiteurs de TbREL1. Ces études ont conduit à l'identification et la caractérisation de nouveaux inhibiteurs qui se traduisent par l'inactivation de la fonction de l'éditosome. En outre, l'élucidation du mécanisme d'inhibition de l'édition de l'ARN fournit une base pour la sélection future d'inhibiteurs plus efficaces et plus puissants contre les protéines de l'éditosome. Par conséquent, ce travail contribue à la fois aux études fonctionnelles d'un mécanisme d'expression d'un gène essentiel et à une possibilité passionnante pour le développement de futur médicament contre trois agents pathogènes liés de la famille des trypanosomatides.
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Porter, Christopher John Hamilton. "Targeting collodial drug carriers to the bone marrow." Thesis, University of Nottingham, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315061.
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Chung, Terence. "Staphylococcus aureus DNA gyrase : mechanism and drug targeting." Thesis, University of East Anglia, 2012. https://ueaeprints.uea.ac.uk/54338/.
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Increases in Staphylococcus aureus resistance against existing treatment options and the shortage of new antibiotics signals an urgent need for new treatments for the ongoing battle against the development of antibiotic resistance. DNA gyrase is an essential bacterial type II DNA topoisomerase that manipulates DNA topology by performing transient double-strand breaks and DNA strand passage. As gyrase is vital for bacterial survival, it is an effective antibacterial target. By understanding the mechanistic differences between S. aureus gyrase and the better studied Escherichia coli counterpart, we aim to better utilise S. aureus gyrase as an antibacterial target and improve the design of future antibacterial drug. This study has investigated features unique to S. aureus DNA gyrase: the potassium glutamate (KGlu) salt-dependent and salt-specific supercoiling. This KGlu dependency in S. aureus, but not E. coli gyrase, was partially attributed to the differences in the Cterminal domain of the gyrase A-subunit (GyrA). The discovery of the two novel monovalent alkali metal cation (M+) binding sites located in N-terminal domain of GyrB by protein crystallography has suggested a novel role of these M+ ions in the supercoiling functions of DNA gyrase, providing theoretical links to the unique KGlu dependency in S. aureus gyrase and the dependency of monovalent ions in E. coli and B.subtilis gyrase. Diospyrin, a phyto-naphthoquinone, was found to be active against S. aureus in vivo. It inhibits S. aureus gyrase and topo IV in vitro, with gyrase as the preferred target. Further studies suggested the binding site of Diospyrin to be located in the N-terminal domain of GyrB. Diospyrin also partially inhibits the ATPase activity of GyrB in an allosteric manner. Diospyrin is hypothesized to bind to a novel binding site between the ATPase domain and the transducer domain. Diospyrin also inhibits both the relaxation and the DNA cleavage ability of gyrase, suggesting it inhibits gyrase with a novel mechanism.
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Al-Shammaa, Zaid. "Targeting Drug-Resistant Tuberculosis Using SMART Nanotechnology Approach." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439310613.
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Sieg, Jacob P. "Spectroscopic methods for drug-discovery targeting RNA thermometers." Ohio University Honors Tutorial College / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ouhonors1492763707328646.
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Zhang, Liang. "Strategies for local drug delivery targeting the oesophagus." Thesis, Aston University, 2008. http://publications.aston.ac.uk/15410/.
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Localised, targeted drug delivery to the oesophagus offers the potential for more effective delivery and reduced drug dosages, coupled with increased patient compliance. This thesis considers bioadhesive liquids, orally retained tablets and films as well as chewable dosage forms as drug delivery systems to target the oesophagus. Miconazole nitrate was used as a model antifungal agent. Chitosan and xanthan gum hydrogels were evaluated as viscous polymer viables with the in vitro retention, drug release and minimum inhibitory concentration values of the formulations measured. Xanthan showed prolonged retention on the oesophageal surface in vitro yet chitosan reduced the MIC value; both polymers offer potential for local targeting to the oesophagus. Cellulose derivatives were investigated within orally retained dosage forms. Both drug and polymer dissolution rates were measured to investigate the drug release mechanism and to develop a formulation with concomitant drug and polymer release to target the oesophagus with solubilised drug within a viscous media. Several in vitro dissolution methods were evaluated to measure drug release from chewable dosage forms with both drug and polymer dissolution quantified to investigate the effects of dissolution apparatus on drug release. The results from this thesis show that a range of drug delivery strategies that can be used to target drug to the oesophagus. The composition of these formulations as well as the methodology used within the development are crucial to best understand the formulation and predict its performance in vivo.
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BARDELLI, DONATELLA. "SHWACHMAN-DIAMOND SYNDROME: FROM PATHOGENESIS TO DRUG TARGETING." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2017. http://hdl.handle.net/10281/170787.
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La Sindrome di Shwachman (SDS) è una rara malattia genetica, autosomica recessiva, caratterizzata da insufficienza pancreatica, disfunzioni ematologiche, displasie scheletriche e disordini cognitivi. Nel 90% dei pazienti vengono riscontrate mutazioni a carico del gene SBDS. Similarmente ad altre sindromi midollari, i pazienti affetti da SDS hanno un aumentato rischio di insorgenza di mielodisplasie e leucemia, ma i meccanismi responsabili di questa predisposizione non sono ancora stati indagati in modo approfondito. Le cellule mesenchimali stromali (MSCs) vengono considerate fattori con un ruolo fondamentale nel mantenere e sostenere la plasticità e la sopravvivenza delle cellule staminali all’interno della nicchia midollare. Studi recenti hanno dimostrato inoltre come mutazioni specifiche a livello delle MSCs possono essere fattori sufficienti per disregolare i sottili equilibri omeostatici all’interno della nicchia e dare inizio ad un processo di trasformazione neoplastica. Il nostro gruppo ha dimostrato che MSCs derivate da pazienti affetti da SDS erano comparabili a quelli di donatori sani per quanto riguarda le loro caratteristiche in vitro (marcatori di superficie, capacità di differenziare in diversi lineages, abilità nel sostenere la vitalità di cellule CD34). La gene expression analysis condotta su 16 SDS-MSCs in realtà mostra come queste cellule avessero un pattern di espressione genica differente da quello delle mesenchimali di donatori sani, suggerendo come le mesenchimali SDS potessero avere un ruolo nei disordini ematologici riscontrati nella malattia. In questo studio abbiamo aumentato la corte di pazienti e, avvalendoci di un modello in vivo, abbiamo studiato il possibile coinvolgimento delle MSCs nei disordini ematopoietici. Il nostro modello prevedeva l’impianto sottocutaneo in topi immunocompromessi di pellet cartilaginei derivanti da MSCs da donatori sani e pazienti stimolate per 21 giorni con un particolare medium di differenziamento. Dopo 60 giorni, gli animali sono stati sacrificati e gli ossicoli recuperati per l’analisi istologica. Dai nostri dati emerge come, al termine del periodo sperimentale, solo i pellet derivati da MSCs di donatore sano siano stati in grado di formare una nicchia midollare completa, con presenza di trabecole ossee, adipociti e cellule ematopoietiche murine. Di contro, nessuno dei pellet derivati da paziente è stato ritrovato vascolarizzato o colonizzato da cellule ematopoietiche. L’analisi a time point precoci ci ha permesso di individuare dei difetti nel processo differenziativo dei pellet derivati da pazienti, che non mostravano riassorbimento cartilagineo, né deposizione di matrice ossea o processi di vascolarizzazione. Questo dato ci suggerisce come nel nostro modello le mesenchimali da paziente mostrino difetti nel loro processo differenziativo e di conseguenza possano essere coinvolte anche nei disordini ematologici a carico del midollo. Nella seconda parte del nostro studio abbiamo testato un farmaco su cellule ematologiche e non ematologiche di paziente. Questo farmaco agisce sulle nonsense stop codon mutation, una delle mutazioni più diffuse nei pazienti SDS a carico del gene SBDS, consentendo il read-through della mutazione non senso e quindi la produzione di una proteina completa. I nostri risultati hanno mostrato l’azione positiva di questo farmaco in diverse linee cellulari (linfoblastoidi, mesenchimali e mononucleate da midollo), restorando la produzione della proteina. Inoltre, il trattamento con questo farmaco ha anche prodotto miglioramenti a livello funzionale nelle cellule mononucleate. In particolare queste cellule, in seguito al trattamento, hanno mostrato un significativo aumento nella capacità di dare colonie CFU-GM. Questo risultato ha forti conseguenze a livello clinico poiché, non avendo mostrato effetti tossici, questo farmaco potrebbe essere proposto per la cura dei disordini ematologici in questi pazienti.Shwachman-Diamond Syndrome (SDS) is a rare autosomal recessive disease, characterized by exocrine pancreatic disorder, hematological aberrancies, bone marrow failure and cognitive impairment. In 90% of patients the SBDS gene is found mutated. Similar to other marrow failure syndromes, SDS patients have an increased risk for developing myelodysplastic syndrome and AML. To date, the mechanisms underlying the bone marrow failure in SDS patients are not fully understood. Microenvironment constituents and in particular mesenchymal stromal cells (MSCs) are considered the pivotal organizers for the generation, maintenance and plasticity of the hematopoietic stem cell niche. Recent studies show that specific changes in MSCs may be sufficient to initiate a complex phenotype of disordered homeostasis with similarities to myelodysplasia. We have demonstrated that MSCs obtained from SDS patients were comparable in vitro to HD but gene expression analysis of 16 SDS-MSCs showed that these cells had a specific gene expression signature compared to HD. These results suggest that it is possible that MSCs could be involved in the pathogenesis of the SDS marrow disorders. We increased our patients cohort and investigated whether SDS-MSCs were able to sustain malignant evolution using an innovative scaffold-free in vivo system based on the ex vivo generation of semi-cartilaginous pellets (SCPs) from human MSCs. We obtained SCPs stimulating MSCs for 21 days with a specific differentiating medium and a complete and correct formation of cartilaginous tissues both in HD and SDS samples. These SCPs were transplanted heterotopically into subcutaneous tissue of immunocompromised mice. After 60 days, we sacrificed mice and collected ossicles. We found that in 90% of cases, HD were able to recreate the hematopoietic microenvironment, with the establishment of a complete marrow niche, while none of the transplanted SDS-SCPs was able to recreate the hematopoietic microenvironment, revealing a defect in these differentiating process. The second part of our study was focused on testing a specific drug able to act on nonsense stop codon mutation, one of the most diffuse alterations in SDS patients, linked to risk of developing myelodysplastic syndrome. We successfully obtained restoration of SBDS protein in different cell lineages deriving from patients (Lymphoblastoids, MSCs, mononuclear cells from bone marrow). Protein restoration was also accompanied in some cases with an improvement of functionality. In particular, mononuclear cells from bone marrow treated with drug showed an increase in their ability to form colonies when cultured in a specific assay. This represents a powerful result, due to the potential clinical consequences related to possible therapeutic strategy. Indeed, SDS patients in future could take advantage of this drug to ameliorate their hematological defects and abolish other symptoms.
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Kim, Gloria J. "Cancer nanotechnology engineering multifunctional nanostructures for targeting tumor cells and vasculatures /." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/22610.
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Thesis (Ph. D.)--Biomedical Engineering, Georgia Institute of Technology, 2007.Committee Chair: Nie, Shuming; Committee Member: Lyon, L. Andrew; Committee Member: McIntire, Larry V.; Committee Member: Murthy, Niren; Committee Member: Prausnitz, Mark R.
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Baumann, Romy [Verfasser]. "Ferrofluid-Aerosole als Drug Carrier für das inhalative magnetische Drug Targeting / Romy Baumann." Greifswald : Universitätsbibliothek Greifswald, 2011. http://d-nb.info/1017185212/34.
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兰林林. "细胞特异性核酸适配体介导的靶向葯物传输系统及其在疾病诊断与治疗中的应用." HKBU Institutional Repository, 2013. http://repository.hkbu.edu.hk/etd_ra/1366.
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Koosha, Fariba. "Preparation and characterisation of biodegradable polymeric drug carriers." Thesis, University of Nottingham, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.329839.
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Zephyr, Jacqueto. "Robust Drug Design Strategies and Discovery Targeting Viral Proteases." eScholarship@UMMS, 2021. https://escholarship.umassmed.edu/gsbs_diss/1157.
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Viral proteases play crucial roles in the life cycle and maturation of many viruses by processing the viral polyprotein after translation and in some cases cleaving host proteins associated with the immune response. The essential role of viral proteases makes them attractive therapeutic targets. In this thesis, I provide an introductory summary of viral proteases, their structure, mechanism, and inhibition, while the breadth of this thesis focuses on the Hepatitis C virus (HCV) NS3/4A and Zika virus (ZIKV) NS2B/NS3 viral proteases.
HCV NS3/4A protease inhibitors (PIs) have become a mainstay in combination therapies. However, drug resistance remains a major problem against these PIs. In this thesis, I applied insights from the HCV substrate envelope (SE) model to develop strategies for designing PIs that are less susceptible to resistance. Also, I used the HCV NS3/4A protease as a model system to decipher the molecular mechanism and role of fluorination in HCV PIs potency and drug resistance. The drug design strategies described in this thesis have broad applications in drug design.
The ZIKV is an emerging global threat, and currently, with no treatment available. In this thesis, I described the discovery, biochemical and antiviral evaluation of novel noncompetitive quinoxaline-based inhibitors of the ZIKV NS2B/NS3 protease. The inhibitors are proposed to interfere with NS2 binding to NS3, thereby preventing the protease from adopting the closed and active conformation. The inhibitors from this work will serve as lead compounds for further inhibitor development toward the goal of developing antivirals.
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Yap, Damian Boon Siew. "Investigating how the apoptopic pathways of E2F1 and p53 may be inhibited." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246744.
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Norman, Maria Elizabeth. "The adsorption of proteins to colloidal carriers." Thesis, University of Nottingham, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.280291.
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Morgan, Peter John. "Hydrodynamic properties of polyisoprene/polyoxyethylene block copolymers." Thesis, University of Nottingham, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293600.
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Senior, Judith Helen. "Liposomes in drug delivery : site-directed approaches using active and passive targeting." Thesis, University College London (University of London), 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261677.
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Stevens, Phillip James. "An approach to drug formulation and targeting liposomes and lipid nanoparticles for folate receptor targeting." Connect to this title online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1111092653.
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Thesis (Ph. D.)--Ohio State University, 2005.Title from first page of PDF file. Document formatted into pages; contains xvi, 110 p.; also includes graphics (some col.) Includes bibliographical references (p. 98-110). Available online via OhioLINK's ETD Center
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Tabata, Yasuhiko. "Drug targeting through polymer conjugation based on metal coordination." 京都大学 (Kyoto University), 2003. http://hdl.handle.net/2433/148611.
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Marouf, W. M. Y. "Design and characterisation of targeting drug-loaded polymeric nanoparticles." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484986.
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The aim of this work was the design and characterisation of drug-loaded, polymeric targeting nanoparticles (NP). Poly(lactide-co-glycoIide) (PLGA), a well known biodegradable and biocompatible polymer, was used for NP preparation. NP were formulated using controllable diffusion and emulsification combinations. This procedure was able to produce NP with narrow particle size distribution, high drug entrapment efficiency and ability to sustain drug release. To achieve drug targeting, ligand was conjugated to the NP surface using carbodiimide chemistry. The density of reactive carboxyl groups on the surface of PLGA NP was modulated by combining high molecular weight, end-capped PLGA, RG 505 S with a low molecular weight, non end-capped PLGA, RG 502 H. Such apprC?ach was able to conjugate protein-type targeting ligand onto NP surface along with modulation of drug release profile. Increasing the RG 502 H proportion in PLGA blend was found to increase the amount of ligand conjugation to NP surface as well as rate of drug release. Anti-Siglec-7 polyclonal antibody directed toward an endocytotic receptor was conjugated to the NP surface. Confocal laser scanning microscopy images obtained with Nile Red-loaded NP and fluorescence. microscopy images obtained with Acridine Orange-loaded NP, suggested selective binding of anti-Siglec- 7 conjugated NP to cells expressing Siglec-7 receptor with possible intracellular uptake. The ability of cytotoxic drug-loaded targeting NP to improve cytotoxicity was evaluated by encapsulating camptothecin, topoisomerase-I inhibitor, into PLGA NP with different densities of surface carboxylic acid, which was then conjugated with IgG anti-Fas monoclonal antibody. In vitro antitumour activity, evaluated using human colorectal cancer cell lines (HCT116), indicated that PLGA NP were able to improve CPT anti-tumour activity compared with CPT solution. Conjugating anti-Fas mAb onto the surface of CPT-loaded NP resulted in improved potency compared to corresponding naked NP, and was able to synergise with CPT.
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Wamsley, Andrea Kay. "Poly(amino acid) as a targeting drug delivery carrier." Scholarly Commons, 2002. https://scholarlycommons.pacific.edu/uop_etds/2726.
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Novel terpolymers of leucine (L), aspartic acid (D), and valine (V) were developed as targeting drug delivery carriers that specifically interact with the α 4 β 1 integrin, which is over-expressed in human malignant melanoma cells. As such, copolymerization and terpolymerization of leucine-N-carboxyanhydride (NCA), β-benzyl-aspartate-NCA, and valine-NCA, in dioxane, initiated with triethylamine, were investigated to determine the random nature of the terpolymer composition, for potential application as a targeting drug delivery carrier. The reactivity ratio of each monomer was determined by using Fineman-Ross, Kelen-Tüdös, and nonlinear least-squares curve fitting methods. The product of the estimated reactivity ratios from the monomers in the binary copolymerizations indicated that random polymers were predominantly formed. Based on the reactivity ratios determined from the binary copolymers, Alfrey-Goldfinger equations were used to estimate the composition of the terpolymers. There was no statistical difference between the actual monomer compositions and the calculated compositions of the terpolymers, which validate the randomness of the terpolymers. Therefore, the poly (Leucine-Aspartate-Valine) synthesized in this study is primarily a random terpolymer. The probability of the appearance of LDV sequences occurring within the random polymers were assessed by analyzing the influence of tacticity on the 13 C NMR signals of LDV terpolymers, a statistical method based on the terminal terpolymerization model, and the Poisson distribution, with the highest probability (∼13%) of LDV occurring in a random terpolymer of LDV to be approximately 8 to 9 triad units. Poly (LDV) polymers were shown to exhibit strong binding affinity for A-375 human malignant melanoma cells. The effectiveness of poly (LDV) to target malignant melanoma was evaluated and it showed that 21.3 ± 2.10% of melanoma cells adhered to poly (LDV) films compared to 39.0 ± 3.90% with the positive control fibronectin, whereas binding to HTB-129 human breast carcinoma cells and NHEK normal human keratinocytes were not significant. Poly (LDV)-doxorubicin conjugates displayed excellent selectivity and cytotoxicity in the delivery of doxorubicin. It was shown that the poly (LDV)doxorubicin conjugates exhibited cytotoxicity toward human malignant melanoma cells, but were less toxic than free doxorubicin. In addition, poly (LDV)-doxorubicin conjugates displayed a substantial reduction in toxicity per mole of doxorubicin against normal human keratinocyte cells when compared to free doxorubicin. Fluorescence microscopy showed poly (LDV)-FITC conjugates bound to the A-375 cells and were internalized within 30 minutes. Scatchard plots of poly (LDV)-doxorubicin conjugates were generated, which determined the association constants and established that there is one class of binding sites. It was shown that poly (LDV) could be internalized in a target specific manner by human malignant melanoma cells, which is dependent on the number of LDV targeting moieties in the polymer. These results established that poly (LDV) could be used as a drug delivery carrier that specifically targets the α 4 β 1 integrin.
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Muttha, Dharmendra Kumar. "Spray dried drug delivery systems for ileo-colonic targeting." Thesis, Kingston University, 2014. http://eprints.kingston.ac.uk/29882/.
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Purpose: There is interest in targeting the ileo-colonic region of the gastro-intestinal tract either to treat colonic disorders, or take advantage of the low enzymatic activity and relatively high residence time. Four main approaches have been proposed for ileo-colonic delivery; pH triggered, time-dependent and bacterial degradable release systems, and prodrug formation. pH triggered systems are commonly used although there are inherent problems with such systems. Researchers have ascribed failures of disintegration with enteric coated tablets in the colon to the low volume of fluid content and high viscosity in the local environment. The aim of this work is to target the ileo-colonic region with a solid dispersion technique using polyvinylpyrrolidone (PVP) to maximise dissolution, and a methacrylic acid-methacrylate copolymer (Eudragit S/L 100) to trigger release. Methods: Solid dispersions were produced using two model drugs; indomethacin (a poorly-soluble weak acid) and atenolol (a soluble weak base). The optimisation of drug polymer ratio and effect of order of mixing the constituents to the feed solution for spray drying were investigated with indomethacin and subsequently performed with atenolol. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to examine the polymorphic form of the drug in the dispersion. The molecular interactions in the dispersion were studied by using infrared (IR) spectroscopy. Dissolution studies were performed across a range of pH. Results: DSC and XRD confirmed the formation of amorphous solid dispersions when drug (atenolol or indomethacin) was spray dried with the polymers. IR spectra showed peak-shifts indicative of molecular interactions between drug and polymer. Carrier controlled release was achieved with solid dispersions containing 10 % drug loading with 80:20 PVP- Eudragit S/L 100 contents. The alteration in dissolution rate of solid dispersions was ascribed to a mixture of particle size reduction, conversion to the amorphous form of the drug, the polymer characteristics, drug-polymer molecular interactions and particle surface morphological properties. Conclusion: pH-triggered drug release was successfully demonstrated in vitro with solid dispersions. The presence of strong molecular interactions and the high glass transition temperature of the resultant dispersions ensured they remained amorphous at least for six months under accelerated conditions.
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Ma, Leyuan. "Targeting Drug Resistance in Chronic Myeloid Leukemia: A Dissertation." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/870.
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Inhibiting BCR-ABL kinase activity with tyrosine kinase inhibitors (TKIs) has been the frontline therapy for CML. Resistance to TKIs frequently occurs, but the mechanisms remain elusive.
First, to uncover survival pathways involved in TKI resistance in CML, I conducted a genome-wide RNAi screen in human CML cells to identify genes governing cellular sensitivity to the first generation TKI called IM (Gleevec). I identified genes converging on and activating the MEK/ERK pathway through transcriptional up-regulation of PRKCH. Combining IM with a MEK inhibitor synergistically kills TKI-resistant CML cells and CML stem cells.
Next, I performed single cell RNA-seq to compare expression profiles of CML stem cells and hematopoietic stem cells isolated from the same patient. Among the genes that are preferentially expressed in CML stem cells is PIM2, which encodes a pro-survival serine-threonine kinase that phosphorylates and inhibits the pro-apoptotic protein BAD. Inhibiting PIM2 function sensitizes CML stem cells to IM-induced apoptosis and prevents disease relapse in a CML mouse model.
Last, I devised a CRISPR-Cas9 based strategy to perform insertional mutagenesis at a defined genomic location in murine hematopoietic Ba/F3 cells. As proof of principle, we showed its capability to perform unbiased, saturated point mutagenesis in a 9 amino acid region of BCR-ABL encompassing the socalled “gatekeeper” residue, an important determinant of TKI binding. We found that the ranking order of mutations from the screen correlated well with their prevalence in IM-resistant CML patients.
Overall, my findings reveal novel resistance mechanisms in CML and provide alternative therapeutic strategies.
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Benzine, Youcef. "Enzymatically triggered polymeric drug delivery systems for colon targeting." Thesis, Lille 2, 2019. http://www.theses.fr/2019LIL2S036.
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De nos jours, les maladies inflammatoires chroniques de l'intestin (MICI) comme la rectocolite hémorragique et la maladie de Crohn touchent près de 200 000 personnes en France. Elles se caractérisent par l'inflammation de la paroi de différentes régions du tractus gastro-intestinal (TGI). Les deux sont des maladies chroniques qui impliquent une inflammation de la muqueuse colique. La principale différence entre la maladie de Crohn et la rectocolite hémorragique réside dans la localisation et la nature de l’inflammation. La maladie de Crohn peut toucher n’importe quelle partie du tractus gastro-intestinal (TGI), de la bouche à l’anus, mais dans la plupart des cas, elle atteint l’iléon. En revanche, la rectocolite hémorragique est limitée au côlon et au rectum.Le ciblage du colon peut offrir des avantages majeurs pour le traitement des MICI. Les formes galéniques conventionnelles entraînent une libération prématurée de la substance active dans l'estomac et l’intestin grêle. La substance active est alors absorbée dans la circulation sanguine ce qui provoque de sérieux effets secondaires. De ce fait la concentration de substance active qui arrive au site d’action (partie distale du TGI) est très faible, ce qui entraîne une faible efficacité thérapeutique voire échec de la thérapie.Pour pallier ce problème, une forme galénique idéale devrait effectivement protéger la substance active dans le haut TGI, puis la libérer dans la partie distale du TGI de manière contrôlée. Des systèmes réservoirs (granules enrobés, capsules…) ou des systèmes matriciels (comprimés, extrudats…) peuvent être utilisés pour protéger la substance active dans le haut TGI. Les polysaccharides qui ne sont dégradés que par des enzymes bactériennes localisées dans le colon peuvent être utilisés dans le développement des formes galéniques pour le traitement des MICI. L’objectif de ce travail était de développer de nouvelles formes galéniques contenant un polysaccharide (pectine, gomme de guar…) dégradable par la flore colique et d’un polymère thermoplastique hydrophobe (éthylcellulose, HPMC…) qui vas réduire l’hydrophilicité du polysaccharide. Or, le mélange des deux polymères ne doit pas enrober le polysaccharide qui va servir pour le ciblage de la partie distale du TGIChronic inflammatory bowel diseases (IBD) today affects close to 200,000 people in France. They are characterized by the inflammation of the wall of a part of the digestive tract. They usually include Ulcerative Colitis and Crohn’s disease. Both are chronic diseases that involve inflammation of the colonic mucosa. The main difference between Crohn’s disease and Ulcerative Colitis is the location and nature of inflammation. Crohn’s disease can affect any part of the GIT from mouth to anus but in most cases attacks the terminal ileum. In contrast, Ulcerative Colitis is restricted to the colon and the rectum. An ideal dosage form should effectively protect the drug in the stomach and small intestine and subsequently release the drug in the colon in a targeted and controlled manner. The objective of this work was to develop new drug delivery systems containing a polysaccharide (pectin, guar gum, inulin ...), which are degradable by the colonic bacteria and a hydrophobic thermoplastic polymer (ethylcellulose, polyurethane, polyvinyl acetate ...), which will reduce the hydrophilicity of the polysaccharide. The technique used for the preparation of these dosage forms is hot-melt extrusion. It is a continuous and free solvent process that allows the manufacturing of a dosage form called "extrudate" by forcing the soften material through an orifice. It has been demonstrated that extrudates based on polyvinyl acetate/polyurethane and inulin can minimize the release of a model active substance in the upper part of GIT due to the hydrophobic properties of polyvinyl acetate. Indeed, these extrudates uptake low amount of water and lose low dry mass upon exposure to media simulating the stomach and the small intestine. However, once in contact with the colonic flora, these systems show a considerable loss of mass due to the degradation of inulin by enzymes secreted by colonic bacteria. In another study, hot melt extrudates based on ethylcellulose blended with different types of polysaccharides (guar gum, inulin, corn starch, maltodextrin, pectin and chitosan) were studied for the development of controlled drug delivery systems. Anhydrous theophylline and diprophylline have been used as model drugs. This study was useful to set the extrusion parameters: temperature 100 °C; screw speed 30 rpm; feed rate 3 cc/min; 30 % dibutyl sebacate as a plasticizer. Importantly, hot melt extrudates based on ethylcellulose:guar gum blends offer an interesting potential as controlled drug delivery systems: They can be prepared at temperatures of about 100 °C, provide broad spectra of drug release patterns (in particular about constant drug release rates). Finally, hot melt extrudates remained stable after 1 year storage at ambient conditions
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Ma, Leyuan. "Targeting Drug Resistance in Chronic Myeloid Leukemia: A Dissertation." eScholarship@UMMS, 2011. http://escholarship.umassmed.edu/gsbs_diss/870.
Full textAbstract:
Inhibiting BCR-ABL kinase activity with tyrosine kinase inhibitors (TKIs) has been the frontline therapy for CML. Resistance to TKIs frequently occurs, but the mechanisms remain elusive.
First, to uncover survival pathways involved in TKI resistance in CML, I conducted a genome-wide RNAi screen in human CML cells to identify genes governing cellular sensitivity to the first generation TKI called IM (Gleevec). I identified genes converging on and activating the MEK/ERK pathway through transcriptional up-regulation of PRKCH. Combining IM with a MEK inhibitor synergistically kills TKI-resistant CML cells and CML stem cells.
Next, I performed single cell RNA-seq to compare expression profiles of CML stem cells and hematopoietic stem cells isolated from the same patient. Among the genes that are preferentially expressed in CML stem cells is PIM2, which encodes a pro-survival serine-threonine kinase that phosphorylates and inhibits the pro-apoptotic protein BAD. Inhibiting PIM2 function sensitizes CML stem cells to IM-induced apoptosis and prevents disease relapse in a CML mouse model.
Last, I devised a CRISPR-Cas9 based strategy to perform insertional mutagenesis at a defined genomic location in murine hematopoietic Ba/F3 cells. As proof of principle, we showed its capability to perform unbiased, saturated point mutagenesis in a 9 amino acid region of BCR-ABL encompassing the socalled “gatekeeper” residue, an important determinant of TKI binding. We found that the ranking order of mutations from the screen correlated well with their prevalence in IM-resistant CML patients.
Overall, my findings reveal novel resistance mechanisms in CML and provide alternative therapeutic strategies.
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Karrout, Youness [Verfasser]. "Innovative drug delivery systems for colon targeting / Youness Karrout." Berlin : Freie Universität Berlin, 2008. http://d-nb.info/1027497586/34.
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Wang, Feng. "Structure-based drug mechanism study and inhibitor design targeting tuberculosis." [College Station, Tex. : Texas A&M University, 2007. http://hdl.handle.net/1969.1/ETD-TAMU-1439.
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Wong, Ka Yeung Mark. "Drug clearance mechanisms and chemotherapy response." Thesis, The University of Sydney, 2007. https://hdl.handle.net/2123/28094.
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Cytotoxic chemotherapeutic agents have a major role in the treatment of cancers. However, many cytotoxic agents have a narrow therapeutic window with best treatment response achieved only within a small range of drug concentrations.
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Malek, Kotiba. "Redox-Active Silver N-Heterocyclic Carbene Complexes: A Dual Targeting Antibacterial Drug." Wright State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=wright1535290903921698.
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Kok, Robbert Jan. "Targeting of captopril to the kidney: towards selective renal ACE inhibition." [S.l. : [Groningen : s.n.] ; University of Groningen] [Host], 2008. http://irs.ub.rug.nl/ppn/.
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Quader, Sabina, and N/A. "Selective Synthetic Modification of Aminoglycosides for Drug Targeting to Tuberculosis." Griffith University. School of Biomolecular and Physical Sciences, 2007. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20071024.151619.
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The work presented in this thesis details the synthetic modification of the clinically important aminoglycoside antibiotics, neomycin B, paromomycin and tobramycin. We sought to modify aminoglycosides by attaching lipophilic groups, including fatty acids and steroids, with a view to improving the bacterial membrane permeability of these species, and ultimately their efficacy in the treatment of tuberculosis. Our initial synthetic strategy involved direct and specific functionalization of the singular primary hydroxyl group of the aminoglycoside antibiotic neomycin B, with lipophilic groups containing carboxylic acid functions via Mitsunobu esterification. Although, direct and selective Mitsunobu acylation of the primary hydroxyl group proved unsuccessful in the case of the pseudo tetrasaccharide neomycin B, the Mitsunobu reaction did however result in selective chemistry elsewhere in the molecule and this has been exploited for modification of the ido (ring IV) and streptamine (ring II) ring systems. Under carefully controlled conditions, the Mitsunobu reaction has been used for the selective dehydration of the ido ring, to give the talo epoxide, and, under more forcing Mitsunobu dehydration conditions, an aziridine function has been introduced into the streptamine moiety. Both the epoxide and the epoxide-aziridine neomycin building blocks were utilized as synthons in subsequent chemical transformations. Seventeen novel neomycin derivatives featuring modification of ring IV and/or ring II were obtained using this approach. Explicit structural elucidation of all the synthetic intermediates and the final products was achieved using high temperature NMR spectroscopy. Direct and specific functionalization of the singular primary hydroxyl group at the C5 position of the ribose ring (ring III) of neomycin B was achieved, via a procedure based in part on selective tripsylation of the C5III primary hydroxyl group of neomycin B reported previously, followed by subsequent displacement of the tripsyl group by azide. Terminal alkyne containing lipophilic esters were then successfully attached to the ribose residue of neomycin B via Cu(I)-mediated azide-alkyne coupling reaction. In addition to the isolation of two fortuitous, new and versatile synthons i.e. monoanhydro neomycin and bis-anhydro neomycin for modification of ring IV and ring II of neomycin, a third synthon based on neomycin framework, allowing stepwise modification of ring III and ring IV was designed and synthesized. This synthon features an epoxide function in the ido ring, and a protected amine function at the C5 position of the ribose ring. Examples of the stepwise use of this synthon for further synthetic modification of the neomycin framework were demonstrated. Fourteen novel neomycin derivatives featuring modification of ring III and /or ring IV were obtained and characterized. Regioselective Mitsunobu esterification of the single primary hydroxyl group of the pseudo trisaccharide tobramycin was utilized successfully to link a variety of hydrophobic esters with tobramycin. Nine lipophilic tobramycin derivatives with significant structural diversity were synthesised and characterized. In a preliminary study, the applicability of the Mitsunobu dehydration reaction for the regioselective formation of an epoxide ring in the ido moiety of the pseudo tetrasaccharide aminoglycoside antibiotic paromomycin system was confirmed. The regioselective ring-opening of the derived epoxide with azide at C3IV of paromomycin was also successfully demonstrated. In total, forty-two new potential aminoglycoside antibiotics have been synthesized and characterized.
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Armstrong, Trevor Ian. "Protein adsorption onto polymeric nanoparticles : its relevance to drug targeting." Thesis, University of Nottingham, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284047.
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Saraf, Poonam S. "RGD based peptide amphiphiles as drug carriers for cancer targeting." Scholarly Commons, 2014. https://scholarlycommons.pacific.edu/uop_etds/137.
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Specific interactions of ligands with receptors is one of the approaches for active targeting of anticancer drugs to cancer cells. Over expression of integrin receptors is a physiological manifestation in several cancers and is associated with cancer progression and metastasis, which makes it an attractive target for cancer chemotherapy. The peptide sequence for this integrin recognition is the Arg-Gly-Asp (RGD). Self-assembly offers a unique way of presenting ligands to target receptors for recognition and binding. This study focuses on development of integrin specific peptide amphiphile self-assemblies as carriers for targeted delivery of paclitaxel to α v β 3 integrin overexpressing cancers. Amphiphiles composed of conjugates of different analogs of RGD (linear, cyclic or glycosylated) and aliphatic fatty acid with or without 8-amino-3,6-dioxaoctanoic acid (ADA) as linker were synthesized and characterized. The amphiphiles exhibited Critical Micellar Concentration in the range of 7-30 μM. Transmission electron microscopy images revealed the formation of spherical micelles in the size range of 10-40 nm. Forster Resonance Energy Transfer studies revealed entrapment of hydrophobic dyes within a tight micellar core and provided information regarding the cargo exchange within micelles. The RGD micelles exhibited competitive binding with 55% displacement of a bound fluorescent probe by the cyclic RGD micelles. The internalization of fluorescein isothiocynate (FITC) loaded RGD micelles was significantly higher in A2058 melanoma cells compared to free FITC within 20 minutes of incubation at 37°C. The same micelles showed significantly lower internalization at 4°C and on pretreatment with 0.45M sucrose confirming endocytotic uptake of the RGD micellar carriers. The IC50 of paclitaxel in A2058 melanoma cells was lower when treated within RGD micelles as compared to treatment of free drug. On the other hand, IC50 values increased by 2 to 9 fold for micellar treatment in comparison to free drug in Detroit 551 cells. In A2058 melanoma xenograft mice model, the Paclitaxel-RGD micelles exhibited a significant inhibition of tumor growth in comparison to control treatment for both alternate day and twice weekly treatments. The studies showed the feasibility of using the non covalent peptide based self-assemblies as vehicles for targeted delivery in cancer.
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Quader, Sabina. "Selective Synthetic Modification of Aminoglycosides for Drug Targeting to Tuberculosis." Thesis, Griffith University, 2007. http://hdl.handle.net/10072/367086.
Full textAbstract:
The work presented in this thesis details the synthetic modification of the clinically important aminoglycoside antibiotics, neomycin B, paromomycin and tobramycin. We sought to modify aminoglycosides by attaching lipophilic groups, including fatty acids and steroids, with a view to improving the bacterial membrane permeability of these species, and ultimately their efficacy in the treatment of tuberculosis. Our initial synthetic strategy involved direct and specific functionalization of the singular primary hydroxyl group of the aminoglycoside antibiotic neomycin B, with lipophilic groups containing carboxylic acid functions via Mitsunobu esterification. Although, direct and selective Mitsunobu acylation of the primary hydroxyl group proved unsuccessful in the case of the pseudo tetrasaccharide neomycin B, the Mitsunobu reaction did however result in selective chemistry elsewhere in the molecule and this has been exploited for modification of the ido (ring IV) and streptamine (ring II) ring systems. Under carefully controlled conditions, the Mitsunobu reaction has been used for the selective dehydration of the ido ring, to give the talo epoxide, and, under more forcing Mitsunobu dehydration conditions, an aziridine function has been introduced into the streptamine moiety. Both the epoxide and the epoxide-aziridine neomycin building blocks were utilized as synthons in subsequent chemical transformations. Seventeen novel neomycin derivatives featuring modification of ring IV and/or ring II were obtained using this approach. Explicit structural elucidation of all the synthetic intermediates and the final products was achieved using high temperature NMR spectroscopy. Direct and specific functionalization of the singular primary hydroxyl group at the C5 position of the ribose ring (ring III) of neomycin B was achieved, via a procedure based in part on selective tripsylation of the C5III primary hydroxyl group of neomycin B reported previously, followed by subsequent displacement of the tripsyl group by azide.
Terminal alkyne containing lipophilic esters were then successfully attached to the ribose residue of neomycin B via Cu(I)-mediated azide-alkyne coupling reaction. In addition to the isolation of two fortuitous, new and versatile synthons i.e. monoanhydro neomycin and bis-anhydro neomycin for modification of ring IV and ring II of neomycin, a third synthon based on neomycin framework, allowing stepwise modification of ring III and ring IV was designed and synthesized. This synthon features an epoxide function in the ido ring, and a protected amine function at the C5 position of the ribose ring. Examples of the stepwise use of this synthon for further synthetic modification of the neomycin framework were demonstrated. Fourteen novel neomycin derivatives featuring modification of ring III and /or ring IV were obtained and characterized. Regioselective Mitsunobu esterification of the single primary hydroxyl group of the pseudo trisaccharide tobramycin was utilized successfully to link a variety of hydrophobic esters with tobramycin. Nine lipophilic tobramycin derivatives with significant structural diversity were synthesised and characterized. In a preliminary study, the applicability of the Mitsunobu dehydration reaction for the regioselective formation of an epoxide ring in the ido moiety of the pseudo tetrasaccharide aminoglycoside antibiotic paromomycin system was confirmed. The regioselective ring-opening of the derived epoxide with azide at C3IV of paromomycin was also successfully demonstrated. In total, forty-two new potential aminoglycoside antibiotics have been synthesized and characterized.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
Faculty of Science, Environment, Engineering and Technology
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PERIN, ELENA. "Passive drug targeting and delivery of antitumor Pt(IV) prodrugs." Doctoral thesis, Università del Piemonte Orientale, 2017. http://hdl.handle.net/11579/86923.
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Cisplatin and its analogues are important drugs for the treatment of many malignant tumors, but many side effects and deactivation processes may occur. In order to overcome these limits, the Pt(IV) complexes higher inertness can be exploited. They are activated to their corresponding Pt(II) active metabolite only in the tumor site, taking advantage of the hypoxic and reducing milieu of neoplastic cells: for this reason, they are considered prodrugs. Furthermore, passive Drug Targeting and Delivery (DTD) strategies can be developed to improve the selective accumulation of such species. The tumor tissue increased vascular permeability, due to an irregular architecture of the blood vessels, and the reduced drainage of the lymphatic system allow macromolecules of suitable dimensions (e.g. nanoparticles (NPs), liposomes, etc.) to extravasate and to be retained for longer time. Therefore, nanosized carriers decorated with anticancer molecules should be accumulated into the tumor cells increasing the drug selectivity.
This Ph.D. work is focused on the exploration of several passive DTD methods. The first phase consists in the synthesis of Pt(IV) complexes, containing suitable functionalities to be exploited in coupling reactions with nanosized vectors. Alternatively, Pt complexes can be encapsulated into liposomes. Then, the loading of selected nanocarriers with the metal complexes and the biological evaluation of the resulting conjugates are performed.
The developed projects are listed below:
- synthesis, characterization of Pt(IV) complexes, their couplings with different types of amino-functionalized nonporous silica NPs and in vitro tests of the resulting conjugates;
- coupling reactions of the previously prepared Pt(IV) compounds with chitosan and its derivatives;
- synthesis, characterization of Pt(IV) prodrugs able to link magnetic iron oxide NPs and their couplings with such vectors;
- encapsulation of antitumor drugs into liposomes and their in vitro studies.
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Strich, Samuel. "Oral drug delivery systems based on polysaccharides for colon targeting." Electronic Thesis or Diss., Université de Lille (2022-....), 2023. http://www.theses.fr/2023ULILS081.
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10 millions dans le monde, 3 millions en Europe, 250000 en France. Ces nombres représentent la prévalence des maladies inflammatoires chroniques de l'intestin (MICI), respectivement dans chaque région citée. Le plus souvent diagnostiquées entre 15 et 35 ans, les MICI regroupent la Maladie de Crohn (MC) et la Rectocolite Hémorragique (RCH), et se caractérisent par une inflammation de la paroi du tube digestif, évoluant par poussées.Le ciblage de la partie distale du tractus gastro-intestinal (TGI), ou côlon, permet d'envisager une libération locale et optimale de substance active au niveau des zones lésées, tout en diminuant les effets indésirables des traitements. Différentes stratégies sont employées pour le ciblage du côlon par voie orale, parmi lesquelles : *) l'utilisation de prodrogues, **) Les systèmes pH-dépendants, ***) Les systèmes temps-dépendants, et ****) les systèmes sensibles au microbiote intestinal.De toutes, l'approche basée sur l'activité du microbiote reste la plus fiable. Les quelques mille milliards de bactéries par gramme de selle présentes dans le côlon peuvent, via leur activité enzymatique, dégrader les polysaccharides de structure complexe. Afin de pallier les limites des approches pH- et temps-dépendantes, les systèmes à double stimuli intéressent aussi de plus en plus les équipes de recherches. En combinant plusieurs approches différentes mais complémentaires, il est possible d'améliorer significativement la libération de la substance active in situ.Notre projet a consisté à fabriquer, pelliculer, et développer des mini-comprimés de 5 mm de diamètre pour le ciblage du côlon. Au terme d'une étape de criblage de films polymériques, permettant d'identifier le mélange le plus résistant dans le haut TGI, un pelliculage associant éthylcellulose et shellac a été retenu. Différents ratios de mélanges ont été exploités. Des tests de libération in vitro ont été menés sur une durée totale de 32h, impliquant différents milieux digestifs reconstitués. Les expériences en milieu colique ont été réalisées avec et sans selles de patients sous atmosphère anaérobie, permettant de travailler au plus près des conditions physiopathologiques.Incontestablement, la protection de la substance active a été totale dans le haut TGI. Les formes galéniques pelliculées ont aussi présenté un profil de libération contrôlée dans le côlon.La formulation finale allie plusieurs propriétés :- Une prise en eau et une dissolution contrôlées grâce à l'éthylcellulose- Une dissolution pH-dépendante liée à la shellac- Une sensibilité au microbiote grâce à la présence d'un polysaccharideLes données obtenues se sont avérées encourageantes. La libération de la substance active en milieu colique peut être modulée selon la quantité de polysaccharide ajouté. Cette phase d'optimisation a été un enjeu capital10 million people worldwide, over 1.5 million in North America and 2 million in Europe. Those are the numbers of people affected by inflammatory bowel disease (IBD) in each region quoted, respectively. Including both Crohn's disease (CD) and ulcerative colitis (UC), inflammatory bowel disease has emerged as a public health challenge worldwide in the past decades. Often diagnosed between 15 and 35 years old, IBD are characterized by moderate to severe symptoms, and have in common relapsing-remitting cycles of mucosal inflammation.To date, there is no cure for IBD. Defined as colon targeting, targeted drug delivery systems is a way to get selective and efficient delivery of pharmacologically active compounds to the predetermined targeted region in therapeutic concentrations along with minimizing side effects of the drug. Current strategies for colon targeting rely on : *) prodrugs, **) pH-dependant systems, ***) time-dependant systems, ****) microbially triggered systems.Of all approaches, microbiota sensitive systems are currently known as the best ones for colonic drug delivery. It is also possible to combine several complementary approaches (pH- and microbiota sensitive) to significantely favor localized drug release.Our project aimed to develop 5 mm mini-tablets for colon targeting. First, a comparison of different film coatings was made to highlight the most interesting drug release profiles. Then, an innovative formulation, combining synthetic and natural polymers as well as polysaccharides, was evaluated. Different blend ratios were selected as well for films as for coated mini-tablets. In vitro drug release was carried out in simulated digestive fluids for a 32 h duration, including:- 0.1 N HCl or simulated gastric fluid (2 h)- PBS 6.8 or simulated intestinal fluid (6 h)- Colonic simulated medium with and without patients' faeces (24 h).Colonic simulated medium inoculated with patients' faeces allowed for working closer to pathophysiological conditions. Relevant results were obtained and paved the way for a promising monolayer technology. None or negligible drug release occurred up to 8 h, in the upper GIT. Also, drug could be totally protected in the lower gastrointestinal tract.Ethylcellulose, as a thermoplastic polymer, prevented from premature dissolution.Shellac, as a natural resin, provided pH-dependant properties.The adjunction of a polysaccharide acted as a substrate of microbiota.Interestingly, colonic release profiles could be optimized depending on the amount of polysaccharide added into the system
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Drieman, Johannes Cornelis. "Drug targeting to the kidney N-acetyl-L-[gamma]-glutamyl derivatives as kidney-selective prodrugs /." Maastricht : Maastricht : Datawyse ; University Library, Maastricht University [Host], 1989. http://arno.unimaas.nl/show.cgi?fid=6187.
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