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Foulkes, Broderick M. "Developing novel drug delivery methods for anti-leishmanial drugs". Thesis, Griffith University, 2020. http://hdl.handle.net/10072/393974.
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Background: Leishmaniasis is a DNDi listed disease caused by protozoan parasites of the kinetoplastida class. The disease currently spans over 80 countries, across the New World and Old World, potentially affecting 500 million people with 1 million new cases reported annually. Leishmaniasis is a vector-driven disease, utilizing two genus of sand fly, Phlebotomus sand fly is responsible for Old World transmission, whereas the Lutzomyia sand fly is responsible for New World transmission. The two main stages of leishmaniasis, are the diagnostic stage (promastigote in sand fly) and the infective stage (amastigote in mammalian cells). Dependent on strain, geography and location of infection, there are three main forms of leishmaniasis: cutaneous (subdivided into diffuse-cutaneous leishmaniasis (DCL) and disseminated-cutaneous leishmaniasis (DL)); mucocutaneous; and visceral (subdivided into post-kala azar dermal leishmaniasis (PKDL)).
The DNDi status of leishmaniasis indicates that the pharmaceutical interest into research and development is shockingly low, resulting in very little progress into new treatments, limited to current therapeutics that suffer from severe toxicities (cardio, nephro, hepato, oto). These issues can be circumvented by utilising liposomal drug-carriers, as part of an increased interest in nanoparticle research across all glycosciences, modifying these drugs to interact better with the target cell or liposomal carrier can be of great benefit.
Aims and Objectives: This project investigated the modification of current therapeutics in leishmanial treatment, paromomycin and compare the changes in antimicrobial efficacy. These modifications would revolve around enhanced binding affinity for macrophages and for liposomal carriers. This was achieved by modifying paromomycin at its reactive primary alcohols, using previously explored chemistry to attach long-chain fatty acids (LCFAs) to these reactive groups to create potential prodrugs. These were then subject to comparative kill efficiency studies against S. aureus, P. aeruginosa, and L. donovani DD8 cells in MIC assays and a resazurin based assay. A further objective was to investigate novel drug targets in leishmania, using LCFA-ligase as a potential target, as it has been reported this protein is differentially expressed, showing prominence and a potential for inhibition. This compound was also tested against L. donovani DD8 in the resazurin based assay.
Methods: Paromomycin laurate and palmitate-based derivatives were synthesised by simple esterification, and the LCFA directive synthesised tert-butyl (4-(2-(decanesulfonyl)acetamido)butyl)carbamate) (N-Boc DSA) was synthesised by known methods. These compounds were characterised and subjected to MIC assays on S. aureus and P. aeruginosa, and a resazurin-based high content imaging (HCI) assay on axenic amastigotes of L. donovani DD8. Parallel synthesis and testing of neomycin LCFA derivatives were made by Dylan Farr, and tested against the same pathogens, comparatively with paromomycin derivatives.
All experiments were conducted in triplicate and quadruplicate, with statistical differences being analysed by two-way analysis of variance (Two-way ANOVA). Values with P<0.05 were considered significant.
Results and Discussion: Paromomycin palmitate and dipalmitate were synthesised with preference on dipalmitate testing due to increased binding affinity for liposomal carriers and macrophages. Laurate synthesis was much less effective under a multitude of conditions. Secondary compound Boc-DSA was synthesised for use in conjunction with the paromomycin derivatives. The paromomycin dipalmitate compound was tested against S. aureus and P. aeruginosa, with comparative aminoglycosides: neomycin palmitate, amikacin palmitate, and kanamycin palmitate. Against S. aureus, all compounds showed reduced activity at all concentrations, with paromomycin and amikacin being the least affected. Lower concentrations of antibiotic saw antagonistic effects with the lipid chain synergistically enhancing bacterial growth. P. aeruginosa testing was inconclusive due to increased pyocyanin expression, potentially increasing biofilm aggregation of the bacterial cells, reducing interactable surface-area for the aminoglycosides. Further testing with biofilm disruptors in conjunction may show improved results.
Candidates paromomycin dipalmitate, N-Boc DSA, and neomycin palmitate were tested by V.Avery group at GRIDD (Griffith Institute for Drug Discovery) against L. donovani DD8 axenic amastigotes. Results showed <50% activity among derivative candidates, with lower activity even for paromomycin, a known anti-leishmanial agent. Morphological and pathophysiological changes due to geographical variations in leishmanial strains have been reported to have different effects on therapeutic efficacy. Although the reduced activity of the candidates can be noted for the DD8 strain, further testing on a variety of geographically relevant strains may show different activities. Human monocyte cytotoxicity THP-1 assays were performed in conjunction, <50% activity was similarly found for the described compounds.
Conclusions and Future Remarks: Overall, the modification of ring-1 C6’ and ring-3 C5’ into a LCFA-derivative via esterification chemistry showed reduced activity at all concentrations against S. aureus, P. aeruginosa, and L. donovani DD8 amastigotes. Similar for comparative aminoglycosides of neomycin, amikacin, and kanamycin, although results against P. aeruginosa indicate potential biofilm aggregation. The reference compounds, including DSA, tested against L. donovani DD8 showed <50% inhibition, this may be indicative of morphological and pathophysiological changes due to geographical differences in the test strain. Future avenues worth pursuing is a range of LCFA-derivatives such as C10,12,14,18 for synergistic studies. The use of biofilm disruptors in conjunction with the reference compounds may improve P. aeruginosa activity, in addition to biofilm disruptors, the addition of surfactants to improve solubility of the LCFAs, these additions may have antagonistic effects and are worth investigating. Further testing among various geographically relevant strains of L. donovani would prove the theory put forth by Stuart et al. and show the efficacy of the reference compound across multiple geographically-dependent strains. Incorporation of the test compounds into liposomes were not achieved within this project, however investigations against the aforementioned L. donovani DD8 amastigotes, and against RAW 264.7 cells using the encapsulated compounds as comparative data is warranted.Thesis (Masters)
Master of Medical Research (MMedRes)
School of Medical Science
Griffith Health
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Leach, Jeffrey Harold. "Magnetic Targeted Drug Delivery". Thesis, Virginia Tech, 2003. http://hdl.handle.net/10919/31261.
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Methods of guiding magnetic particles in a controlled fashion through the arterial system in vivo using external magnetic fields are explored. Included are discussions of applications, magnetic field properties needed to allow guiding based on particle characteristics, hemodynamic forces, the uniformity of field and gradients, variable tissue characteristics, and imaging techniques employed to view these particles while in transport. These factors influence the type of magnetic guidance system that is needed for an effective drug delivery system.
This thesis reviews past magnetic drug delivery work, variables, and concepts that needed to be understood for the development of an in vivo magnetic drug delivery system. The results of this thesis are the concise study and review of present methods for guided magnetic particles, aggregate theoretical work to allow proper hypotheses and extrapolations to be made, and experimental applications of these hypotheses to a working magnetic guidance system. The design and characterization of a magnetic guidance system was discussed and built. The restraint for this system that balanced multiple competing variables was primarily an active volume of 0.64 cm3, a workspace clearance of at least an inch on every side, a field of 0.3T, and a local axial gradient of 13 T/m. 3D electromagnetic finite element analysis modeling was performed and compared with experimental results. Drug delivery vehicles, a series of magnetic seeds, were successfully characterized using a vibrating sample magnetometer. Next, the magnetic seed was investigated under various flow conditions in vitro to analyze the effectiveness of the drug delivery system. Finally, the drug delivery system was successfully demonstrated under limiting assumptions of a specific magnetic field and gradient, seed material, a low fluid flow, and a small volume.Master of Science
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Wang, Yan. "Peptide-drug conjugate for Her2-targeted drug delivery". Scholarly Commons, 2018. https://scholarlycommons.pacific.edu/uop_etds/3567.
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Recent strategies for anticancer drug design have been focused on utilizing antibody as a drug or targeted moiety for targeted drug delivery. Antibody−drug conjugates (ADCs) have become a promising new class of targeted therapeutic agents for treatment of cancer. ADCs are designed to preferentially direct a cytotoxic drug to a cell-surface antigen recognized by an antibody. However, there are some challenges in developing ADCs, such as limited solid tumor penetration, high manufacturing costs and antibody-drug stoichiometry. Smaller molecules such as peptides have been shown to specifically bind to cancer related targets. These peptides can be used to form peptide-drug conjugates (PDCs) to overcome above-mentioned drawbacks presented by ADCs.
In this study, it was hypothesized that novel synthesized PDCs can be a strategy for breast cancer therapy. HER2 specific binding peptides, MARAKE and MARSGL, were modified by addition of a cysteine at C-terminus. The modified peptides were coupled with monomethylauristatin E (MMAE) by using maleimidocaproyl (MC) as a non-cleavable linker to form peptide-drug conjugates (YW1, YW2) and maleimidocaproyl-valine-citrulline (MC-VC) as a cleavable linker to form peptide-drug conjugates (YW3 and YW4). The peptides, peptide-drug conjugates and MC-MMAE, MC-VC-MMAE were characterized using ESI-MS and purified by using high-performance liquid chromatography (HPLC). Cellular uptake study was performed to determine binding specificity and internalization of two HER2 specific peptides and cysteine-modified peptides (MARAKEC, MARSGLC). In vitro cell viability assay was conducted to assess the cytotoxicity and determine the targeting specificity as well as the potency of the peptide-drug conjugates.
The purity of each compound was greater than 90%. Internalization of both HER2 specific binding peptides and cysteine-modified peptides were significantly higher than random peptides in HER2 over-expressed cell lines, MDA-MB361 and ZR75, while negligible uptake in HER2 negative cell line, HEK293. MC linked PDCs showed similar cytotoxicity as peptide in all cell lines; while MC-VC linked PDCs have higher cytotoxicity than MMAE in HER2 positive cell line and significant lower cytotoxicity than MMAE in normal cell line HEK293. However, PDCs with MC link do not show significant difference in cytotoxicity compared to the peptide in all cell lines.
In conclusion, specificity of HER2 binding for both peptides was preserved after modification with cysteine. The derivation of MMAE to link drug and peptide played a crucial role in the anticancer activity. Peptide-MMAE conjugates with cleavable linker showed a promising targeting capability for delivery of MMAE to HER2 overexpressed cancer cells.
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Kim, Yoo C. "Targeted drug delivery within the eye". Diss., Georgia Institute of Technology, 2013. http://hdl.handle.net/1853/52971.
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This work introduces novel approaches to enhance targeting of pharmacotherapies to cornea, ciliary body, choroid, and posterior segment of the eye using microneedles as a drug delivery platform. The first part of the work determines the ability to deliver protein therapeutics into the cornea using coated microneedles to suppress corneal neovascularization in a rabbit model. The data show that highly targeted delivery of the anti-vascular endothelial growth factor protein therapeutic gave a better biological response of suppressing neovascularization with 11,900 times less dosage compared to topical administration. The second part of the research aims to develop novel formulations to target ciliary body and choroid via suprachoroidal delivery. The results show that a strongly non-Newtonian fluid can be used to slow down the spreading of the particles at the injection site up to 2 months. The results also show that a high molecular weight formulation with weakly non-Newtonian fluid can be used to reach 100% coverage of the choroidal surface with a single injection. The third part of the research aims to determine the biological response of targeting anti-glaucoma therapeutics to the ciliary body in a rabbit model. The results show we can achieve 500- to 1000-fold dose sparing by targeted delivery via supraciliary delivery. The fourth and last part of the research aims to develop novel emulsion droplets to target different locations within the eye using a gravity-mediated delivery technique via suprachoroidal space injection. The results show that we can deliver up to 73% of injected polymeric particles posterior to the equator of the eye. Overall this work demonstrates that microneedles have the capability to deliver pharmacotherapies to cornea, ciliary body, choroid, and posterior of the eye in a highly targeted manner and provide significant dose sparing in the rabbit model.
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Forbes, Zachary Graham Barbee Kenneth A. "Magnetizable implants for targeted drug delivery /". Philadelphia, Pa. : Drexel University, 2005. http://dspace.library.drexel.edu/handle/1860/472.
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Baki, Mert. "Bone Marrow Targeted Liposomal Drug Delivery Systems". Master's thesis, METU, 2011. http://etd.lib.metu.edu.tr/upload/12613251/index.pdf.
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Homing is the process that stem cells move to their own stem cell niches under the influence of chemokines like stromal-derived factor-1&alpha(SDF-1&alpha
) upon bone marrow transplantation (BMT). There is a need for increasing homing efficiency after BMT since only 10-15% of the transplanted cells can home to their own niches and a limited amount of donor marrow can be transplanted. In this study, we aimed to develop and characterize bone marrow targeted liposomal SDF-1&alpha
delivery system prepared by extrusion method. Alendronate conjugation was chosen to target the liposomes to bone marrow microenvironment, particularly the endosteal niche. Optimization studies were conducted with the model protein (
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Woods, Stephen. "Wireless capsule endoscope for targeted drug delivery". Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/39241.
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The diagnosis and treatment of pathologies of the gastrointestinal (GI) tract are performed routinely by gastroenterologists using endoscopes and colonoscopes, however the small intestinal tract is beyond the reach of these conventional systems. Attempts have been made to access the small intestines with wireless capsule endoscopes (WCE). These pill-sized cameras take pictures of the intestinal wall and then relay them back for evaluation. This practice enables the detection and diagnosis of pathologies of the GI tract such as Crohn's disease, small intestinal tumours such as lymphoma and small intestinal cancer. The problems with these systems are that they have limited diagnostic capabilities and they do not offer the ability to perform therapy to the affected areas leaving only the options of administering large quantities of drugs or surgical intervention. To address the issue of administering therapy in the small intestinal tract this thesis presents an active swallowable microrobotic platform which has novel functionality enabling the microrobot to treat pathologies through a targeted drug delivery system. This thesis first reviews the state-of-the-art in WCE through the evaluation of current and past literature. A review of current practises such as flexible sigmoidoscopy, virtual colonoscopy and wireless capsule endoscopy are presented. The following sections review the state-of-the-art in methods of resisting peristalsis, drug targeting systems and drug delivery. A review of actuators is presented, in the context of WCE, with a view to evaluate their acceptability in adding functionality to current WCEs. The thesis presents a novel biologically-inspired holding mechanism which overcomes the issue of resisting natural peristalsis in the GI tract. An analysis of the two components of peristaltic force, circumferential and longitudinal peristaltic contractions, are presented to ensure correct functionality of the holding mechanism. A detailed analysis of the motorised method employed to deploy the expanding mechanism is described and a 5:1 scale prototype is presented which characterises the gearbox and validates the holding mechanism. The functionality of WCE is further extended by the inclusion of a novel targeting mechanism capable of delivering a metered dose of medication to a target site of interest in the GI tract. A solution to the problem of positioning a needle within a 360 degree envelope, operating the needle and safely retracting the needle in the GI tract is discussed. A comprehensive analysis of the mechanism to manoeuvre the needle is presented and validation of the mechanism is demonstrated through the evaluation of scale prototypes. Finally a drug delivery system is presented which can expel a 1 ml dose of medication, stored onboard the capsule, into the subcutaneous tissue of the GI tract wall. An analysis of the force required to expel the medication in a set period of time is presented and the design and analysis of a variable pitch conical compression spring which will be used to deliver the medication is discussed. A thermo mechanical trigger mechanism is presented which will be employed to release the compressed conical spring. Experimental results using 1:1 scale prototype parts validate the performance of the mechanisms.
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Sudimack, Moseley Jennifer Jo. "Targeted drug delivery via the folate receptor /". The Ohio State University, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=osu1486459267519529.
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Zhou, Zilan. "Engineered Nanoparticle for Targeted and Controlled Drug Delivery". University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505831582487098.
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Bhattacharya, Shiladitya. "Novel folate amphiphile conjugates for targeted drug delivery". Scholarly Commons, 2008. https://scholarlycommons.pacific.edu/uop_etds/2360.
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Cancer is not only difficult to treat but the patients also suffer from the pain associated with anticancer treatments. Targeted chemotherapeutics can reduce the adverse effects by reducing the dose required for tumor cell kill. Cancers of various origins often have characteristic marker molecules that distinguish them from the normal tissues. Folate receptors are such marker molecules present in ovarian and cervical cancers. The hypothesis for the current study is that amphiphiles constructed out of folic acid, the natural ligand for the folate receptor, can deliver paclitaxel, a chemotherapeutic compound, to folate receptor expressing cancer cells. To test this hypothesis, amphiphilic molecules were synthesized out of folic acid and fatty acids or long chain aliphatic amines. The gamma carboxylic group of folic acid was converted to an N-alkyl substituted amide. The alkyl group had various chain lengths varying from eleven methylene groups to seventeen methylene groups giving rise to a number of amphiphiles. The amphiphiles formed micelles in aqueous solutions. The critical micellization concentrations of the amphiphiles were measured by pyrene fluorescence and were found to be in the range of 10–70μM. HeLa and Caco-2 cells were taken as in vitro tumor models. Folate receptor expression was verified in HeLa and Caco-2 cells by western blot analysis. HeLa showed more than forty fold expression of the receptor when compared to Caco-2 and was chosen as receptor positive cell line while Caco-2 served as a negative control. Uptake of the folate labeled delivery system in the cell lines was tested by a fluorescent probe (aminocoumarin) labeled amphiphile. To test the specificity of the delivery system towards the receptor positive HeLa cells, the receptors were knocked down (70%) by folate receptor specific siRNA. Fluorescent amphiphile uptake in the knockdown cells was comparable to that of the negative control, Caco-2. Finally cytotoxicity studies were performed for paclitaxel formulated with the folate labeled amphiphiles and compared to free drug treatment in HeLa and Caco-2. IC50 values in HeLa for formulations with the folate labeled amphiphiles were ten folds less than those observed for free drug treatment whereas in Caco-2 no significant difference was noted.
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Hage, N. "Helicobacter pylori biomimics for gastric-targeted drug delivery". Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/32134/.
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Drugs that are preferentially absorbed through the stomach or the small intestine have a narrow time window for absorption since passage through this region of the gastrointestinal tract is rapid. A drug delivery system that can adhere to the gastric epithelium will substantially slow down drug transit and help overcome this problem. To achieve this, this study proposes the novel use of a glycan-binding adhesion protein from Helicobacter pylori, BabA, to create targeted drug delivery vectors that can mimic the attachment of this bacterium to the gastric epithelium. In this work, a recombinant form of BabA was expressed in the periplasmic space of Escherichia coli; it was found that after the incorporation of a C-terminal hexa-lysine tag, the expression and purification of this protein was significantly improved to amounts that enabled its subsequent characterisation and application. Recombinant BabA retained the highly selective glycan-binding properties of H. pylori and next, its crystal structure was solved in the absence and presence of Lewisb – a glycan well studied for its role in serving as a receptor for BabA. The structural models revealed that Lewisb binding occurred through a network of hydrogen bonds within a single, shallow binding pocket at the tip of a β-unit in BabA. Binding studies then confirmed that this site was also responsible for the recognition of other glycan receptors. Using this insight, recombinant BabA was conjugated to model drug delivery vectors via a linkage that favoured exposure of its glycan-binding β-unit; the binding properties of BabA successfully translated to these model BabA-vectors. The research presented in this thesis lays a strong foundation for future work to assess the in vitro and in vivo efficacy of biomimetic BabA drug carriers.
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Yang, Xiaojuan. "Development of Nanoparticle Systems for Therapeutic Drug Delivery". The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1248972068.
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Tu, Mai H. "Lipooligosaccharide-modified polymeric particles for targeted pulmonary drug delivery". Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/5666.
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Targeted delivery of drugs directly to the lung epithelium is a promising, though challenging, strategy for the treatment of diseases that affect the lung tissues, such as infections caused by cell-penetrating pathogens, cystic fibrosis, and cancer. With appropriate surface functionality, such as through the attachment of ligands that recognize receptors on cellular surfaces, particulate carriers show improved efficiency in penetrating cells in vitro. A useful class of ligands is produced by many natural human pathogens that infect the respiratory tract. A variety of phylogenetically distinct respiratory bacterial pathogens, such as Haemophilus influenzae, invade host cells in the upper airways by binding of the platelet-activating factor (PAF) receptor via lipooligosaccharide (LOS) glycoforms. By expressing host carbohydrate structures, including phosphorylcholine (ChoP), as a terminal structure on the LOS, the bacteria exhibit molecular mimicry of the host and are able to evade the host immune system. The effectiveness of LOS to induce cellular uptake of the bacteria is dependent on the specific glycoform, with higher ChoP content inducing more bacterial adherance into the lung epithelial. These ligands naturally expressed on bacterial cell surfaces can be isolated and utilized as targeting ligands for delivery vehicles. The studies described in this thesis focus on the development of particulate drug carriers coated with LOS bacterial ligands to enhance the targeting and binding of the carriers to the lung epithelium.
Three NTHi clinical isolates were screened to select the strain with the highest ChoP level, and NTHi 3198, an isolate from a patient with chronic obstructive pulmonary disease (COPD), was selected due to its high ChoP activity. LOS from NTHi 3198 was isolated from the bacterial cell membrane, and its activity verified using dot immunoblot and ELISA techniques. Particles (0.2 and 1 µm) composed of polystyrene or poly(lactic-co-glycolic acid) were passively coated with 0.005-50 µg/mL of the isolated LOS 3198 with or without gelatin, coated with gelatin alone, or left uncoated. The LOS coating on the particles was verified using either XPS or ELISA.
The association of particles with human bronchial epithelial cells was investigated using two cell culture models, 16HBE14o- and Calu-3, as a function of particle concentration and incubation time. The expression of PAFR on both cells types was confirmed, though the expression of PAFR on 16HBE14o- cells was significantly greater than on Calu-3 cells. Enhancement of 0.2 µm particle-cell association was achieved through coating of the particles with LOS. However, no significant difference in particle-cell association was observed for the 1 µm particles based on particle coating. Control particles of 0.2 µm size, those coated with gelatin (with or without LOS) or uncoated, exhibited low cell binding with a maximum of about 10-18% of cells associated with particles. The ability of the LOS ligand to enhance particle-cell association was coating concentration dependent, with a low coating concentration of LOS having little effect on association, but a concentration 1000-fold higher causing a doubling of the percentage of cells associated with particles at 24 hours. This enhancement was attributed to increased cellular binding of the 0.2 µm particles to the cell surface by confocal microscopy, and was further increased by activating the PAFR prior to incubation with particles. These results suggest the potential application of LOS as a targeting ligand for lung epithelial cells, especially under conditions where PAFR has been activated, such as occurs in lungs infected with Haemophilus influenzae. A significant reduction in particle-cell association was observed when particles were incubated with Calu-3 cells due to the presence of mucus on the cellular surface. This suggests that further optimization of the drug carrier system is needed to efficiently overcome the mucosal fluids.
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Shafi, Zerina Bibi. "The effect of surface modification of albumin microspheres upon particulate uptake in the gastrointestinal tract". Thesis, University of Brighton, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282830.
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Deo, Devendra Inder. "Controlled release and targeted drug delivery using polyelectrolyte microcapsules". Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8927.
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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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Li, Jie. "Polymeric Nanoparticles for Ultrasonic Enhancement and Targeted Drug Delivery". The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1280349038.
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Badkas, Apurva H. "Modified Antibody for Targeted Drug Delivery and Reduced Immunogenicity". University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1407410100.
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De, Cogan Felicity Jane. "Targeted delivery in vitro from magnetic vesicle gels". Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/targeted-delivery-in-vitro-from-magneticvesicle-gels(952ff942-ae4f-48e0-8bcc-1b744755a10a).html.
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Membrane sacs, known as vesicles and liposomes have been widely used as stores for bioactive materials both in vitro and in vivo. The vesicles are biocompatible and in vitro experiments often use them in conjunction with magnetic nanoparticles. The magnetic nanoparticles allow the liposomes to be magnetically located and act as a trigger for release of the encapsulated materials. However, these magnetic vesicles or 'magnetoliposomes' as they are also known have not mananged to cross the barrier into clinical use. The work in this thesis aims to develop a novel system of magnetoliposomes for use in a biological environment. Magnetoliposomes are created from phospholipid suspensions extruded to give a spherical bilayer membrane. This membrane is doped with biotinylated lipids. These lipids are key to allowing the system to work in vitro. The magnetic nanoparticles are formed from iron and are coated with a novel synthetic linker to allow them to interact with the liposomes. When the liposomes and the nanoparticles are mixed in the presence of the protein avidin, large heirarchacal structures are formed which are stable under physiological conditions. The magnetoliposomes are held in an alginate hydrogel scaffold which acts as a support for the liposomes and as an adherent cell scaffold for tissue culture. This work demonstrates that this system can be used to encapsulate and release a range of bioactive molecules such as nickel chloride as a mimic for cytotoxic cancer drugs, ascorbic acid-2-phosphate for the upregulation of collagen production in chondrocytes and SB 431542 for the differentiation of mouse embryonic stem cells. The results shown in this work demonstrate that it is possible to use this novel linking system to create a new form of magnetoliposomes which are stable, biocompatible and easy to form and use. This work also demonstrates a strong model for possible drug delivery in vivo.
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Oswald, Mira [Verfasser], i Achim [Akademischer Betreuer] Göpferich. "Targeted CNS Delivery via Nanoparticulate Drug Delivery Systems / Mira Oswald ; Betreuer: Achim Göpferich". Regensburg : Universitätsbibliothek Regensburg, 2017. http://d-nb.info/1139170708/34.
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NAIRI, VALENTINA. "Functional ordered mesoporous silica in nanomedicine: target and drug delivery systems". Doctoral thesis, Università degli Studi di Cagliari, 2018. http://hdl.handle.net/11584/255981.
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Ordered mesoporous materials (OMMs) are characterized by high surface area (up to 1000 m2/g), high pore volume (1-3 cm3/g) and narrow pore size (2-30 nm) distribution. Recently, mesoporous silica nanoparticles (MSNs), a subclass of OMMs, have had great development as nanocarriers for drug delivery, particularly for cancer treatment. The research activity of my PhD work was aimed to study SBA-15 and MCM-41 mesoporous silica samples for biomedical applications. The texture and the structure of the synthesized materials were characterized through N2 adsorption/desorption isotherms, SAXS, and TEM. The functionalization of the mesoporous silica samples was verified by means of Fourier-transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA). DLS and ELS were used to determinate hydrodynamic diameter and zeta potential of the studied systems under different conditions. The PhD thesis focused on different aspects of the use of OMMs, particularly MSNs, as drug nanocarriers.
In the first paper how different features of OMMs (surface area, pore size and surface charge) can affect the adsorption and release of drugs was investigated. Ampicillin, a penicillin-like -lactam antibiotic was loaded on MCM-41, SBA-15, and amino-functionalized SBA-15, then its release in simulated physiological conditions was studied. This study demonstrated that to obtain a sustained drug release, the chemical nature of the matrix’s surface plays a role which is more important than its textural features. SBA-15-NH2 matrix is a suitable candidate as depot system for local sustained release of ampicillin.
Common target systems have the disadvantage that the targeting molecule can be recognized by several receptors. A possible strategy to solve this issue was investigated in the second paper. The targeting molecule was hidden by preparing a double sequential targeting system. To this purpose a double target system was synthesized. Alendronate was used as a tissue target to recognize a diseased bone, and an encrypted cellular target, Arg-Gly-Asp (RGD) was used to improve the internalization in human osteosarcoma cells (collaboration with Universidad Complutense de Madrid). This preliminary study showed the efficacy of the double target systems. The next step could be the functionalization of MSNs with the previously described systems for the synthesis of a smart target systems usable as a carrier for anticancer drugs against bone cancer.
In the third paper, the effect of surface charge on the internalization of MCM-41-type MSNs, functionalized with chitosan (CHIT) and hyaluronic acid (HA) biopolymers, on 3T3 mouse fibroblast cells was then investigated. The opposite surface charge of the biopolymer-functionalized MSNs (negative for MSN-HA and positive for MSN-CHIT) gave a different interaction with BSA, used as a model protein to investigate the formation of the protein corona (forth paper). Finally, in the fifth paper, MSNs were functionalized with HA samples having three different molecular weights (HAS, HAM, and HAL). The effect of HA molecular weight on the internalization of HA-MSNs particles on HeLa cells was evaluated. These last studies showed the importance of the external functionalization on the interaction between MSNs and the components of body fluids, that change their surface properties. These changes as well as the polymer’s features (i.e. the molecular weight) are able to modulate the cellular uptake.
The obtained results highlight the importance of the physico-chemical phenomena occurring at the nano-biointerface for the future use of functionalized OMMs and MSNs in nanomedicine. The present findings confirm that these nanocarriers are very promising matrices for the obtainment of targeting drug delivery systems for cancer treatment.
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McNeeley, Kathleen Margaret. "Modulating liposomal stealth properties to evade RES and target tumors". Diss., Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/26650.
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Thesis (Ph.D)--Biomedical Engineering, Georgia Institute of Technology, 2009.Committee Chair: Ravi V. Bellamkonda; Committee Member: Ananth V. Annapragada; Committee Member: Andrew Lyon; Committee Member: Gang Bao; Committee Member: Niren Murthy. Part of the SMARTech Electronic Thesis and Dissertation Collection.
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Guerrant, William. "Targeted histone deacetylase inhibition". Diss., Georgia Institute of Technology, 2012. http://hdl.handle.net/1853/44907.
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Histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated a wealth of biological effects, including anti-proliferative, anti-inflammatory, anti-parasitic, and cognition-enhancing activities. The recent FDA approvals of the inhibitors SAHA and FK-228 have validated HDACi clinical use in cutaneous T cell lymphoma, while numerous clinical trials are currently ongoing using HDACi against a variety of disease states. While the future of the HDAC field looks increasingly promising, there are lingering issues hindering broader use. Recent data point to dysregulation of specific HDAC isoforms in many disease states. However, most current HDACi are pan-inhibitors, lacking the specificity to target individual isoforms. Adding to this, there are currently 18 identified HDAC isoforms, and most lack a defined crystal structure, further complicating the task of designing isoform-specific inhibitors. Most importantly, HDACi have demonstrated a lack of efficacy against solid tumors in the clinic, a major obstacle to broader use in cancer therapy. Several of these issues could more fully be addressed through specific targeting of HDACi, and could bring HDACi into wider and more efficacious pharmaceutical use. Targeting the specific tissue or organelle where HDAC dysregulation occurs could confer greater efficacy in vivo. To this end, we have created four classes of compounds: (1) aryltriazolyl HDACi that potently inhibit HDAC activity and prostate cancer cell growth, (2) dual-targeted inhibitors of Topoisomerase II and HDAC and (3) dual-targeted inhibitors of Topoisomerase I and HDAC, both of which have potent inhibition against both target enzymes as well as cancer cell lines, and finally (4) macrocyclic HDACi that potently inhibit the growth of lung cancer cell lines and preferentially target lung tissue in vivo.
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Sagar, Vidya. "Magnetic Nanoparticle-based Targeted Drug Delivery for Treatment of Neuro-AIDS and Drug Addiction". FIU Digital Commons, 2013. http://digitalcommons.fiu.edu/etd/909.
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Brain is one of the safe sanctuaries for HIV and, in turn, continuously supplies active viruses to the periphery. Additionally, HIV infection in brain results in several mild-to-severe neuro-immunological complications termed neuroAIDS. One-tenth of HIV-infected population is addicted to recreational drugs such as opiates, alcohol, nicotine, marijuana, etc. which share common target-areas in the brain with HIV. Interestingly, intensity of neuropathogenesis is remarkably enhanced due to exposure of recreational drugs during HIV infection. Current treatments to alleviate either the individual or synergistic effects of abusive drugs and HIV on neuronal modulations are less effective at CNS level, basically due to impermeability of therapeutic molecules across blood-brain barrier (BBB).
Despite exciting advancement of nanotechnology in drug delivery, existing nanovehicles such as dendrimers, polymers, micelles, etc. suffer from the lack of adequate BBB penetrability before the drugs are engulfed by the reticuloendothelial system cells as well as the uncertainty that if and when the nanocarrier reaches the brain. Therefore, in order to develop a fast, target-specific, safe, and effective approach for brain delivery of anti-addiction, anti-viral and neuroprotective drugs, we exploited the potential of magnetic nanoparticles (MNPs) which, in recent years, has attracted significant importance in biomedical applications. We hypothesize that under the influence of external (non-invasive) magnetic force, MNPs can deliver these drugs across BBB in most effective manner. Accordingly, in this dissertation, I delineated the pharmacokinetics and dynamics of MNPs bound anti-opioid, anti-HIV and neuroprotective drugs for delivery in brain. I have developed a liposome-based novel magnetized nanovehicle which, under the influence of external magnetic forces, can transmigrate and effectively deliver drugs across BBB without compromising its integrity. It is expected that the developed nanoformulations may be of high therapeutic significance for neuroAIDS and for drug addiction as well.
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Urbán, Patricia. "Development of nanovectors for the targeted drug delivery of antimalarials". Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/104509.
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Malaria is arguably one of the main medical concerns worldwide because of the numbers of people affected, the severity of the disease, and the complexity of the life cycle of its causative agent, the protozoan Plasmodium sp. The clinical, social and economic burden of malaria has led for the last 100 years to several waves of serious efforts to reach its control and eventual eradication, without success to this day.
At present, administration methods of antimalarial drugs release the free compound in the blood stream, from where it can be significantly removed by many tissues and organs, thus reducing its availability for Plasmodium-infected erythrocytes. Due to this lack of specificity regarding the target cells, current oral or intravenous delivery approaches for most antimalarial drugs require high doses. However, unspecificity of toxic drugs demands low concentrations to minimize undesirable side-effects, thus incurring the risk of sublethal doses favouring the appearance of resistant pathogen strains. Targeted nanovector systems can fulfill the objective of achieving the intake of total doses sufficiently low to be innocuous for the patient but that locally are high enough to be lethal for the malaria parasite.
With the advent of nanoscience, renewed hopes have appeared of finally obtaining the long sought-after magic bullet against malaria in the form of a nanovector for the targeted delivery of antimalarial drugs exclusively to Plasmodium-infected cells.
We work on the development of antimalarial drug-carrying nanovectors specifically targeted to Plasmodium-infected red blood cells (pRBCs). Our first immunoliposomal prototype delivers its contents exclusively to pRBCs containing the P. falciparum late forms trophozoites and schizonts, and improves on average tenfold the efficacy of the antimalarial drugs chloroquine and fosmidomycin. Using chloroquine concentrations well below its IC50, and by modifying parameters such as liposome size, density of targeting antibodies on the liposome surface, targeted antigen, and intraliposomal drug concentration, we approach 100% of parasitemia reduction both in vitro and in vivo using a murine model for P. falciparum malaria. We are working in the improvement of the nanovector through modification of (i) the targeting element: better antibodies, non-protein molecules such as DNA aptamers and polysaccharides, (ii) the encapsulated drug(s), and (iii) the type of nanocapsule, making special emphasis on polymeric structures. Our objective in the short term is the design of a nanostructure adequate to enter the preclinical pipeline as an economically affordable new antimalarial therapy.Desarrollo de nanovectores para la liberación dirigida de antimaláricos Los métodos actuales de administración oral o intravenosa requieren dosis elevadas que a menudo desencadenan efectos secundarios perniciosos. Por el contrario, el riesgo de suministrar dosis subletales a causa de dichas concentraciones terapéuticas críticas o por razones de inestabilidad del compuesto, favorece la aparición de cepas resistentes de Plasmodium. La liberación dirigida de antimaláricos es una aproximación prometedora para evitar ese riesgo. El trabajo presentado en esta tesis doctoral tiene como objetivo principal el desarrollo de un nanovector para la mejora de la eficacia de los antimaláricos existentes y la comprensión de los parámetros fundamentales de su diseño que determinan la eficacia de dicho nanovector. Liposomas con quantum dots en su interior y que han sido funcionalizados con hemi-anticuerpos contra formas tardías del parásito se unen en menos de 90 minutos a eritrocitos infectados por Plasmodium y liberan su contenido en el interior de las células diana. Cuando se encapsulan fármacos antimaláricos en el modelo inmunoliposomal, se incrementa hasta diez veces la eficacia de los fármacos. La formulación para administración oral de anticuerpos y liposomas es complicada, nanovectores adecuados para esta vía de administración serían una contribución valiosa para el tratamiento de la malaria en zonas endémicas, alejadas de centros de salud. Durante la última parte de esta tesis, nos hemos centrado en el desarrollo de nuevos nanovectores poliméricos que liberen de forma específica los fármacos a pRBCs, ya que las nanopartículas poliméricas pueden ser formuladas para administración oral más fácilmente que los liposomas. Las diferentes partes de futuros nanovectores (moléculas direccionalizadoras, formulación liposomal, recubrimiento exterior, fármaco encapsulado) están diseñadas de tal manera que puedan ser sustituidas por nuevos elementos para su utilización contra diferentes especies del parásito o para reconocer diferentes dianas intracelulares.
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Sánchez, Purrà Maria. "Development of novel vesicle-like nanocarriers for targeted drug delivery". Doctoral thesis, Universitat Ramon Llull, 2015. http://hdl.handle.net/10803/288318.
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Les dificultats existents en l’administració de certs fàrmacs, que es tradueix en una considerable reducció de la seva eficàcia terapèutica, ha portat a l’exploració d’un nou camp en la recerca de fàrmacs, l’ús de polímers per a transportar fàrmacs. Aquests polímers es presenten com a vehicles transportadors que aporten protecció al fàrmac, evitant la seva degradació, i permeten la seva distribució dirigida fins la diana terapèutica, disminuint així els efectes secundaris. Una combinació adequada del polímer transportador amb el fàrmac, permet l’alliberament d’aquest en el teixit on ha de desenvolupar el seu efecte terapèutic. Tot i així, per tal de garantir l’èxit d’aquests sistemes de distribució de fàrmacs, aquests han de complir una sèrie de requisits pel que fa a la mida, càrrega superficial, composició, capacitat d’encapsular i d’alliberar un fàrmac, funcionalització i biocompatibilitat.
En aquest treball, s’ha explorat la fabricació de diversos sistemes de distribució de fàrmacs per tal d’aportar coneixement sobre la modificació d’aquests polímers, que permetin obtenir plataformes de distribució de fàrmacs que reuneixi els requisits prèviament esmentats.
Per una banda, s’ha obtingut un sistema termosensible i versàtil a través d’una estratègia de core-shell, que permet ajustar la seva mida i el seu comportament termosensible, com també la seva modificació superficial mitjançant un mètode fàcil i ràpid basat en una química clàssica.
Per altra banda, la preparació de sistemes polimersòmics s’ha explorat per polimerització de tipus RAFT, és a dir, s’empra una química més sofisticada, que permet la síntesi de copolímers de multibloc amfifílics i auto-ensamblables, des de dos fins a cinc blocs, de manera controlada, obtenint polímers de pes molecular determinada amb distribucions de pes molecular molt estretes. De manera similar a l’anterior sistema, la modulació de la proporció entre blocs i del nombre de blocs permet el control de la mida de les nanoestructures formades i de la seva capacitat d’encapsular fàrmacs.
Finalment, els sistemes polimersòmics desenvolupats s’han comparat amb un sistema de distribució de fàrmacs molt ben establert, com ara els liposomes, pel que fa a funcionalització, encapsulació i alliberament de fàrmacs, com a potencials sistemes de distribució de fàrmacs per al tractament de metàstasis de càncer de mama al cervell a través d’una estratègia de doble funcionalització, per tal d’avaluar la idoneïtat del sistema desenvolupat en aquest treball.Las dificultades existentes en la administración de ciertos fármacos, que se traduce en una considerable reducción de su eficacia terapéutica, ha llevado a la exploración de un nuevo campo en el desarrollo de fármacos, el uso de polímeros como transportadores de estos. Estos polímeros se presentan como vehículos transportadores que aportan protección al fármaco, evitando así su degradación i permitiendo su distribución dirigida hasta la diana terapéutica, disminuyendo a su vez los efectos secundarios. Una combinación adecuada del polímero transportador con el fármaco, permite la liberación de este en el tejido dónde debe desarrollar su efecto terapéutico. Aun así, con tal de garantizar el éxito de estos sistemas de distribución de fármacos, estos deben cumplir una serie de requisitos por lo que respecta a tamaño, carga superficial, composición, capacidad de encapsular i liberar un fármaco, funcionalización i biocompatibilidad. En este trabajo, se ha explorado la fabricación de varios sistemas de distribución de fármacos con la finalidad de aportar conocimiento sobre la modificación de estos polímeros, que permitan obtener plataformas de distribución de fármacos que reúnan los requisitos previamente mencionados. Por un lado, se ha obtenido un sistema termosensible i versátil a través de una estrategia de core-shell, que permite ajustar su tamaño i su comportamiento termosensible, como también su modificación superficial mediante un método fácil i rápido basado en química clásica. Por otro lado, la preparación de sistemas polimersómicos se ha explorado mediante polimerización RAFT, es decir, utilizando una química más sofisticada, que permite la síntesis de copolímeros de multibloque amfifílicos i auto-ensamblables, desde dos a cinco bloques, de manera controlada, obteniendo polímeros de peso molecular determinado con distribución de peso molecular muy estrecha. De manera similar al anterior sistema, la modulación de la proporción entre bloques i del número de bloques permite el control del tamaño de las nanoestructuras formadas i de su capacidad de encapsular fármacos. Finalmente, los sistemas polimersómicos desarrollados se han comparado con un sistema de distribución de fármacos muy bien establecido, como son los liposomas, por lo que respecta a su funcionalización, encapsulación i liberación de fármacos, como potenciales sistemas de distribución de fármacos para el tratamiento de metástasis de cáncer de mama al cerebro a través de una estrategia de doble funcionalización, con tal de evaluar la idoneidad del sistema desarrollado en este trabajo.
The existing difficulties in the delivery of certain drugs, having a direct influence on their therapeutic efficiency, has lead to the exploration of a new field in pharmaceuticals, the use of polymers as drug carriers. Polymers are presented as carrier vehicles, which provide drug protection preventing its degradation and targeted delivery to the site of action diminishing side effects. An appropriate combination of the drug and the polymer allows the release of the drug in the tissue where it has to develop its therapeutic effect. However, in order to ensure the success of these drug delivery systems, they must fulfil a list of requirements according to size, surface charge, composition, drug loading capacity and release, targetability and biocompatibility. In this work, the fabrication of diverse drug delivery systems has been explored in order to provide know-how regarding polymers’ tunability to achieve delivery platforms that fulfil the aforementioned requirements. On one hand, a versatile thermo-responsive delivery system has been obtained trough a core-shell approach, allowing the tailoring of its size and thermosensitivity, while providing a simple and fast method to decorate its surface by means of classic chemistry. On the other hand, the preparation of polymersomic systems was explored by RAFT polymerization, a more sophisticated chemistry, which allowed the synthesis of self-assembling amphiphilic multiblock copolymers, ranging from diblock to pentablock, in a controlled manner, obtaining predetermined molecular weight polymers with narrow molecular weight distributions. Similarly to the previous system, the tunability of blocks ratio and number allowed the control over nanostructures size and loading capacity. Finally, polymersomes have been compared with a very well established delivery system, such as liposomes, in terms of targeting and drug loading and release, as potential drug delivery systems to breast cancer metastasis in the brain through a dual-targeting approach, in order to evaluate the suitability of the system developed in this work.
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Fiabane, Joe. "A novel method of producing microbubbles for targeted drug delivery". Thesis, Robert Gordon University, 2016. http://hdl.handle.net/10059/1579.
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Microbubbles, currently employed in diagnostic ultrasound as a contrast agent, have a potential new application as vehicles for targeted drug delivery, which could revolutionise medicine by eliminating side-effects. A new device is developed which outperforms all existing devices in terms of minimum microbubble size:channel diameter ratio. A numerical model is established to describe the flow behaviour and it is determined that the flow regime and resulting microbubble size are dependent on the ratio of inner- to outer Weber number.
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Abedin, Farhana. "Magnetic and albumin targeted drug delivery for breast cancer treatment". Thesis, Wichita State University, 2011. http://hdl.handle.net/10057/5054.
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This research work involves multifunctional magnetically targeted drug delivery
microspheres for treatment against breast cancer. A combination therapy approach was followed
by encapsulating two chemotherapeutics, 5-Fluorouracil (5-Fu) and cyclophosphamide in
poly(D, L-lactide-co-glycolide) (PLGA) microspheres. Magnetite nanoparticles and albumin
were also incorporated in the microspheres to achieve targeted treatment. The microspheres were
fabricated using oil-in-oil emulsion/solvent evaporation technique. Albumin is attracted to cancer
cells and thus it is likely to draw the microspheres towards tumor cells. On application of
magnetic field near tumor site, magnetites in the microspheres are likely to guide them to the
region of magnetic field. This will allow release of drugs from microspheres in the cancer cells.
Also the burst release of drugs and then slow release due to diffusion in the cancer cells lead to
effective treatment and also limit excessive spreading of drugs in other regions of the body.
Release rate study was carried out using high performance liquid chromatography (HPLC). Invitro
and in-vivo study was carried out to check the efficacy of treatment.Thesis (M.S.)--Wichita State University, College of Engineering, Dept. of Mechanical Engineering.
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Witt, Sandra [Verfasser]. "Entwicklung von Nanopartikeln für Targeted Drug Delivery Systeme / Sandra Witt". Hannover : Gottfried Wilhelm Leibniz Universität Hannover, 2020. http://d-nb.info/1220422177/34.
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Cureton, Natalie. "Development of nanocarriers for targeted drug delivery to the placenta". Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/development-of-nanocarriers-for-targeted-drug-delivery-to-the-placenta(696cfc4f-0bd7-4fbe-9b23-d2b83a7fec7d).html.
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Pregnancy complications such as fetal growth restriction (FGR) are often attributed to poor uteroplacental blood flow, but the risk of systemic side-effects hinders therapeutic intervention. We have utilised novel placental-specific homing peptides to overcome this and have conjugated these to biocompatible liposomes. Peptide-conjugated liposomes were found to selectively bind to the outer syncytiotrophoblast layer of the human placenta and to the uteroplacental vasculature and labyrinth region of the mouse placenta. The novel vasodilator SE175 was selected as a nitric oxide donor with a favourable stability and release profile, to encapsulate in peptide-conjugated liposomes in an attempt to restore impaired uteroplacental blood flow in a mouse model of FGR, the endothelial nitric oxide synthase knockout mouse. Liposomes containing SE175 or PBS were prepared by lipid film hydration and targeting peptides coupled to the liposomal surface. Vehicle control, free SE175, PBS- or SE175-containing liposomes were intravenously injected on embryonic (E) days 11.5, 13.5, 15.5 and 17.5. Animals were sacrificed at E18.5 and fetal and placental weights recorded. Targeted delivery of SE175 significantly increased fetal weight compared to vehicle control but no other treatment groups, whilst significantly decreasing placental weight, indicating improved placental efficiency. Treatment was well tolerated, having no impact on litter size or resorptions. Targeted delivery of SE175, but no other treatment group, reduced a marker of lipid peroxidation in the placenta, indicating a reduction in oxidative stress. These data suggest that selective delivery of SE175 to the uteroplacental vasculature in peptide decorated liposomes may represent a novel treatment for FGR.
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Lundberg, Sara, Emelia Karlsson, Hugo Dahlberg, Mathilda Glansk, Sara Larsson, Sofia Larsson i Karl Carlsson. "Exosomes and lipid nanoparticles - the future of targeted drug delivery". Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-411993.
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In this project an overview of how synthetic lipid nanoparticles and exosomes can be used for targeted drug delivery is compiled. The goal is to identify aspects that can be in favor for targeted drug delivery and the development of products at Cytiva. The most important fields for Cytiva to understand is the methods and the challenges of cell culturing for production of exosomes, productions of lipid nanoparticles, purification of exosomes, analysis of both exosomes and lipid nanoparticles, and how exosomes and lipid nanoparticles are used as tools for drug delivery. To understand these aspects a description focusing on structural components, specific delivery and cargo loading is also included in the report. Many different components and methods have been found in the different fields mentioned, and the ones that we believe are the most relevant for Cytiva are presented and discussed in the report. We conclude that both exosomes and lipid nanoparticle are suitable options as drug delivery vehicles, especially for their ability to be modified for targeted delivery, encapsulate therapeutic compounds and cross biological barriers. Exosomes are also biostable and possess low immunogenicity. For production the methods identified with highest potential are Hollow-Fiber Bioreactor for cell culturing in production of exosomes and Microemulsion and High-Pressure Homogenization for lipid nanoparticles. Purification is required for exosomes and the most prominent method is Size-Exclusion Chromatography, because of its scalability. After production and purification it is important to be able to detect the vesicles and the most developed and used methods are Nanoparticle Tracking Analysis and Flow Cytometry, beacuse they can use labeling techniques and single vesicle analysis.
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Mishra, Kaushik. "Folate Receptor-Targeted Polymeric Micellar Nanocarriers as Drug Delivery Systems". University of Akron / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=akron1629218263972419.
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Pande, Maneesha. "Development of targeted / site - specific drug - delivery systems for cancer". Thesis, IIT Delhi, 2019. http://eprint.iitd.ac.in:80//handle/2074/8110.
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Cheng, Yu. "Gold Nanoparticles as Drug Delivery Vectors for Photodynamic Therapy of Cancers". Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1301503263.
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Falahat, Rana. "Tunable Nano-Delivery System for Cancer Treatment: A New Approach for Targeted Localized Drug Delivery". Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6234.
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Localized drug delivery systems have been widely studied as potential replacements for conventional chemotherapy with the capability of providing sustained and controlled drug release in specific targeted sites. They offer numerous benefits over conventional chemotherapy such as enhancing the stability of embedded drugs and preserving their anticancer activity, providing sustained and controlled drug release in the tumor site, reducing toxicity and diminishing subsequent side effects, minimizing the drug loss, averting the need for frequent administrations, and minimizing the cost of therapy.
The aim of this study is to develop a localized drug delivery system with niosomes embedded in a chitosan hydrogel with targeting capabilities. The incorporation of niosomes into a chitosan hydrogel has several advantages over each individually being used. First, embedding niosomes in a chitosan hydrogel can yield control over drug release especially for small molecule drugs. Second, chitosan hydrogel may improve the release time and dosage of drugs from niosomes by protecting them with an extra barrier, resulting in tunable release rates. Third, as a localized delivery system, chitosan hydrogels can prevent the migration of niosomes away from the targeted tumor sites. Finally, chitosan has mucoadhesive property which can be used in the targeting of the tumor cells with the mucin over expression.
To enhance the specific targeting, the capacity of chitosan to target MUC1 overexpression in cancer cells will be analyzed. Similarly, the incorporation of chlorotoxin in this system will be achieved and evaluated. Chlorotoxin, a 36-amino acid peptide, is purified from Leiurus quinquestriatus scorpion venom with a distinct characteristic of binding preferentially to neuroectoderma tumors such as glioma, but not to normal tissue.
The overexpression of MUC1, a mucin antigen, in certain cancer cells has been used as an attractive therapeutic target in the design of a drug delivery system consisting of chitosan with a distinct mucoadhesive property. To determine the level of MUC1expression in different cell lines, Cell based Enzyme Linked Immunosorbent Assay (Cell ELISA) was developed for the first time.
Attenuated Total Reflectance- Fourier Transform Infra-Red (ATR-FTIR) Spectroscopy is used to investigate the possible molecular interaction between chlorotoxin and glioma cells. This study presents a new approach in monitoring the biochemical and biophysical changes in glioma cells after being exposed to CTX. In addition to characterizing the signature spectra of CTX and glioma cells, we evaluated the differences in biochemical compositions of the spectra of the glioma cells treated with and without CTX over different incubation time periods.
The results indicate that the proposed localized drug delivery system with the distinct tumor targeting features and extended release profiles would tune and control the specific delivery of chemotherapeutics in tumor sites.
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Chau, Ying. "Targeted drug delivery by novel polymer-drug conjugates containing linkers cleavable by disease-associated enzymes". Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/32332.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2005.Includes bibliographical references.
We have conceptualized a new class of polymer-linker-drug conjugates to achieve targeted drug delivery for the systemic treatment of cancer and other inflammatory diseases. The physiochemical properties of the polymer allow the conjugate to circulate longer in the body by minimizing renal and hepatic clearance, thereby improving the pharmacokinetics of the attached drugs. Traditionally, linkers are degraded by acidity or by some ubiquitous intracellular enzymes. We incorporate linkers that are sensitive to a specific extracellular enzyme whose overexpression is co-localized with the diseased tissue. The drug molecules remain inactive when attached to the polymer, thus preventing normal tissues from harmful side effects. When the conjugate is transported to the diseased area where there is a high level of the target enzyme, the linkers are cleaved to release the drugs at the specific site. As an example, we designed and synthesized two generations of novel polymer-peptide-drug conjugates for the tumor-targeted delivery of chemotherapeutics. To allow for passive targeting and enhanced permeation and retention (EPR), dextran with a size greater than 6 nm was selected as the polymeric carrier. This biocompatible and biodegradable carrier was chemically modified to allow for conjugation with doxorubicin and methotrexate, two common chemotherapeutics with undesirable side effects.
(cont.) Since matrix-metalloproteinases (MMPs) are associated with a number of types of cancer and their functions are essential to disease progression, including degrading extracellular matrix, releasing angiogenic factors and activating growth factors, we explored the possibility of MMP-mediated drug release. The synthesis procedures combined solid phase and solution phase techniques to enable flexibility in the linker design and in the charge modification of the polymer. This scaleable and robust process produced new conjugates that demonstrated excellent stability under physiological conditions and optimized sensitivity to enzymatic cleavage by MMP-2 and MMP-9. The new conjugate, dextran-peptide-methotrexate, was assessed for its in vivo anti-tumor efficacy and systemic side effects. It was compared to free methotrexate and a similar conjugate, differing by an MMP-insensitive linker, at equivalent intraperitoneal dosages administered weekly. The MMP-sensitive conjugate resulted in effective inhibition of in vivo tumor growth in each of the two separate tumor models that overexpress MMP-2 and MMP-9 (HT-1080 and U- 87). In contrast, free methotrexate resulted in no significant tumor reduction in the same models. Neither free methotrexate nor the conjugate caused any tumor inhibition in mice bearing RT- 112, a slower-growing model which expresses significantly less MMP than HT-1080 and U-87 . The anti-proliferative effect of the drug contributed to the inhibition of tumor growth. Systemic side effects caused by the MMP-sensitive conjugates were tolerable.
(cont.) MMP-insensitive conjugates, though able to inhibit tumor growth, caused toxicity in the small intestine and bone marrow and the experiment was terminated after one injection. We conducted a biodistribution study in HT-1080 bearing mice to investigate the targeting mechanism of the new conjugate. Independent of the linker sequence, passive targeting was evidenced by the prolonged plasma circulation and higher tissue accumulations of the conjugates in comparison with free methotrexate. The ratios of drug accumulation at the tumor versus the major site of side effects (small intestine) for both conjugates were enhanced by the EPR effects. The difference in the drug accumulation at the tumor site was insignificant between conjugates with MMP-sensitive and MMP-insensitive linkers. We concluded that the tumor targeting effect of the dextran-peptide-methotrexate conjugate was dominantly due to passive targeting and EPR. The difference in the systemic side effects observed for the conjugates with different linkers was attributed to their varying susceptibility towards enzymes in normal tissues.
by Ying Chau.
Ph.D.
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Shen, Steve I. "Arg-Gly-Asp (RGD) conjugated aliphatic acids as micellar drug carrier for targeted drug delivery". Scholarly Commons, 2004. https://scholarlycommons.pacific.edu/uop_etds/2641.
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Targeted drug delivery is desired in cancer therapy since most of the side effects common to chemotherapy are related to the toxicity of the drug. Integrin over-expression has been shown in various cancer cells and can be exploited for targeted drug delivery. The goal of this study is to design amphiphilic conjugates with targeting motifs as a targeted drug delivery carrier. Toward this effort, novel amphiphilic conjugates of the Arg-Gly-Asp (RGD) peptide or GRGDS was linked to aliphatic acids of varying chain length. The hypothesis is that these novel amphiphilic conjugates, at concentrations above the critical micelle concentration (CMC), can form micelles in aqueous environment, encapsulate poorly-water soluble drugs, and target the α v β 3 integrin. The amphiphilic conjugate is also hypothesized to serve as targeting moiety in mixed micelle drug delivery system using Pluronic block copolymer. Synthesis of RGD amphiphilic conjugates was achieved by converting carboxylic acids into more reactive N-hydroxysuccinimidyl derivative and converting the carboxylic functional group of peptide into methyl ester. Then the activated NHS aliphatic ester was conjugated with methyl-protected peptide in the presence of organic base and methyl ester was removed in NaOH and subsequently neutralized. Intermediates and final products were characterized by MS, FTIR, and NMR. Micelle formation occurred in concentration of 0.015 to 0.12 mM for C 14 -RGD, C 16 -RGD, C 18 -RGD, and C 18 -GRGDS. Amphiphilic conjugate mixed with Pluronic L121 and Pluronic P104 (5% C 18 -RGD/L121 and 10% C 18 -GRGDS/P104) formed micelles at lower CMC of 0.0006 and 0.01 mM, respectively. Solubility of Taxol in water was improved by 87% when encapsulated in C 18 -RGD micelle above CMC. The solubility was increased 7 fold and 18 fold in mixed micelles of 5% C 18 -RGD/P104 and 5% C 18 -RGD/L121 above CMC. Three different drugs (DOX, Taxol, and etoposide) were used to evaluate the efficacy of the targeting C 18 -GRGDS micelle carrier alone or C 18 -RGD mixed with Pluronic block copolymers micelle. All 3 drugs significantly enhanced cytotoxicity toward cancer cells when loaded in micelle carrier above CMC. With same DOX concentration, C 18 -GRGDS micelle carrier significantly decreased percent of viable cells (12.9 ± 1.2%) above CMC when compared to concentrations below CMC (24.1 ± 1.0%). Mixed micelle of targeting amphiphile and Pluronic loaded with Taxol above CMC significantly decreased the percent of viable cells (38.3 ± 7.9%) when compared to non-targeting Pluronic block copolymer micelle (56.0 ± 2.8%). (Abstract shortened by UMI.)
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Safdar, Shahana. "Peptide-targeted nitric oxide delivery for the treatment of glioblatoma multiforme". Diss., Georgia Institute of Technology, 2012. http://hdl.handle.net/1853/45797.
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Glioblastoma multiforme (GBM) is the most common malignant central nervous system tumor. The ability of glioma cells to rapidly disperse and invade healthy brain tissue, coupled with their high resistance to chemotherapy and radiation have resulted in extremely poor prognoses among patients. In recent years, nitric oxide (NO) has been discovered to play a ubiquitous of role in human physiology and studies have shown that, at sufficient concentrations, NO is able to induce apoptosis as well as chemosensitization in tumor cells. This thesis discusses the synthesis and characterization of targeted NO donors for the treatment of GBM.
Two glioma targeting biomolecules, Chlorotoxin (CTX) and VTWTPQAWFQWVGGGSKKKKK (VTW) were reacted with NO gas to synthesize NO donors. These NO donors, CTX-NO and VTW-NO, released NO for over 3 days and were able to induce cytotoxicity in a dose dependent manner in glioma cells. The biggest advantage, a result of the targeted delivery of NO, was that the NO donors did not have toxic effects on astrocytes and endothelial cells. To characterize the chemosensitizing effects of CTX-NO, cells were incubated with CTX-NO prior to exposure to temozolomide (TMZ) or carmustine (BCNU). These drugs are the most popular chemotherapeutics used in the treatment of GBM, but have only shown modest improvements in patient survival. Viability studies showed that CTX-NO selectively elicited chemosensitivity in glioma cells, whereas the chemosensitivty of astrocytes and endothelial cells remained unaffected. Further investigation showed that CTX-NO pretreatment decreased O6-methylguanine DNA methyltransferase (MGMT) and p53 levels, suggesting that a decrease in DNA repair ability may be the mechanism by which chemosensitivity is induced.
Lastly, the effects of CTX-NO on glioma cell invasion and migration were studied using Boyden chamber and modified scratch assays. Non-toxic doses of CTX-NO decreased glioma cell invasion in a dose dependent manner. Studies quantifying matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) surface expression demonstrated that while MMP-2 expression was decreased by both CTX and CTX-NO, MMP-9 expression was decreased only by CTX-NO. Furthermore quantifying MMP-2 and MMP-9 activity levels showed that NO and CTX work synergistically to decrease the activity of the enzymes. These studies demonstrate that the decrease in glioma invasion resulting from CTX-NO treatment was partially a consequence of decreased levels of surface and activated MMP-2 and MMP-9. The work presented in this thesis describes a novel approach to treating GBM that can be modified to develop treatments for various other tumors. Furthermore this is the first study to develop glioma-targeting NO donors.
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Blackburn, William H. "Microgel bioconjugates for targeted delivery to cancer cells". Diss., Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/31792.
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Thesis (Ph.D)--Chemistry and Biochemistry, Georgia Institute of Technology, 2009.Committee Chair: Lyon, L. Andrew; Committee Member: Barry, Bridgette; Committee Member: Fahrni, Christoph J.; Committee Member: Hud, Nicholas V.; Committee Member: Le Doux, Joseph M. Part of the SMARTech Electronic Thesis and Dissertation Collection.
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Master, Alyssa M. "EGFR-Targeted Polymeric Micelles For Targeted Pc 4-PDT Of Oropharyngeal Tumors". Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1364833269.
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Escolà, Jané Anna. "Somatostatin analogues as drug delivery systems for receptor-targeted cancer therapy". Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/663804.
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Somatostatin (SST or SRIF14) is a peptidic hormone secreted throughout the central nervous system and in the gastrointestinal tract which has anti-secretory, anti-proliferative and anti-angiogenic effects. Although its administration as a drug is effective in certain conditions, its therapeutic use is limited by its short plasma half-life (< 3 min), the broad spectrum of biological responses and the lack of selectivity over its receptors (SSTRs).
In order to obtain more stable and selective analogues we have incorporated both non-natural electron-rich and electron-poor aromatic amino acids at key positions of the native sequence to overcome the above-mentioned drawbacks. In this regard, we have obtained different analogues which have been studied by NMR obtaining the structures of the major set of conformations. Their binding profile and half-lives have also been determined. Among all the analogues, one stood out due to its half-life of around 40 h, the highest one known for a SRIF14 analogue. Furthermore, it displayed a major set of conformations in solution and high selectivity towards SSTR2.
In recent years, receptor-targeted cancer therapy has gained interest as certain receptors are overexpressed in cancer cells. This is the case of SSTRs in endocrine tumours. On this subject, we have coupled different molecules at the N-terminal part of the previously mentioned analogue. The first one was a chromophore which enabled us to follow the internalisation of the analogue inside CHO-K1 wild type (WT) and CHO-K1 SSTR2-overexpressing (ST) cell lines which turned to be far more better in ST than in WT. In light of these findings, we decided to go one step further and test this analogue as a drug delivery system thus coupling it to a colour-changing chromophore (green: bonded to the peptide, blue: when released). As before, both the internalisation and the drug release was better in ST than in WT. Last step was to test the analogue as a p38α inhibitor by coupling the inhibitor directly at the N-terminal part. As for the other assays, the inhibition of p-Hsp27 (p38α downstream target) was better in ST than in WT which was attributed to a better internalisation of the analogue.La somatostatina (SST o SRIF14) es una hormona peptídica secretada por el sistema nervioso central y el tracto gastrointestinal que tiene efectos anti-secretores, anti-proliferativos y anti-angiogénicos. Aunque su administración como fármaco es eficaz en ciertas condiciones, su uso terapéutico está limitado por su corta vida media plasmática (<3 min), el amplio espectro de respuestas biológicas y la falta de selectividad entre sus receptores. Con el fin de obtener análogos más estables y selectivos, hemos incorporado aminoácidos aromáticos no naturales ricos y pobres en electrones en posiciones clave de la secuencia nativa para superar dichos inconvenientes. Así, se obtuvieron diferentes análogos que fueron estudiados por RMN obteniendo la estructura de sus conformaciones mayoritarias. También se determinó su perfil de unión a los receptores y sus vidas medias. Entre los análogos, uno destacó por tener una vida media de 40 h, la más alta conocida para un análogo de 14 aminoácidos. Además, mostró un conjunto de conformaciones en solución parecido y una gran selectividad para SSTR2. Recientemente, la terapia contra el cáncer dirigida a receptores ha ganado interés ya que ciertos receptores están sobre-expresados en las células cancerosas. Este es el caso de los receptores de somatostatina en tumores endocrinos. Así, acoplamos diferentes moléculas en la parte N-terminal del análogo mencionado anteriormente. La primera fue un cromóforo que nos permitió seguir la internalización del análogo en dos líneas celulares: CHO-K1 de tipo salvaje (WT) y CHO-K1 con SSTR2 sobre-expresado (ST); dicha internalización fue mucho mejor en ST que en WT. Al ver estos resultados prometedores, fuimos un paso más allá y probamos el análogo cómo sistema de liberación de fármacos, acoplándolo a un cromóforo que cambia de color (verde: unido al péptido, azul: cuando se libera). Cómo antes, tanto la internalización como la liberación fueron mejores en ST que en WT. El último paso fue probar el análogo como inhibidor de p38α acoplando el inhibidor directamente en la parte N-terminal. Cómo en los ensayos anteriores, la inhibición de p-Hsp27 (diana downstream de p38α) fue mejor en ST que en WT, lo que se atribuyó a una mejor internalización del análogo en ST.
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Tinkov, Steliyan. "Development of Ultrasound Contrast Agents for Targeted Drug and Gene Delivery". Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-107213.
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Rodzinski, Alexandra. "Targeted and Controlled Anticancer Drug Delivery and Release with Magnetoelectric Nanoparticles". FIU Digital Commons, 2016. http://digitalcommons.fiu.edu/etd/2976.
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A major challenge of cancer treatment is successful discrimination of cancer cells from healthy cells. Nanotechnology offers multiple venues for efficient cancer targeting. Magnetoelectric nanoparticles (MENs) are a novel, multifaceted, physics-based cancer treatment platform that enables high specificity cancer targeting and externally controlled loaded drug release. The unique magnetoelectric coupling of MENs allows them to convert externally applied magnetic fields into intrinsic electric signals, which allows MENs to both be drawn magnetically towards the cancer site and to electrically interface with cancer cells. Once internalized, the MEN payload release can be externally triggered with a magnetic field. MENs uniquely allow for discrete manipulation of the drug delivery and drug release mechanisms to allow an unprecedented level of control in cancer targeting. In this study, we demonstrate the physics behind the MEN drug delivery platform, test the MEN drug delivery platform for the first time in a humanized mouse model of cancer, and characterize the biodistribution and clearance of MENs. We found that MENs were able to fully cure the model cancer, which in this case was human ovarian carcinoma treated with paclitaxel. When compared to conventional magnetic nanoparticles and FDA approved organic PLGA nanoparticles, MENs are the highest performing treatment, even in the absence of peripheral active targeting molecules. We also mapped the movement through peripheral organs and established clearance trends of the MENs. The MENs cancer treatment platform has immense potential for future medicine, as it is generalizable, personalizable, and readily traceable in the context of treating essentially any type of cancer.
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Xu, Doudou. "Targeted drug delivery with cyclodextrin-based nanocarriers and focused ultrasound triggering". Thesis, University of Dundee, 2014. https://discovery.dundee.ac.uk/en/studentTheses/e7aa1925-3553-48e4-90e7-dcccdf8f8c05.
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Background: The Nanoporation project set out to explore specific solutions to overcome the current challenges of targeted drug delivery (TDD) to tumours using magnetic resonance imaging guided focused ultrasound (MRgFUS) to cavitate microbubbles (MBs) for increasing cell permeability and to open ‘drug nano-capsules’ to release proven active anticancer drugs directly to the tumour site with reduction of systemic drug dosage needed for the desired therapeutic effect. Objective: The work reported here aimed to develop novel nano-carriers for existing anticancer drugs, by establishment of human cancer cell models to evaluate the carriers’ encapsulation efficiency in vitro and in vivo, by using animal models and a clinical MRgFUS system to investigate the carrier-drug vehicles’ in vivo distribution and localised drug release / cellular drug uptake. Methods: A novel ?-cyclodextrin (?-CD) based carrier for encapsulation of doxorubicin (DOX) was synthesised and fully characterised. The encapsulation efficiency was assessed under various temperatures and pH levels by both chemical analysis and in vitro human cancer cell modeling with KB and HCT116 cells. A high-throughput in vitro FUS device was designed and applied, in combination with carrier-DOX inclusion. SonoVue® MBs was used to investigate TDD in cell monolayers. Ex vivo and in vivo trials were carried out with a clinically approved ExAblate MRgFUS system (InSightec, Israel) to establish a safe and efficient clinical TDD protocol on small rodents. Results: The desired ?-CD based carrier greatly reduced DOX’s toxicity and the carrier-DOX inclusion was highly stable under physiological temperature conditions as well as under a wide range of acidic conditions (pH 1.0 ~ 7.0); the encapsulated DOX is slowly released under hyperthermic conditions (up to 50 °C). In the presence of MBs, application of FUS with low mechanical indexes, under which no thermal effect was observed, enhanced the drug uptake into tumour cells for both encapsulated and free DOX. Optimal setups of MR parameters and FUS parameters were identified ex vivo and in vivo, allowing application of MRgFUS treatments to 4 live mice bearing tumours (human colorectal carcinoma, up to 1059.71 mm3) under anaesthesia with full recovery. Conclusions: The study demonstrated the possibility of translation of the constructed ?-CD derivative to potential clinical use as a delivery vehicle for DOX using combined thermal and mechanical release mechanisms by clinically applicable MRgFUS– triggered TDD with the potential for cancer therapy.
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Gourevich, Dana. "Ultrasound mediated Targeted Drug Delivery in vitro : design, evaluation and application". Thesis, University of Dundee, 2013. https://discovery.dundee.ac.uk/en/studentTheses/0a3943df-4330-44b5-9f06-814ba2379d11.
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Background Targeted Drug Delivery (TDD) is a therapeutic modality which allows an increase in the medication dose at a treatment site, while simultaneously avoiding effects in the rest of the human body. This can be achieved via different types of delivery vehicles or carriers which encapsulate the free drug and release it only at the needed location. There are various methods of drug release, one of which is ultrasound, as in ultrasound-mediated TDD (USmTDD). The combination of focused ultrasound (FUS) and magnetic resonance imaging (MRI) provides a controllable system of drug release and impact assessment.In the work reported here, a novel drug carrier was synthesized and assessed. Ultrasonic drug release from the carrier was evaluated in vitro using a clinical MRI-guided Focused Ultrasound Surgery (MRgFUS) system. As there was no properly controllable research environment for in-vitro studies available prior to the investigation of the carriers, such an environment was built and characterized.Methods MCF7 and A375m human cancer cell lines were subjected to FUS using the ExAblate 2000 and 2100 systems (InSightec, Haifa, Israel). The experiments were conducted in a specially designed research environment, which was comprehensively evaluated to ensure both cell sterility and proper FUS propagation. Various sonication parameters were applied, in conjunction with a commercially available ultrasound contrast agent (USCA), to achieve maximal cellular uptake of Doxorubicin (Dox) with minimal decrease in cell viability. A novel cyclodextrin (CD) based drug carrier was synthesized, chemically evaluated, and investigated in vitro via two release mechanisms: heating and physical effects.Results Two clinical MRgFUS systems were adapted for in-vitro work, showing controllable and repeatable results. Both of the assessed release mechanisms showed their competency: the application of FUS in the presence of USCA increased the cellular drug uptake of Dox by an average factor of 3 ±0.9, and up to a factor of 4 due to heating. The Dox release from the CD-based carrier was around 100% with both mechanisms.Conclusions Adaptation of a clinical MRgFUS system for in-vitro research allows the use of a single system starting from in-vitro studies, through the pre-clinical stage to clinical trials. This gives physicians the ability to be a part of a wider USmTDD research group, from the beginning of the product definition, bringing real meaning to the term “from bench to bedside”. The baseline studies reported here have verified that intracellular drug uptake is increased through heating and sonoporation processes. The release mechanisms from the carriers were also observed, validating the concept of USmTDD from CD-based carriers.
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Huang, Guofeng. "ENGINEERING RGD-MODIFIED LIPOSOMES FOR TARGETED DRUG DELIVERY TO ACTIVATED PLATELETS". Case Western Reserve University School of Graduate Studies / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=case1153187042.
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Heister, Elena. "Functionalized carbon nanotubes as a multimodal drug delivery system for target cancer therapy". Thesis, University of Surrey, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.529424.
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Johnston, Alyssa N. "A Ternary Drug Delivery Complex to Target CD44 Over Expressing Cancerous Cell Lines". Kent State University Honors College / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ksuhonors1335737666.
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Lyon, P. C. "Targeted release from lyso-thermosensitive liposomal doxorubicin (ThermoDox®) using focused ultrasound in patients with liver tumours". Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:4817361a-e7f8-4773-ac81-8445ace05301.
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Helfrich, Marcus Robert. "Preliminary investigations into the development of novel layered phosphonic acid vesicles for targeted drug delivery applications /". view abstract or download file of text, 2002. http://wwwlib.umi.com/cr/uoregon/fullcit?p3045088.
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Thesis (Ph. D.)--University of Oregon, 2002.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 184-193). Also available for download via the World Wide Web; free to University of Oregon users. Address: http://wwwlib.umi.com/cr/uoregon/fullcit?p3045088.
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Hartley, Jonathan Michael. "Surface Modification of Liposomes Containing Nanoemulsions". BYU ScholarsArchive, 2011. https://scholarsarchive.byu.edu/etd/2846.
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Many attempts have been made to make cancer therapy more selective and less detrimental to the health of the patients. Nanoparticles have emerged as a way to solve some of the problems of traditional chemotherapy. Nanoparticles can provide protection for the therapeutic from degradation or clearance, as well as protection to healthy tissue from the damaging effects of chemotherapy drugs. Researchers are pursuing different strategies but all have the same goals of improving the outcomes of cancer patients. The field of controlled release of drugs has increased significantly in hopes of better treating diseases like cancer. Improved control of drug release has great potential for improving patient outcomes. Still there exist certain barriers such as circulation time, cell specificity, and endosomal escape.In this study a novel drug delivery vehicle was studied in vitro. The novel construct consisted of a liposome containing perfluorocarbon emulsions—an eLiposome—that was activated by ultrasound to break open on demand. Two targeting moieties were attached to the eLiposome to increase cell specificity and induce endocytosis. These studies determined the localization of eLiposomes in vitro using flow cytometry and confocal microscopy. Results indicated that eLiposomes modified with a targeting moiety attached to HeLa cells to a greater extent than non-targeting eLiposomes. Confocal images indicated localization of eLiposomes around the membrane of cells. Flow cytometer results indicated that ultrasound does in fact disrupt the eLiposomes but evidence of significant delivery to the cytoplasm was not obtained. However cells that were incubated with eLiposomes for 24 hours showed over 60% of the cells had green color association indicating eLiposome uptake.