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Huynh, Grace. "Convection administered drug delivery to the brain." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3251934.
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Boltman, Taahirah. "Liposomal drug delivery to brain cancer cells." University of the Western Cape, 2015. http://hdl.handle.net/11394/4706.
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Master of Science (Nanoscience)<br>Neuroblastomas (NBs) are the most common solid extra-cranial tumours diagnosed in childhood and characterized by a high risk of tumour relapse. Like in other tumour types, there are major concerns about the specificity and safety of available drugs used for the treatment of NBs, especially because of potential damage to the developing brain. Many plant-derived bioactive compounds have proved effective for cancer treatment but are not delivered to tumour sites in sufficient amounts due to compromised tumour vasculature characterized by leaky capillary walls. Betulinic acid (BetA) is one such naturally-occurring anti-tumour compound with minimum to no cytotoxic effects in healthy cells and rodents. BetA is however insoluble in water and most aqueous solutions, thereby limiting its therapeutic potential as a pharmaceutical product. Liposomes are self-assembling closed colloidal structures composed of one or more concentric lipid bilayers surrounding a central aqueous core. The unique ability of liposomes to entrap hydrophilic molecules into the core and hydrophobic molecules into the bilayers renders them attractive for drug delivery systems. Cyclodextrins (CDs) are non-reducing cyclic oligosaccharides which proximate a truncated core, with features of a hydrophophilic outer surface and hydrophobic inner cavity for forming host-guest inclusion complexes with poorly water soluble molecules. CDs and liposomes have recently gained interest as novel drug delivery vehicles by allowing lipophilic/non-polar molecules into the aqueous core of liposomes, hence improving the therapeutic load, bioavailability and efficacy of many poorly water-soluble drugs. The aim of the study was to develop nano-drug delivery systems for BetA in order to treat human neuroblastoma (NB) cancer cell lines. This was achieved through the preparation of BetA liposomes (BetAL) and improving the percent entrapment efficiency (% EE) of BetA in liposomes through double entrapment of BetA and gamma cyclodextrin BetA inclusion complex (γ-CD-BetA) into liposomes (γ-CD-BetAL). We hypothesized that the γ-CD-BetAL would produce an increased % EE compared to BetAL, hence higher cytotoxic effects. Empty liposomes (EL), BetAL and γ-CD-BetAL were synthesized using the thin film hydration method followed by manual extrusion. Spectroscopic and electron microscopic characterization of these liposome formulations showed size distributions of 1-4 μm (before extrusion) and less than 200 nm (after extrusion). As the liposome size decreased, the zeta-potential (measurement of liposome stability) decreased contributing to a less stable liposomal formulation. Low starting BetA concentrations were found to be more effective in entrapping higher amounts of BetA in liposomes while the incorporation of γ-CD-BetA into liposomes enhanced the % EE when compared to BetAL, although this was not statistically significant. Cell viability studies using the WST-1 assay showed a time-and concentration-dependent decrease in SK-N-BE(2) and Kelly NB cell lines exposed to free BetA, BetAL and γ-CD-BetAL at concentrations of 5-20 ug/ml for 24, 48 and 72 hours treatment durations. The observed cytotoxicity of liposomes was dependant on the % EE of BetA. The γ-CD-BetAL was more effective in reducing cell viability in SK-N-BE(2) cells than BetAL whereas BetAL was more effective in KELLY cells at 48-72 hours. Exposure of all cells to EL showed no toxicity while free BetA was more effective overall than the respective liposomal formulations. The estimated IC₅₀ values following exposure to free BetA and BetAL were similar and both showed remarkable statistically significant decrease in NB cell viability, thus providing a basis for new hope in the effective treatment of NBs.
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Lungare, Shital. "Development of novel delivery systems for nose-to-brain drug delivery." Thesis, Aston University, 2017. http://publications.aston.ac.uk/37491/.
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The blood brain barrier (BBB) poses a significant hurdle to brain drug delivery. However, the location of the olfactory mucosa, within the nasal cavity, is a viable target site for direct nose-to-brain (N2B) delivery, thereby bypassing the BBB. To exploit this target site innovative nasal formulations are required for targeting and increasing residency within the olfactory mucosa. We developed and characterised three formulation systems for N2B delivery, (i) thermoresponsive mucoadhesion nasal gels sprays; (ii) mesoporous silica nanoparticles and (iii) nasal pMDI devices. We developed an optimal mucoadhesive formulation system incorporating amantadine as a model, water-soluble anti-Parkinson’s drug using carboxymethy cellulose and chitosan as mucoadhesives. Formulations demonstrated droplet sizes of < 130mm and stability over 8-weeks when stored at refrigeration conditions with no significant cellular toxicity against olfactory bulb (OBGF400) and nasal epithelial (RPMI 2650) cells. Mesoporous silica nanoparticles (MSNP) were prepared (~220nm) and demonstrated cellular uptake into OBGF400 within 2-hours of incubation with minimal toxicity. MSNP were loaded with two novel phytochemicals known to possess CNS activity, curcumin and chrysin, with loading efficiencies of ~12% confirmed through TGA, DSC and HPLC-UV analysis. Furthermore, a pH dependant release profile was identified with curcumin with greater release at nasal cavity pH 5.5 compared to pH 7.4. Furthermore, successful incorporation of MSNP into nasal gels was demonstrated through rheological studies with a decrease in Tsol-gel. A pilot study was conducted to assess the feasibility of modified existing pulmonary pMDI to deliver diazepam intranasally, targeting the olfactory mucosa. Diazepam was formulated with HFA134a and using ethanol as a co-solvent, and demonstrated stability in formulation over 3 months. Deposition studies within a nasal cast model demonstrated 5-6% deposition onto the olfactory mucosa under optimal administration conditions in the absence of any nozzle attachments. Our studies have provided a basis for the development to innovative intranasal formulation systems potentially capable of targeting the olfactory mucosa for both water soluble and poorly soluble drugs.
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Charlton, Stuart Thomas. "Drug delivery to the brain via intranasal administration." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275962.
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Ibegbu, Madu Daniel. "Functionalised dextran nanoparticles for drug delivery to the brain." Thesis, University of Portsmouth, 2015. https://researchportal.port.ac.uk/portal/en/theses/functionalised-dextran-nanoparticles-for-drug-delivery-to-the-brain(c2da4093-315e-4647-90e1-4340acf2b8bd).html.
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Towards the development of drug carriers that are capable of crossing the Blood Brain Barrier, the techniques of emulsion polymerisation and nanoprecipitation have been utilised to produce nanoparticulate carriers from a systematic series of alkylglyceryl dextrans (of two different average molecular weights, 6 kDa and 100 kDa) that had been functionalised with ethyl and butyl cyanoacrylates. Also, zero length grafting of polylactic acid to butyl, octyl and hexadecylglyceryl dextrans has allowed the preparation of polylactic acid-functionalised nanoparticles. All materials and derived nanoparticles have been characterised by a combination of spectroscopic and analytical techniques. The average size of nanoparticles has been found to be in the range 100-500 nm. Tagging or loading of the nanoparticles with fluorophores or model drugs allowed the preliminary investigation of their capability to act as controlled-release devices. The effects of an esterase on the degradation of one such nanoparticulate carrier have been studied. Testing against bend3 cells revealed that all materials display dose-dependent cytotoxicity profiles, and allowed the selection of nanocarriers that may be potentially useful for further testing as therapeutic delivery vehicles for conditions of the brain.
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Ong, Qunya. "Local drug delivery for treatment of brain tumor associated edema." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/95865.
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Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2014.<br>Cataloged from PDF version of thesis.<br>Includes bibliographical references (pages 115-127).<br>Brain tumor associated edema, a common feature of malignant brain neoplasms, is a significant cause of morbidity from brain tumor. Systemic administration of corticosteroids, the standard of care, is highly effective but can introduce serious systemic complications. Agents that inhibit the vascular endothelial growth factor (VEGF) pathway, such as cediranib, are promising alternatives, but are also associated with systemic toxicity as VEGF is essential for normal physiological functions. A miniature drug delivery device was developed for local drug delivery in rodents. It comprises of a drug reservoir and a cap with orifice(s) through which drug is released. Drug release kinetics is dependent on the payload, the drug solubility, and the surface area for diffusion. Sustained releases of dexamethasone (DXM), dexamethasone sodium phosphate (DSP), and solid dispersion of cediranib (AZD/PVP) were achieved. Employing the solid dispersion technique to increase the solubility of cediranib was necessary to enhance its release. Therapeutic efficacy and systemic toxicity of local drug administration via our devices were examined in an intracranial 9L gliosarcoma rat model. Local delivery of DSP was effective in reducing edema but led to DXM induced weight loss at high doses in a pilot study. DXM, which is much less water-soluble than DSP, was used subsequently to reduce the dose delivered. The use of DXM enabled long-term, sustained zero-order release and a higher payload than DSP. Local deliveries of DXM and AZD/PVP were demonstrated to be as effective as systemic dosing in alleviating edema. Edema reduction was associated with survival benefit, despite continuous tumor progression. Animals treated with locally delivered DXM did not suffer from body weight loss and corticosterone suppression, which are adverse effects induced by systemic DXM. Local drug administration using our device is superior to traditional systemic administration as it minimizes systemic toxicity and allows increased drug concentration in the tumor by circumventing the blood brain barrier. A much lower dose can therefore be utilized to achieve similar efficacy. Our drug delivery system can be used with other therapeutic agents targeting brain tumor to achieve therapeutic efficacy without systemic toxicity.<br>by Qunya Ong.<br>Ph. D.
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Sharma, Gitanjali. "Dual Modified Liposomes for Drug and Gene Delivery to Brain." Diss., North Dakota State University, 2014. https://hdl.handle.net/10365/27310.
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The overall goal of our research was to design a vector for efficient delivery of therapeutic genes/drugs to brain. Specifically, this research work was focused on designing PEGylated liposomes surface modified with the receptor targeting protein, transferrin and cell penetrating peptides (CPPs) for targeting and improving the delivery of desired therapeutic agent to brain. Various CPPs including poly-L-arginine, TAT, Penetratin and Mastoparan were investigated for their influence on transport of transferrin receptor targeted liposomes across brain endothelial cells. The dual-modified liposomes were synthesized using thin film hydration and post-insertion technique. The biocompatibility of the liposomes was evaluated at increasing concentrations to obtain an optimum value for safe and effective delivery of drugs or genes. The liposomes showed excellent cellular, blood and tissue compatibility at the optimized concentration. In addition, the combination of targeting ligand transferrin and CPPs resulted in considerable translocation of the therapeutic agent across cellular and brain endothelial barriers both in vitro and in vivo. Among different Tf-CPP liposomes, the Tf-Penetratin liposomes showed maximum translocation of the drug across the brain endothelial barrier (approximately 15% across in vitro and 4% across in vivo BBB) and efficient cellular transport of the encapsulated drug (approximately 90-98%) in various cell lines. In addition, Tf-poly-L-arginine and Tf-Penetratin liposomes showed improved transfection efficiencies in various cell lines. The Tf-Penetratin and Tf-TAT liposomes demonstrated excellent cellular biocompatibility and no hemolytic activity upto 200nM phospholipid concentration. In vivo efficacy of the liposomes was evaluated by performing biodistribution studies in in adult Sprague Dawley rats. The liposomes were intended for delivery of small molecule drug, doxorubicin and pDNA to brain. The dual modified liposomes showed significantly (p<0.05) higher transport of encapsulated agents in rat brain as compared to single ligand (Tf) or plain liposomes. Histological examination of the tissues, from various organs, did not show any signs of toxicity including necrosis, inflammation, fibrosis etc. The study underlines the potential of bifunctional liposomes as high-efficiency and low-toxicity gene delivery system for the treatment of central nervous system disorders.
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Bin, Bostanudin Mohammad Fauzi. "Butylglyceryl-modified polysaccharide nanoparticles for drug delivery to the brain." Thesis, University of Portsmouth, 2016. https://researchportal.port.ac.uk/portal/en/theses/butylglycerylmodified-polysaccharide-nanoparticles-for-drug-delivery-to-the-brain(a91de9ba-3070-40a4-bf66-400f4d63027d).html.
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The limited access to the brain of a large number of therapeutic actives due to the presence of the blood-brain barrier (BBB) has led to intensive research toward the development of nanotechnology-based approaches. Polysaccharides such as chitosan, guar gum, pectin and pullulan have been selected as starting materials for this study due to their biocompatibility, biodegradability, good drug carrier properties, and ease of chemical modification with short chain alkylglycerol-like moieties (expected to enhance drug permeability through the BBB). A series of butylglyceryl-modified polysaccharides were prepared and characterised using chromatographic, spectroscopic and thermal analysis techniques prior to formulation into nanoparticles (NPs) by means of a selection of methods that include reverse emulsification, nanoprecipitation, and ionotropic gelation. Dynamic Light Scattering, Nanoparticle Tracking Analysis, Electrophoretic Mobility Measurements and Electron Microscopy were employed to characterise all NPs (overall size range 120–200 nm, and zeta potential values ranging from -27 to +39 mV). Modified pullulan (PUL-OX4) and guar gum (GG-OX4) NPs were found to be most stable at physiological pH (7.4), in contrast to chitosan (CS-OX4) NPs that demonstrated an increase in size as a result of aggregation. PUL-OX4 NPs (< 145 nm) had the highest Angiotensin II model peptide loading (8.46 %), while GG-OX4 NPs showed the highest loading degree with Doxorubicin (19.11 %) and Rhodamine B (3.78 %). Drug release studies demonstrated that PUL-OX4 NPs released fastest all the model actives tested, while GG-OX4 NPs were able to retain them for the longest period of time. The in vitro interactions of NPs with mouse brain endothelial cells (bEnd3) were investigated using a Transwell permeability model, with results suggesting an increased model membrane permeability in the presence of the modified polysaccharide nanoparticles. The cytotoxicity of these NPs at physiologically-relevant concentrations was studied using MTT assays; all NPs were non-toxic at concentration below 2 mg/mL, however a decrease in cell viability was noticed at higher concentrations. PUL-OX4 nanoparticles were found to be the least toxic, having the lowest LC50 value (9.48 mg/mL; for comparison, CS-OX4 has 7.30 mg/mL). Haemolysis study demonstrated that at concentration below 12 mg/mL, all the NPs studied did not induce a haemolysis effect significantly when compared to PBS control, however an increase in the effect was observed at higher concentration. PUL-OX4 nanoparticles exhibited the highest LC30 value of 19.87 mg/mL while the lowest value was exhibited by CS-OX4 nanoparticles (13.95 mg/mL). Confocal microscopy and flow cytometry investigations confirmed that all modified polysaccharide NPs were successfully taken up by bEnd3 cells, becoming localised in the cytoplasm.
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Molnár, Éva. "Modified-chitosan nanoparticles for drug delivery through the blood-brain barrier." Thesis, University of Portsmouth, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.494005.
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Towards the development of nanoparticulate carriers that cross the blood-brain barrier, a series of alkylglyceryl-modified chitosans with systematically varied degrees of grafting were prepared through synthetic steps that involved the protection of amino moieties via the formation of phthaloyl chitosan. The modified chitosans were formulated into nanoparticle using an ionic gelation technique employing sodium tripolyphosphate. Polymers were characterised by FTER, ¹H- and ¹³C-NMR, and by viscometry and GPC techniques. The size distribution profiles of nanoparticles were determined by dynamic light scattering.
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Toman, Petr. "Nanoparticles from alkylglyceryl-modified polysaccharides for drug delivery to the brain." Thesis, University of Portsmouth, 2012. https://researchportal.port.ac.uk/portal/en/theses/nanoparticles-from-alkylglycerylmodified-polysaccharides-for-drug-delivery-to-the-brain(7c977729-1e45-45d9-b826-f1729a8d784c).html.
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The loading of therapeutic actives into polymeric nanoparticles represents one of the approaches towards drug transport through the blood-brain barrier – the main obstacle to drug delivery into the central nervous system. The non-toxic, biocompatible and biodegradable polysaccharides chitosan and dextran were modified with permeation-enhancing alkylglyceryl pendant chains through reaction with epoxide precursors. The modified polysaccharides were characterised by spectroscopic methods (1H-, 13C-NMR and FT-IR). These polysaccharides were further formulated into nanoparticles using three methods, namely: nanoprecipitation, solvent displacement via dialysis and electrospraying. The resultant colloidal systems formed were characterised using Dynamic Light Scattering, Nanoparticle Tracking Analysis and Electrophoretic Mobility Measurements. Dried nanoparticles were further characterised by Scanning Electron Microscopy and Atomic Force Microscopy. Formulations of alkylglyceryldextran derivatives were found to be stable at the physiologically relevant pH of 7.4. Over the same range of pH values, formulations of alkyglyceryl-chitosans formed aggregates. Respectively dependent upon the method of formulation and the pH, nanoparticles from poly(lactic acid)-graft-butylglyceryl-modified dextran exhibited diameters in the range 100-400 nm and zeta potentials of between -15 and -30 mV. The preparation of nanoparticulate congeners that incorporated a fluorescent marker molecule (Doxorubicin, Rhodamine B or Fluorescein) allowed the studies of the capabilities of nanoparticles to accommodate and release a model therapeutic load. Rhodamine B-loaded nanoparticles further allowed the study of the uptake of nanoformulations by mouse (bEnd3) brain endothelial cells. The interactions of nanoparticles with modelled blood-brain barriers (mouse bEnd3 and human hCMEC/D3) were studied by Electric Cell Substrate Impedance Sensing and also by means of the Transwell model. Data from MTT and Presto Blue assays were consistent with the absence of nanoparticle-induced cytotoxic effects. An in ovo study that used 3-day chicken embryos indicated the absence of whole-organism acute toxicity effects but failed to unmask the biodistribution profile of nanoparticles. The results have shown that poly(lactic)-graftalkylglyceryl- modified dextran nanoparticles possess some promising features (size, stability, loading capacity, and toxicity) that render them candidates for further evaluation as biocompatible nanocarriers for drug delivery to the brain.
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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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Di, Mauro Primiano Pio. "Development of novel and multifunctional polymeric nanoparticles for brain targeted drug delivery." Doctoral thesis, Universitat Ramon Llull, 2015. http://hdl.handle.net/10803/285236.
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Controlled release systems have become an innovative technique to treat diseases like cancer by the targeted delivery to individual cells and tissues. There is an urgent need to achieve efficacious and safe delivery with minimal nonspecific uptake by healthy tissues. Among the polymer-based nanoparticulate systems for drug delivery, nanoparticles (NPs) have represented a promising opportunity as delivery system due to their degradation in water-soluble compounds that enter the normal metabolic pathways of the organism and their capacity to modify pharmacokinetics and the drug tissue distribution profile.
An engineered and versatile targeted nano-platform for the delivery of paclitaxel (PTX) across the blood brain barrier (BBB) with the aim to improve its therapeutic effect on human glioma cells has been developed. A novel biodegradable polymer has been synthetized and custom tailored NPs have been obtained. The method allows to modify the targeted drug delivery for efficiently transport and release of active drug molecule across the BBB. Aiming a dual targeting strategy, functionalization with ligands known to be efficiently transported across BBB by a membrane receptor that also is over-expressed on human glioma cells has been employed to shuttle PTX from blood to brain and then target glioma cells. In vivo properties of the NPs have been explored to assess their biological profile and since the pressing need for careful evaluation, new strategies for NPs radiolabeling with the aim to investigate their in vivo fate, specifically stability in biological environments (stealthiness), biodistribution and pharmacokinetic, have been adopted.<br>Los sistemas de liberación controlada de medicamentos, mediante la administración dirigida individualmente a células y tejidos, se han convertido en una técnica innovadora para tratar enfermedades como el cáncer. Existe una necesidad urgente para lograr una liberación eficaz y segura que incluya una mínima absorción no específica para los tejidos sanos. Entre los sistemas nanopartículados a base de polímeros para la administración de fármacos, las nanopartículas (NPs) han representado una oportunidad prometedora como sistema de suministro. Entre sus ventajas se puede destacar su perfil de degradación en compuestos hidrosolubles y no tóxicos, que se eliminan siguiendo las vías metabólicas normales del organismo. Por otro lado, presentan una elevada capacidad de modificar la farmacocinética y el perfil de distribución del medicamento en los tejidos.
En esta tesis se ha desarrollado una nano-plataforma específica y versátil para la liberación de paclitaxel (PTX) a través de la barrera hematoencefálica (BHE) con el objetivo de mejorar su efecto terapéutico sobre las células de glioma humano.
Se ha sintetizado un nuevo polímero biodegradable gracias al cual se han obtenido NPs personalizadas a medida. El método permite modificar el tipo administración dirigida de los fármacos para conseguir un transporte y una liberación de las moléculas de principio activo eficiente y segura. Se ha desarrollado el objetivo de seguir una estrategia de selección dual que consiste en transportar el PTX desde la sangre hasta el cerebro y luego dirigirse a las células de glioma. Para ello se ha empleado la funcionalización con marcadores capaces de atravesar eficientemente la BHE a través de un receptor de membrana que también está sobre-expresado en las células de glioma humano. Para evaluar el perfil biológico de las NPs se han explorado sus propiedades in vivo y dada la urgente necesidad de una evaluación fiable, se han adoptado nuevas estrategias para radiomarcar NPs con el objetivo de investigar su destino in vivo, la estabilidad en entornos biológicos, la biodistribución y la farmacocinética.<br>Els sistemes d'alliberament controlat de medicaments, mitjançant l'administració dirigida individualment a cèl•lules i teixits, s'han convertit en una tècnica innovadora per tractar malalties com el càncer. Hi ha una necessitat urgent per aconseguir un alliberament eficaç
i segura que inclogui una mínima absorció no específica per als teixits sans. Entre els sistemes nanoparticulats a base de polímers per a l'administració de fàrmacs, les nanopartícules (NPs) han representat una oportunitat prometedora com a sistema de subministrament. Entre els seus avantatges es pot destacar el seu perfil de degradació en
en compostos hidrosolubles i no tòxics, que s'eliminen seguint les vies metabòliques normals de l'organisme. D'altra banda, presenten una elevada capacitat de modificar la
farmacocinètica i el perfil de distribució del medicament en els teixits.
En aquesta tesi s'ha desenvolupat una nano‐plataforma específica i versàtil per a l'alliberament de paclitaxel (PTX) a través de la barrera hematoencefàlica (BHE) amb l'objectiu de millorar el seu efecte terapèutic sobre les cèl•lules de glioma humà.
S'ha sintetitzat un nou polímer biodegradable gràcies al qual s'han obtingut NPs personalitzades a mida. El mètode permet modificar el tipus administració dirigida dels fàrmacs per aconseguir un transport i un alliberament de les molècules de principi actiu eficient i segura. S'ha desenvolupat l'objectiu de seguir una estratègia de selecció dual que consisteix a transportar el PTX des de la sang fins al cervell i després dirigir‐se a les cèl•lules de glioma. Per a això s'ha emprat la funcionalització amb marcadors capaços de travessar eficientment la BHE a través d'un receptor de membrana que també està sobre-expressat en les cèl•lules de glioma humà. Per avaluar el perfil biològic de les NPs s'han explorat les seves propietats in vivo i donada la urgent necessitat d'una avaluació fiable, s'han adoptat noves estratègies per radiomarcar NPs amb l'objectiu d'investigar la seva destinació in vivo, l'estabilitat en entorns biològics, la biodistribució i la farmacocinètica.
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Krishan, Mansi. "Enhanced Intranasal Delivery of Gemcitabine to the Central Nervous System." University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1384850749.
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Guduru, Rakesh. "Bionano Electronics: Magneto-Electric Nanoparticles for Drug Delivery, Brain Stimulation and Imaging Applications." FIU Digital Commons, 2013. http://digitalcommons.fiu.edu/etd/979.
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Nanoparticles are often considered as efficient drug delivery vehicles for precisely dispensing the therapeutic payloads specifically to the diseased sites in the patient’s body, thereby minimizing the toxic side effects of the payloads on the healthy tissue. However, the fundamental physics that underlies the nanoparticles’ intrinsic interaction with the surrounding cells is inadequately elucidated. The ability of the nanoparticles to precisely control the release of its payloads externally (on-demand) without depending on the physiological conditions of the target sites has the potential to enable patient- and disease-specific nanomedicine, also known as Personalized NanoMedicine (PNM). In this dissertation, magneto-electric nanoparticles (MENs) were utilized for the first time to enable important functions, such as (i) field-controlled high-efficacy dissipation-free targeted drug delivery system and on-demand release at the sub-cellular level, (ii) non-invasive energy-efficient stimulation of deep brain tissue at body temperature, and (iii) a high-sensitivity contrasting agent to map the neuronal activity in the brain non-invasively. First, this dissertation specifically focuses on using MENs as energy-efficient and dissipation-free field-controlled nano-vehicle for targeted delivery and on-demand release of a anti-cancer Paclitaxel (Taxol) drug and a anti-HIV AZT 5’-triphosphate (AZTTP) drug from 30-nm MENs (CoFe2O4-BaTiO3) by applying low-energy DC and low-frequency (below 1000 Hz) AC fields to separate the functions of delivery and release, respectively. Second, this dissertation focuses on the use of MENs to non-invasively stimulate the deep brain neuronal activity via application of a low energy and low frequency external magnetic field to activate intrinsic electric dipoles at the cellular level through numerical simulations. Third, this dissertation describes the use of MENs to track the neuronal activities in the brain (non-invasively) using a magnetic resonance and a magnetic nanoparticle imaging by monitoring the changes in the magnetization of the MENs surrounding the neuronal tissue under different states.
The potential therapeutic and diagnostic impact of this innovative and novel study is highly significant not only in HIV-AIDS, Cancer, Parkinson’s and Alzheimer’s disease but also in many CNS and other diseases, where the ability to remotely control targeted drug delivery/release, and diagnostics is the key.
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Meng, Weina. "Evaluation of a nanoparticle drug delivery vehicle in medulloblastoma and organotypic brain cell cultures." Thesis, University of Nottingham, 2006. http://eprints.nottingham.ac.uk/13933/.
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It has been widely reported that cell culture dimension and microenvironment influence cell proliferation, differentiation, and gene expression, which lead to different interactions between drug delivery systems and cells. The development in evaluation of drug delivery systems has reached the stage where investigations are now concentrating on intracellular uptake and subcellular localization of drug delivery systems.This thesis investigates the use of three-dimensional (3-D) tissue culture models to study how nanoparticles (NPs) may behave in vivo. Poly (glycerol-adipate) (PGA) NPs can degrade into glycerol and adipate, which are not having toxic and anyundesirable local or systemic effects in the host. Following on the initial physicochemical characterization of PGA NPs loaded with drug and fluorescent dyes, investigations moved on to the biological studies of NPs in various cell culture model, e.g. monolayer culture, 3-D culture models, and brain tumour invasion model. Particle size, surface charge, and hydrophobicity are important features affecting the amount of particles taken up by cells and intracellular localisation of particles. Thus, the physicochemical properties of drug and fluorescent dye loaded PGA NPs were assessed by Photon Correlation Spectroscopy, Laser Doppler Anemometry, and drug/fluorescent dye loading studies. These studies indicated that physicochemical properties of drug, fluorescent dyes and PGA polymer could influence drug /fluorescent dye loading, which results in different particle size and surface charge of PGA NPs. Quantitative and qualitative investigations into the influence of cell culture dimension on uptake of NPs by cells, both by confocal fluorescence microscopy and flow cytometry, revealed that DAOY cells took up NPs more effectively when in 3-D spherical aggregate culture than in 2-D monolayer culture while uptake of NPs by normal brain cells was lower in 3-D cell culture than that seen in 2-D monolayer culture. This resulted in intracellular fluorescence intensity about 6 times higher in DAOY aggregates than normal brain cell aggregates while in monolayer culture mixed brain cells took up 2 times as many NP as the DAOY cells. The results from studies of NPs migrating through aggregates and tissue slices also indicated that penetration ofNPs in 3-D culture models was affected by the structure of the interstitial compartment and composition of extracellular matrix. Microscopic investigation of the histology of a co-culture invasion model of DAOY aggregates and a organotypic brain slice confirmed that DAOY cells massively invaded into cerebellum slices after a 4-day co-culture while the invasion of DAOY cells were limited within cerebral cortex slices even after a 6-day co-culture. Selective uptake of NPs by host cells and brain tumour cells were also assessed in this 3-D brain tumour invasion model. It showed that most NPs were taken up by DAOY cells instead of brain cells.
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Agarwal, Abhiruchi. "Nanocarrier mediated therapies for the gliomas of the brain." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/39468.
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Existing methods of treating glioma are not effective for eradicating the disease. Therefore, new and innovative methods of treatment alone or in combination with existing therapies are necessary. Delivery of therapeutic agents through delivery carriers such as liposomes diminishes the harmful effects of the agent in healthy tissues and allows increased accumulation in the tumor. In addition, targeted chemotherapy using liposomes provides the opportunity for further increase in drug accumulation in tumor. However, the current targeting strategies suffer accelerated plasma clearance and are not advantageous in improving efficacy. The search for new tumor targets, novel ligands, new strategies for targeting, and particle stabilization will advance our ability to improve delivery at the tumor level while decreasing toxicity to normal tissues.
The global objective of this thesis was to improve the status of current liposomal therapy to achieve higher efficacy in tumors. Here, we show a novel mechanism to increase targeting to tumor while uncompromising on the long circulation of stealth liposomes. Long circulation is essential for passive accumulation of the nanocarriers due to EPR effect, in order to see benefits of targeting. Using phage display technique, a variety of tumor specific peptides were identified for use as targeting moieties. One potential advantage of the approach proposed here is the rapid identification of patient tumor specific peptide that evades the RES. This could lead to the development of a nanocarrier system with high avidity and selectivity for tumors. Therefore, tumor accumulation of the targeted formulations will be higher than that of non‐targeted liposomes due to increased drug retention at the tumor site and uncompromised blood residence time.In addition, it has been shown that the distribution of nanocarriers, spatially within the tumor, is limited that might further hinder the distribution of the encapsulated drug, thereby limiting efficacy. It is necessary to release the drug from within the nanocarrier to promote increased efficacy. Here, we were able to address the problem of drug diffusion within the tumor interstitium using a combination therapy employing a remotely triggered thermosensitive liposomal chemotherapeutic. We fabricated a thermosensitive liposomal nanocarrier that maintained its stability at physiological temperature to minimize toxicity to healthy cells. We, then, showed a remote triggering mechanism mediated by gold nanorods heated via NIR can help in achieving precise control over the desired site for drug release. These strategies enabled increased drug availability at the tumor site and contributed to tumor retardation. Additionally, we show that the synergistic therapy employing gold nanorods and thermosensitive liposomes may have great potential to be translated to the clinic.
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Hashmi, Sumaiya F. "A DNA Computer for Glioblastoma Multiforme Diagnosis and Drug Delivery." Scholarship @ Claremont, 2013. http://scholarship.claremont.edu/cmc_theses/799.
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Glioblastoma multiforme (GBM) is a debilitating malignant brain tumor with expected patient survival of less than a year and limited responsiveness to most treatments, often requiring biopsy for diagnosis and invasive surgery for treatment. We propose a DNA computer system, consisting of input, computation, and output components, for diagnosis and treatment. The input component will detect the presence of three GBM biomarkers: vascular endothelial growth factor (VEGF), caveolin-1α (CAV), and B2 receptors. The computation component will include indicator segments for each of these genes, and ensure that output is only released if all the biomarkers are present. The output component will consist of the therapeutic agent interleukin-12 (IL-12).
This study will designate four groups of animals: untreated tumor-free (control), tumor-inoculated (RG2), treated and tumor-free (DNA), and treated and tumor-inoculated (RG2/DNA). In the RG2 and RG2/DNA groups, we will inoculate adult male Fischer rats with RG2 cells into the striatum to induce tumor growth. Rats in the DNA and RG2/DNA groups will be implanted with the DNA system at the same location via recombinant adeno- associated viral vectors. The effectiveness of the DNA system will be evaluated through tumor size measurements, collected from brain slices stained with hematoxylin and eosin, and survival curve. Additionally, IL-12 localization will confirm the release of the output component.
We anticipate that the DNA treatment will result in a decrease in tumor size, leading to smaller tumor size in the RG2/DNA group versus the RG2 group. The control group is expected to survive the longest, followed by the DNA group, then the RG2/DNA group, and finally the RG2 group. In the DNA group, IL-12 is expected to stay localized to the implantation site, remaining in its unreleased stem-loop form. On the other hand, it is expected to be released and active in the RG2/DNA group.
This study provides a proof of concept to demonstrate the viability and effectiveness of a DNA system using VEGF, CAV, and B2 receptors as biomarkers and IL-12 as a therapeutic output component in the RG2 model. Further research may include varying several of the parameters used in this study, including amount of RG2 administered, choice of biomarkers, quantity and choice of output component, and choice of animal model. This system provides a promising and innovative new approach that is less invasive than surgery yet is still effective in diagnosing, targeting, and treating GBM.
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Aryal, Muna. "Transient disruption of vascular barriers using focused ultrasound and microbubbles for targeted drug delivery in the brain." Thesis, Boston College, 2014. http://hdl.handle.net/2345/bc-ir:104127.
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Thesis advisor: Cyril P. Opeil<br>The physiology of the vasculature in the central nervous system (CNS) which includes the blood-brain-barrier (BBB) and other factors, prevents the transport of most anticancer agents to the brain and restricts delivery to infiltrating brain tumors. The heterogeneous vascular permeability in tumor vessels (blood-tumor barrier; BTB), along with several other factors, creates additional hurdles for drug treatment of brain tumors. Different methods have been used to bypass the BBB/BTB, but they have their own limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Magnetic Resonance Imaging guided Focused Ultrasound (MRIgFUS), when combined with circulating microbubbles, is an emerging noninvasive method to temporarily permeabilize the BBB and BTB. The purpose of this thesis was to use this alternative approach to deliver chemotherapeutic agents through the BBB/BTB for brain tumor treatment in a rodent model to overcome the hinderances encountered in prior approaches tested for drug delivery in the CNS. The results presented in thesis demonstrate that MRIgFUS can be used to achieve consistent and reproducible BBB/BTB disruption in rats. It enabled us to achieve clinically-relevant concentrations of doxorubicin (~ 4.8±0.5 µg/g) delivered to the brain with the sonication parameters (0.69 MHz; 0.55 MPa; 10 ms bursts; 1 Hz PRF; 60 s duration), microbubble concentration (Definity, 10 µl/kg), and liposomoal doxorubicin (Lipo-DOX) dose (5.67 mg/kg) used. The resulting doxorubicin concentration was reduced by 32% when the agent was injected 10 minute after the last sonication. Three weekly sessions of FUS and Lipo-DOX appeared to be safe in the rat brain, despite some minor tissue damage. Importantly, the severe neurotoxicity seen in earlier works using other approaches does not appear to occur with delivery via FUS-BBB disruption. The resuls from three weekly treatments of FUS and Lipo-DOX in a rat glioma model are highly promising since they demonstrated that the method significantly inhibits tumor growth and improves survival. Animals that received three weekly sessions of FUS + Lipo-DOX (N = 8) had a median survival time that was increased significantly (P<0.001) compared to animals who received Lipo-DOX only (N = 6), FUS only (N = 8), or no treatment (N = 7). Median survival for animals that received FUS + Lipo-DOX was increased by 100% relative to untreated controls, whereas animals who received Lipo-DOX alone had only a 16% improvement. Animals who received only FUS showed no improvement. No tumor cells were found in histology in 4/8 animals in the FUS + Lipo-DOX group, and only a few tumor cells were detected in two animals. Tumor doxorubicin concentrations increased monotonically (823±600, 1817±732 and 2432±448 ng/g) in the control tumors at 9, 14 and 17 days respectively after administration of Lipo-DOX. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P<0.05, P<0.01, and P<0.0001 at days 9, 14, and 17, respectively) and were greater than the control tumors by a factor of two or more (2222±784, 3687±796 and 5658±821 ng/g) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (p<0.05) enhanced compared to control tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery for Lipo-DOX are relatively consistent over time, at least in this tumor model. These results are encouraging for the use of large drug carriers, as they suggest that even large/late-stage tumors can benefit from FUS-induced drug enhancement. Corresponding enhancements in Ktrans were found variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (~100 nm) and Gd-DTPA (molecular weight: 938 Da). Overall, this thesis research provides pre-clinical data toward the development of MRIgFUS as a noninvasive method for the delivery of agents such as Lipo-DOX across the BBB/BTB to treat patients with diseases of the central nervous system<br>Thesis (PhD) — Boston College, 2014<br>Submitted to: Boston College. Graduate School of Arts and Sciences<br>Discipline: Physics
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Spencer, Kevin C. (Keven Collen). "A biocompatible, local drug delivery platform for the chronic treatment of neurological disorders of the brain." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/109685.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Materials Science and Engineering, 2017.<br>Cataloged from PDF version of thesis.<br>Includes bibliographical references (pages 148-158).<br>Many neurological disorders are now classified as circuit disorders, in which the underlying pathology arises from a failure in dynamic communication between anatomically distinct regions of the brain. Systemic therapies are often not effective due to their untargeted nature. The injectrode is a multifunctional probe designed to treat neurological disorders through targeted chemical and electrical stimulation directly to a focal point within the implicated neural circuit. This thesis details the characterization and biocompatibility of the injectrode for the treatment of neurological disorders on chronic timescales. In vitro and in vivo infusion tests were conducted to validate the ability to deliver nanoliter scale volumes (10-1000 n1) of drug to targeted brain structures over the course of an eight week implantation period. Muscimol was delivered to deep brain structures to demonstrate effective modulation of neural activity and behavior. These findings highlight the utility of a local chemical delivery approach to treat circuit diseases of the brain. Glial scar is a major barrier to neural probe function. A main objective of this thesis is focused on understanding the process of glial scar formation from a materials perspective. Micromotion and mechanical mismatch are thought to be key drivers of scar formation. This hypothesis was investigated using a novel 3D in vitro glial scar model, which replicates the magnitude and frequency of micromotions that are observed in vivo. Astrocytes were found to have a significant increase in cellular area and perimeter in response to micromotion compared to static control wells. These findings were applied to improve the biocompatibility of the injectrode. Hydrogel coatings, with moduli matched to brain tissue, were formed to mitigate the effects of micromotion. These coatings were found to reduce local strain by up to 70%. In vivo studies were conducted to explore the impact that implant diameter and modulus have on scar formation. Hydrogel coated implants (E=1 1.6 kPa) were found to significantly reduce scarring at 8 weeks post implantation, compared to uncoated implants (E=70 GPa). Size effects from increasing the overall implant diameter were also observed, highlighting the importance of considering both mechanical and geometric factors when designing chronic neural implants.<br>by Kevin C. Spencer.<br>Ph. D.
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Giesen, Beatriz [Verfasser], and Ulf Dietrich [Gutachter] Kahlert. "Gold Nanoparticles as Drug Delivery Systems for Brain Cancer Therapy / Beatriz Giesen ; Gutachter: Ulf Dietrich Kahlert." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2021. http://d-nb.info/1237883814/34.
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Salam, Al-Maliki Shanta Taher. "Nose to Brain Delivery of Antiepileptic Drugs Using Nanoemulsions." University of Toledo Health Science Campus / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=mco1449771501.
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Regberg, Jakob. "Cell-penetrating peptide based nanocomplexes for oligonucleotide delivery." Doctoral thesis, Stockholms universitet, Institutionen för neurokemi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-133794.
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Oligonucleotide-based drugs hold great promise for the treatment of many types of diseases, ranging from genetic disorders to viral infections and cancer. The problem is that efficient delivery across the cell membrane is required for oligonucleotides to have their desired effect. Cell-penetrating peptides (CPPs) provide a solution to this problem. CPPs are capable of transporting cargoes such as drugs or nucleic acids for gene therapy into the cell, either by covalent conjugation to the cargo or by non-covalent complex formation. This thesis is focused on the development of a class of peptides called PepFects, peptides with fatty acid modifications capable of forming nanoparticle-sized complexes with oligonucleotides. These complexes are efficiently internalized by many different cell types and are generally non-toxic and non-immunogenic. We have developed a number of novel PepFect peptides and a quantitative structure-activity model to predict the biological effect of our peptides. In addition, the involvement of scavenger receptors class A in the endocytic uptake of PepFect complexes as well as other CPPs and polymeric transfection agents was studied. Lastly, we have developed a series of PepFect peptides for delivery across the blood-brain barrier and a model system mimicking the blood-brain barrier in order to evaluate the passage of these peptides. The general aim of this thesis is to improve the understanding of intracellular delivery of oligonucleotides with PepFect peptides from both a chemical and a biological viewpoint, and further improve the efficacy of this delivery system with the long-term goal of making it useful in clinical settings.
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Dearborn, Kristina Ok-Hee. "The Characterization of Non-Ionic Surfactant Vesicles: A Release Rate Study for Drug Delivery." [Tampa, Fla] : University of South Florida, 2006. http://purl.fcla.edu/usf/dc/et/SFE0001493.
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Mistry, Alpesh. "The development and application of biological models for evaluation of direct nose-to-brain drug delivery systems." Thesis, University of Nottingham, 2009. http://eprints.nottingham.ac.uk/10654/.
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The olfactory neuroepithelium is the only part of the central nervous system that is exposed directly to the external environment. Therefore, it is the only non-invasive drug delivery route to the brain. Surface modification of PS nanoparticles with chitosan C-PS), polysorbate 80 (P80-PS) and polysorbate 80+FCS (P80-FCS-PS) changed the toxicity and distribution of these nanoparticles in olfactory mucosae. In addition, a reduction in nanoparticle diameter from 200nm to 20nm increased nanoparticle mucosal penetration and possibly also their cellular toxicity. In vitro vertical Franz diffusion chamber and in vivo mouse models were adapted to investigate the transport of nanoparticles via the olfactory system. For the in vitro model, preliminary studies found that olfactory epithelium lined the caudal portion of the dorsal nasal turbinate in the porcine nasal cavity. To ensure the scientific validity of the diffusion chamber studies, it was necessary to prove that the experimental procedures themselves (without the addition of nanoparticles) had no effect on the mounted tissue. Therefore, viability and cellular morphology of the dissected olfactory epithelia were assessed prior to application of nanoparticles to tissues. Alamar Blueâ„¢ viability and histological findings showed that the diffusion chamber experiment did not affect the olfactory tissue when compared to samples that were not mounted on the apparatus. Citrate buffer (pH6.0) had significantly reduced the viability (PD, Isc and Alamar Blueâ„¢) of the porcine olfactory epithelium compared to SNS buffer (pH7.4) but it did not kill it. Citrate buffer may have depleted the mucosal pH gradient in the epithelium. Overall both SNS buffered and citrate buffered porcine olfactory epithelia were suitable for nanoparticle transport studies in the vertical Franz diffusion cell. The in vitro and in vivo biological models showed surface modification had changed the distribution of nanoparticles within the epithelia. There was good agreement between particle losses from donor chamber, fluorescence microscopy images and stereology results that C-PS particles adhered to extracellular mucus to a greater extent compared to PS and P80-FCS-PS. P80-PS nanoparticles were taken into the nasal epithelial cells to a greater extent than C-PS. Nanoparticles were not transported to the receiver chamber in vitro or the olfactory bulbs in vivo. The size of the nanoparticles was also important. Fluorescence microscopy and stereology showed that greater numbers of 100nm PS and 100nm P80-FCS-PS were taken up into mouse olfactory epithelial cells compared to 200nm diameter equivalents. Larger particles may not have penetrated mucus as effectively as smaller ones. Bright field microscopy images of olfactory epithelia dismounted from the diffusion chamber apparatus after transport study with C-PS nanoparticles showed that these particles caused the greatest amount of cellular damage compared to PS, P80-PS and P80-FCS-PS systems. Greater damage was observed for progressively smaller particles. For example, 20nm C-PS may have accessed subcellular organelles such as mitochondria to cause cell death by oxidative stress. However, similar findings in the mouse model were not observed. It was hypothesised that, unlike the in vitro model, the mouse model may have been able to maintain a pH gradient across the mucous layer by neutralising the acidity from the citrate buffer using blood borne HCO3- ions. This would protect the epithelial cells by causing C-PS to aggregate in the mucus thereby preventing them from accessing the epithelial cells.
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Pawar, Shilpa. "The design and evaluation of a targeted nanoparticulate drug delivery system for the treatment of brain cancer." Thesis, University of Central Lancashire, 2018. http://clok.uclan.ac.uk/25463/.
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Daas, Mohammad. "The development of a drug delivery system using brain endothelial non-antibody binding domains as transport carriers." Thesis, Open University, 2018. http://oro.open.ac.uk/55108/.
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The highly specialised brain capillary endothelial cells (BCEC) that constitute the blood brain barrier (BBB) exhibit high resilience to the penetration of xenobiotic and biologic therapeutics, making drug delivery to the central nervous system (CNS) a challenging feat. Endogenous BCEC receptors such as transferrin receptor (TfR) have been proposed as exploitable targets for therapeutic payload transport into the CNS, and have been successfully targeted using monoclonal antibodies to deliver therapeutic molecules into the brains of rodents and non-human primates via receptor mediated transcytosis (RMT). The overall aim of this study was to develop a BCEC drug delivery system using alternative domains to antibodies e.g. peptides and ssDNA aptamers, as a means of exploiting endogenous receptor transport mechanisms to deliver macromolecular drugs into the CNS via RMT. The expression of three receptor candidates, TfR, low-density lipoprotein receptor (LDLR) and low-density lipoprotein-related receptor protein 1 (LRP1) were characterised for use as selectable targets on the cell surface of Immortalised human brain endothelial cells (hCMEC/D3) by flow cytometric analysis. Aptamers and cyclic peptide domains were then selected via <i>in vitro</i> selection techniques. The present findings highlight the selection of 13 peptides that demonstrate species cross-reactivity to human, mouse and rat TfR as determined by phage ELISA. Moreover, the lead candidate Pep1 was identified to share homology with a conserved 'DCSGNFCLF' motif found on transferrin. When expressed as a bivalent peptide-Fc fusion molecule, Pep1 was shown to internalise within the mouse and human brain endothelial cell lines, bEnd.3, and hCMEC/D3. Additionally, the overall enrichment of hTFR specific aptamers was demonstrated following twelve rounds of selection and high throughput sequencing of selected pools, data that warrants further investigation.
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Shukla, Anshu. "A Model for Studying Vasogenic Brain Edema." VCU Scholars Compass, 2006. http://hdl.handle.net/10156/1690.
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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.<br>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.<br>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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Bonakdar, Mohammad. "Microdevices for Investigating Pulsed Electric Fields-Mediated Therapies at Cellular and Tissue Level." Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/81384.
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Recent attempts to investigate living systems from a biophysical point of view has opened new windows for development of new diagnostic methods and therapies. Pulsed electric fields (PEFs) are a new class of therapies that take advantage of biophysical properties and have proven to be effective in drug delivery and treating several disorders including tumors. While animal models are commonly being used for development of new therapies, the high cost and complexity of these models along with the difficulties to control the electric field in the animal tissue are some of the obstacles toward the development of PEFs-based therapies. Microengineered models of organs or Organs-on-Chip have been recently introduced to overcome the hurdles of animal models and provide a flexible and cost-effective platform for early investigation of a variety of new therapies. In this study microfluidic platforms with integrated micro-sensors were designed, fabricated and employed to study the consequences of PEFs at the cellular level. These platforms were specifically used to study the effects of PEFs on the permeabilization of the blood-brain barrier for enhanced drug delivery to the brain. Different techniques such as fluorescent microscopy and electrical impedance spectroscopy were used to monitor the response of the cell monolayers under investigation. Irreversible electroporation is a new focal ablation therapy based on PEFs that has enabled ablation of tumors in a non-thermal, minimally invasive procedure. Despite promising achievements and treatment of more than 5500 human patients by this technique, real-time monitoring of the treatment progress in terms of the size of the ablated region is still needed. To address that necessity we have developed micro-sensor arrays that can be implemented on the ablation probe and give real-time feedback about the size of the ablated region by measuring the electrical impedance spectrum of the tissue.<br>Ph. D.
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Fuchs, Ferdinand Christian. "Sugar conjugates of 3-hydroxy-4-pyridinones : synthesis and investigations into their potential for drug delivery to the brain." Thesis, King's College London (University of London), 2015. http://kclpure.kcl.ac.uk/portal/en/theses/sugar-conjugates-of-3hydroxy4pyridinones(f2b6e057-2a29-4895-a84e-3b42a50968ed).html.
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Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease, with an incidence of 8-18 cases per 100,000 per year and currently about 125,000 cases in the UK. While lifestyle and genetic risk factors for Parkinson’s disease have been identified, the aetiology remains unclear. The current treatment options are limited to the management of symptoms. Iron is misdistributed and accumulates in the affected brain regions (particularly the substantia nigra) as the disease progresses. Iron chelation has been identified as a treatment that slows down disease progression, demonstrating promising results in two clinical trials. Currently available iron chelators only enter the brain to a very limited extent, which restricts their use for the treatment of Parkinson’s disease due to low effective doses achieved in the brain and potential systemic side effects. This thesis focused on the development of novel iron chelators that have been conjugated to sugars. In principle, this strategy could lead to the targeting of molecules to the brain and increase their penetration by facilitated transport across the blood-brain barrier by the glucose transporter GLUT1. The molecules are based on the 3-hydroxypyridin-4-one scaffold, which is the basis of the clinically used iron chelator deferiprone. Hydroxypyridinone iron chelators could be linked to the sugars via ether, amide and triazole linkers, but the deprotection of the resulting conjugates could only be achieved for some molecules, while others could not be successfully deprotected without degradation of the desired conjugate. Thirteen molecules were tested in blood-brain barrier assays based on primary cells from porcine brain endothelial microvessels. The tested chelators did not, however show greater blood-brain barrier permeability when compared to similar non-glycosylated chelators. Instead, permeability was low and correlated with the substances’ lipophilicity. This indicates that glycosylation alone is not sufficient for the transport of the conjugates and may hinder permeability. In order to increase a compound’s brain permeability by glucosylation, the transporter’s substrate binding specificity needs to be considered.
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Jain, Anjana. "Delivery of Cdc42, Rac1, and Brain-derived Neurotrophic Factor to Promote Axonal Outgrowth After Spinal Cord Injury." Diss., Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/16210.
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Injury severs the axons in the spinal cord causing permanent functional loss. After injury, a series of events occur around the lesion site, including the deposition of growth cone inhibitory astroglial scar tissue containing chondroitin sulfate proteoglycan (CSPG)- rich regions. It is important to encourage axons to extend through these inhibitory regions for regeneration to occur. The work presented in this dissertation investigates the effect of three proteins, constitutively active (CA)-Cdc42, CA-Rac1, and brain-derived neurotrophic factor (BDNF) on axonal outgrowth through CSPGs-rich inhibitory regions after spinal cord injury (SCI). Cdc42 and Rac1 are members of the Rho GTPase family and BDNF is a member of the neurotrophin sub-family. These three proteins affect the actin cytoskeleton dynamics. Therefore, Cdc42, Rac1, and BDNF promote axonal outgrowth.
The effect of CA-Cdc42 and CA-Rac1 on neurite extension through CSPG regions was determined in an in vitro model. Rac1 and Cdc42 s ability to modulate CSPG-dependent inhibition has yet to be explored. In this study, a stripe assay was utilized to examine the effects of modulating all three Rho GTPases on neurite extension across inhibitory CSPG lanes. Alternating laminin (LN) and CSPG lanes were created and NG108-15 cells and E9 chick dorsal root ganglions (DRGs), were cultured on the lanes. Using the protein delivery agent Chariot, the neuronal response to exposure of CA and dominant negative (DN) Rho GTPases, along with the bacterial toxin C3, was determined by quantifying the percent ratio of neurites crossing the CSPG lanes. CA-Cdc42, CA-Rac1, and C3 transferase significantly increased the number of neurites crossing into the CSPG lanes compared to the negative controls for both the NG108-15 cells and the E9 chick DRGs. We also show that these mutant proteins require the delivery vehicle, Chariot, to enter the neurons and affect neurite extension. Therefore, activation of Cdc42 and Rac helps overcome the CSPG-dependent inhibition of neurite extension.
In an in vivo study, CA-Cdc42 and CA-Rac1 were locally delivered into a spinal cord cavity. Additionally, BDNF was delivered to the lesion site, either individually or in combination with either CA-Cdc42 or CA-Rac1. The dorsal over-hemisection model was utilized, creating a ~2mm defect that was filled with an in situ gelling hydrogel scaffold containing lipid microtubules loaded with the protein(s) to encourage axons. The lipid microtubules enable slow release of proteins while the hydrogel serves to localize them to the lesion site and permit axonal growth. The results from this study demonstrate that groups treated with BDNF, CA-Cdc42, CA-Rac1, BDNF/CA-Cdc42, and BDNF/CA-Rac1 had significantly higher percentage of axons from the corticospinal tract (CST) that traversed the CSPG-inhibitory regions, as well as penetrate the glial scar compared to the untreated and agarose controls. Although axons from the CST tract did not infiltrate the scaffold-filled lesion, NF-160+ axons were observed in the scaffold. Treatment with BDNF, CA-Cdc42, and CA-Rac1 also reduced the inflammatory response, quantified by analyzing GFAP and CS-56 intensity for reactive astrocytes and CSPGs, respectively, at the interface of the scaffold and host tissue. Therefore, the local delivery of CA-Cdc42, CA-Rac1 and BDNF, individual and combination demonstrated the ability of axons to extend through CSPG inhibitory regions, as well as reduce the glial scar components.
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Sonawane, Amit. "Evaluation of novel efflux transport inhibitor for the improvement of drug delivery through epithelial cell monolayer." Thesis, University of Bradford, 2015. http://hdl.handle.net/10454/14424.
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Blood-brain barrier (BBB) is a unique membranous barrier, which segregates brain from the circulating blood. It works as a physical and metabolic barrier between the central nervous system (CNS) and periphery. In mammals, endothelial cells were shown to be of BBB and are characterized by the tight junctions along with efflux system which are responsible for the restriction of movement of molecules within the cells. Efflux system consists of multidrug resistance proteins such as P-glycoprotein (P-gp). P-gp removes substances out back from the brain to the blood before they reach to the brain. So the barrier is impermeable to many compounds such as amino acids, ions, small peptides and proteins, making it the most challenging factor for the development of new drugs for targeting CNS. Curcumin is a bioactive compound that has a number of health promoting benefits such as anti-inflammatory, anticancer, anti-oxidant agent; as well as a role in neurodegenerative diseases, but low oral bioavailability is the major limiting factor. Low water solubility and rapid metabolism are the two important factors responsible for poor bioavailability of curcumin. Galaxolide is a musk compound and previously known for the bioaccumulation of toxic components in the aquatic animals by interference with the activity of multidrug/multixenobiotic resistance efflux transporters (MDR/MXR). The bioavailability of curcumin can be enhanced when administered with galaxolide. This study was carried out to investigate the effect of galaxolide on the permeation of curcumin through the epithelial cell monolayers. MDCKII-MDR1 cell monolayer is used an in vitro blood-brain barrier model while Caco-2 monolayer is used as an in vitro intestinal model, which also expresses the P-glycoprotein. The curcumin and galaxolide were separately solubilised in the DMSO and used in combination to perform permeation study, to determine the effect of galaxolide on curcumin permeation through epithelial cell monolayers. The galaxolide shows an efflux protein inhibition activity and this activity was used to enhance permeation of curcumin through the Caco-2 monolayer. In summary, galaxolide is a novel permeation enhancer molecule, which can be used for the improvement of drug delivery of other bioactive compounds in future.
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Manickavasagam, Dharani. "Preparation and Characterization of Polymersomes for Nose-to-Brain Delivery of Combination Therapeutics in Neuroinflammation Treatment." Kent State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=kent1555522694193999.
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Hägerström, Helene. "Polymer gels as pharmaceutical dosage forms : rheological performance and physicochemical interactions at the gel-mucus interface for formulations intended for mucosal drug delivery /." Uppsala : Acta Universitatis Upsaliensis, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3538.
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Salade, Laurent. "Development and Characterization of formulations for the nose-to-brain delivery of ghrelin and the management of cachexia." Doctoral thesis, Universite Libre de Bruxelles, 2019. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/293518.
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For many years, the nasal route of administration as part of a therapeutic treatment has been used. This route of administration is easy to implement, especially due to its non-invasiveness the ease of administration that it affords for the patient. In addition, it is suitable for chronic treatment as well as for an emergency situation when the patient is unconscious. For instance, the administration of benzodiazepines, such as midazolam, may be done to stop convulsions in a patient.Traditionally, intranasal administration was mainly borrowed to target a local effect (e.g. treatment of a cold with a decongestant agent). Subsequently, its application for systemic delivery (e.g. treatment of migraine with triptans) was more and more frequently considered. However, the administration of a drug in the nasal cavities for systemic delivery still remains limited. Indeed, even if the intravenous route has several major limitations such as its invasiveness or the pain generated during administration, it remains more widely used than the intranasal route. This can be explained, on the one hand, by the knowledge that was relatively limited regarding the nasal delivery but also because of the unavailability of nasal devices allowing precise control of the nasal administration (i.e. accurate dose delivery, strong deposition in the nasal cavity, etc).Subsequently, the intranasal route has led to a third therapeutic targeting, namely, the “nose-to-brain pathway”. In that case, the nasal cavity was considered as an opportunity to access the central nervous system (CNS). Indeed, the nose-to-brain delivery allows reaching the brain while bypassing the blood-brain barrier which is known to be a major obstacle to the diffusion of drugs in the CNS. Moreover, the passage through the nasal cavity would allow the administration of sensitive molecules (e.g. biopharmaceuticals) while avoiding excessive enzymatic degradation.Therefore, the nose-to-brain pathway appears to be an attractive route for the delivery of unstable molecules, requiring an access to the brain to reach their site of action. In this context, the therapeutic target that has been selected was "cachexia". It is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. It usually results in particular from undernutrition and a generalized inflammatory state in the patient. In order to treat this syndrome and to restore the appetite in these patients, the goal was to use ghrelin (GHRL) as a model drug. GHRL is a peptide hormone that exhibits, among other effects, an orexigenic action. This biopharmaceutical needs to reach its receptors, located in the hypothalamus, to exert its therapeutic effect.In this study, the goal was to develop a formulation that was able to protect GHRL during its nasal administration, while increasing its residence time to promote its diffusion through the nasal olfactory epithelium.In the first part of the project, GHRL was mainly characterized in terms of stability (e.g. temperature and pH), but also in terms of surface charge. These results allowed selecting the most suitable strategy of formulation as well as the optimal storage conditions. After these preformulation evaluations, it was decided to work on the development of a liquid formulation. The first formulation was based on micelles composed of lipids with polyethylene glycol "DSPE-PEG (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino (polyethylene glycol) -2000] (ammonium salt)" as hydrophilic group. This type of pegylated lipids have already shown, in many scientific studies, interesting properties in the context of intranasal administration, especially in terms of mucopenetration. With a slight adaptation of the protocol found in the literature, it was possible to obtain micelles of an adequate size (~15 nm). The micelles produced also showed good ability to encapsulate GHRL with an encapsulation rate of 98%, but micelles of DSPE-PEG failed to increase the GHRL diffusion through epithelial layer. This step is essential in order to obtain high GHRL levels in the brain. The formulation containing DSPE-PEG micelles has thus been abandoned.Still in the goal of combining lipid excipients with hydrophilic polymer, another formulation strategy based on liposomes coated with chitosan has been considered. Since GHRL has a positive charge at physiological pH, anionic liposomes have been developed to get a high loading. Three types of liposomes have been produced: anionic, neutral and cationic. The objective was to evaluate the influence of the liposomes charge on GHRL encapsulation. By working with anionic liposomes, the loading could be 46% higher than that obtained from the cationic liposomes. In order to evaluate a potential relation between the amount of GHRL that was encapsulated in the liposomes and the amount of GHRL that could potentially be degraded in the presence of enzyme, the three types of liposomes were exposed to trypsin. Following enzyme exposure, anionic liposomes showed enzymatic protection 4 times higher than cationic liposomes. These anionic liposomes have also shown high GHRL protection in the presence of another enzyme with another mechanism of digestion, namely, carboxylesterase-1. Subsequently, isothermal titration calorimetry tests were performed to better understand the interaction mechanisms between GHRL and anionic liposomes. This technique showed that hydrophobic interactions between both compounds were predominant. The coating of anionic liposomes by chitosans was performed and confirmed by an increase of the mean diameter (+48 nm) and charge (+6 mV) as well as by the modification of the morphology of the liposomes. This coating of liposomes with chitosans was supposed to confer additional properties to the formulation such as mucoadhesion and permeation enhancement. These both effects can be obtained thanks to the positive charge of chitosans which allows adhering to the mucins of the mucus, on the one hand, and thanks to the opening of the epithelial tight junctions that enhances drug permeation, on the other hand. The chitosan coating allowed increasing the fixation of the liposomes to mucins by about twenty percent compared to uncoated liposomes. In addition, the "absorption promoter" effect of chitosans was confirmed on cells culture. Then, the formulation was introduced into two distinct nasal devices intended for the administration of liquid nasal sprays, namely, the VP3 device from Aptar Pharma and the SP270 device from Nemera. The aerosols produced by each device allowed generating droplets characterized by a mean diameter higher than 10µm, leading to potential satisfactory impaction onto the olfactory region instead of diffusion throughout posterior region of the nasal cavities. In the second part of the work, a dry formulation was produced by spray-drying from the liquid dispersion of coated liposomes. The objective was to increase the stability of GHRL during storage as well as to enhance its remanence and diffusion through the olfactory epithelium. The optimized parameters allowed producing a powder characterized by a mean diameter higher than 10 μm with an acceptable yield. The powder produced exhibited a low residual moisture and showed good homogeneity in terms of GHRL content. Then, a comparative study was carried out between the powder and the liquid formulation to compare the GHRL stability over time during storage at different temperatures (4°C and 25°C) but also their ability to fix mucins. In both cases, the dry powder showed better results The powder was also re-dispersed in aqueous phase to evaluate the ability of the liposomes to be reconstituted without modifying their physicochemical properties (e.g. size distribution, charges, stability). It was demonstrated that the majority of the initial properties could be preserved after reconstitution (i.e. rate of encapsulation). Similarly to the liquid formulation, the powder was loaded into a specific device developed for the nasal administration of powders that allows targeting the olfactory region to optimize the nose-to-brain transfer. The device, "UDS - Unit Dose System " from Aptar Pharma, has shown excellent properties in terms of particle size distribution in the aerosol but also in terms of targeting the olfactory zone. The latest was studied by means of "nasal cast" that is a 3-printed model of artificial nasal cavities. After impaction in the different cavities of the cast, it was possible to quantify the amount of GHRL that was deposited in the olfactory zone. Using our optimized formulation in combination with the device developed by Aptar, it was shown that 52% of the powder was impacted onto the area corresponding to the olfactory region. Such data demonstrated the relative difficulty to target this section of the nasal cavities.Finally, the formulation loaded with fluorescent GHRL was intranasally administered in mice. It was demonstrated that GHRL could reach the brain after intranasal administration of the formulation and that the formulation was essential to allow this transfer to the brain.The administration of such biopharmaceutical by nose-to-brain with this formulation seems to be an interesting alternative to exploit. However, additional studies to quantify this transfer more precisely, to better define its kinetics and also to evaluate the efficacy of the treatment should be carried out.<br>Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie)<br>info:eu-repo/semantics/nonPublished
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Osburg, Berit. "Drug delivery of oligonucleotides at the blood brain barrier a therapeutic strategy for inflammatory diseases of the central nervous system /." [S.l.] : [s.n.], 2003. http://archiv.ub.uni-marburg.de/diss/z2003/0551/.
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Pourbaghi, Masouleh Milad. "Development of lipid nanocapsules for antiangiogenic treatment of glioblastoma and evaluation of their potential for nose-to-brain drug delivery." Thesis, Angers, 2018. http://www.theses.fr/2018ANGE0037.
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Le glioblastome (GB), tumeur primitive du cerveau, la plus agressive, et la plus fréquente chez l’adulte, présente une prolifération vasculaire importante. Des agents thérapeutiques innovants ciblant à la fois l'angiogenèse et les cellules tumorales sont recherchés, ainsi que des systèmes pour augmenter leur délivrance dans la tumeur cérébrale. Un de ces agents est le sorafénib (SFN), un inhibiteur de tyrosine kinase. Sa mauvaise solubilité aqueuse et ses effets secondaires indésirables limitent son utilisation. Le premier objectif de cette thèse était d'encapsuler cet agent dans des nanocapsules lipidiques (NCL) pour contrer ces inconvénients. Nous avons développé des NCL avec une haute efficacité d'encapsulation du SFN qui inhibaient in vitro l'angiogenèse et la viabilité de la lignée de GB humain U87MG. La délivrance intratumorale de SFN-NCL chez des souris porteuses d’une tumeur intracérébrale U87MG induit une normalisation vasculaire tumorale précoce qui pourrait améliorer l'efficacité de la chimiothérapie et de la radiothérapie. Le second objectif était de définir si la délivrance intranasale de NCL pouvait constituer une voie non-invasive alternative. Nous avons étudié via le transfert d'énergie par résonance de type Förster, le devenir des NCL chargées d’un fluorochrome à travers des monocouches de cellules Calu-3, un modèle de l'épithélium nasal. L'utilisation de NCL augmente le passage du fluorochrome à travers les cellules Calu-3, mais les particules sont rapidement dégradées après leur capture. Ces données mettent en évidence que les NCL sont appropriées pour la délivrance locale du SFN mais doivent être modifiées pour une délivrance intranasale<br>Glioblastoma (GB), the most aggressive, and the most frequent primary tumor of the brain in adults, present a prominent vascular proliferation. Innovative therapeutic agents targeting both angiogenesis and tumor cells are urgently required, along with competent systems for their delivery to the brain tumor. One such agent is sorafenib (SFN), a tyrosine kinase inhibitor. However, poor aqueoussolubility and undesirable side effects limit its clinical application. The first objective of this thesis was to encapsulate this drug inside lipid nanocapsules(LNCs) to overcome these drawbacks. We developed LNCs with a high SFN encapsulation efficiency (>90%) that inhibited in vitro angiogenesis and the viability of the human U87MG GB cell line. Intratumoral delivery of SFN-LNCs in mice bearing intracerebral U87MG tumors induced early tumor vascular normalization which could be used to improve the efficacy of chemotherapy and radiotherapy in the treatment of GB. The second objective was to define whether intranasal delivery of LNCs could be an alternative non-invasive route. In this regard, we investigated through Förster resonance energy transfer, the fate of dye-loaded LNCs across Calu-3 cell monolayers, a model of the nasal mucosa. We showed that employment of LNCs dramatically increased the delivery of the dye acrossCalu-3 cell monolayer but they were rapidly degraded after their uptake. These data highlight that LNCs are suitable nanocarriers for the local delivery of SFN but must be redesigned for enhancing their nose-to-brain delivery
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Tawfik, Mohamed [Verfasser], and Bernhard A. [Gutachter] Sabel. "Nanoparticles delivery to the central nervous system in-vivo : PVP nanoparticles for brain drug delivery and neuroprotection with siRNA-caspase-3 / Mohamed Tawfik ; Gutachter: Bernhard A. Sabel." Magdeburg : Universitätsbibliothek Otto-von-Guericke-Universität, 2021. http://nbn-resolving.de/urn:nbn:de:gbv:ma9:1-1981185920-387735.
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Bielecki, Peter. "Advanced Mesoporous Silica Nanoparticles for the Treatment of Brain Tumors." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case159558503832021.
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Gonçalves, Vanessa Santos Silva. "Overcoming Central Nervous System-barriers by the development of hybrid structured systems for nose-to-brain drug delivery using clean technologies." Doctoral thesis, Universidade Nova de Lisboa, Instituto de Tecnologia Química e Biológica António Xavier, 2016. http://hdl.handle.net/10362/56395.
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The effective delivery of therapeutics into the brain is challenging since drugs or drug delivery systems (DDS) candidates are not able to cross the blood-brain barrier (BBB), making the development of new drugs alone not enough to ensure progresses in Central Nervous System (CNS) drug therapy. Due to several problems related with other routes of brain drug administration, the interest has increased towards exploring the possibility of intranasal administration. The nose-to-brain transport and the therapeutic viability of this route have been investigated for rapid and effective transport of drugs to CNS, but the development of nasal drug products for brain targeting is still faced with many challenges.(...)<br>info:eu-repo/semantics/publishedVersion
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Connell, John J. "Selective permeabilisation of the blood-brain barrier at sites of metastasis." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:8c027208-8ea6-4de4-be78-ccead5121509.
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Over one in five cancer patients will develop brain metastases and prognosis remains poor. Effective chemotherapeutics for primary systemic tumours have limited access to brain metastases owing to the blood-brain barrier (BBB). The aim of this study was to develop a strategy for specifically permeabilising the BBB at sites of cerebral metastases. Tumour necrosis factor was injected intravenously into mouse models of haematogenously induced brain metastasis. BBB permeability was assessed through histology and in vivo MRI and SPECT. Tumour burden and neuroinflammation were assessed after injection of TNF with Caelyx or a novel therapeutic. Mechanism of permeabilisation was investigated through histology and receptor-specific agonist antibodies. Administration of TNF dose-dependently permeabilised the BBB to exogenous tracers selectively at sites of brain metastasis, with peak effect after six hours. Metastasis-specific uptake of radiolabelled trastuzumab was also demonstrated following systemic cytokine administration. Administration of liposomal doxorubicin formulations in conjunction with TNF reduced tumour burden and mean metastasis size. Localised expression of TNFR1 was evident on the vascular endothelium associated with brain metastases. Human brain metastases displayed a similar TNF receptor profile compared to the mouse model. These findings describe a new approach to selectively permeabilise the BBB at sites of brain metastases, thereby enabling detection of currently invisible micrometastases and facilitating tumour-specific access of chemotherapeutic agents. We hypothesize that this permeabilisation works primarily though TNFR1 activation and, owing to the similar TNFR1 expression profiles in mouse models and human condition, the strategy has the potential for clinical translation.
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Zhang, Yajie. "Multimodal Imaging PLGA Nanocapsules as Protein Carrier for Potential Neurorepair in Ischemic Brain." Doctoral thesis, Universitat Autònoma de Barcelona, 2020. http://hdl.handle.net/10803/671000.
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Els avenços en sistemes nanoparticulats capaços de proporcionar les funcionalitats necessàries a les noves nanomedicines i oferir la possibilitat de combinar la detecció no invasiva de malalties amb tractaments individualitzats estan convertint en realitat la medicina personalitzada. A més, els progressos en teranòstica estan configurant el desenvolupament de l’ administració de fàrmacs guiats per imatge que milloren l’eficiència en el tractament, visualitzant les seves biodistribucions, efectes sobre les dianes moleculars i cel·lulars específiques i els efectes terapèutics corresponents. Aquesta tesi té com a finalitat el disseny i síntesis de nano-biomaterials teranòstics dirigits a la neuroreparació en el context d’un ictus isquèmic per tal d’estimular l’angiogènesi en la zona d’afectació. Per aconseguir-ho, s’han encapsultat factors de creixement secretats per cèl·lules progenitores endotelials (EPCs-secretoma), amb potencial demostrat per induir angiogènesi, en nanocàpsules magnètiques biocompatibles i biodegradables de poli (D, L àcid co-glicòlic) (PLGA). D’altra banda, les càpsules de PLGA s’han funcionalitzat amb diversos agents de contrast permetent tant la retenció magnètica com la seva visualització in vitro o in vivo. Els principals objectius aconseguits en aquesta tesi són: 1) optimització de nanocàpsules magnètiques de PLGA per afavorir la seva retenció en la zona a tractar i l’encapsulació i alliberament controlats de proteïnes terapèutiques; 2) funcionalització modular de les nanocàpsules amb agents de contrast per: ressonància magnètica d’imatge, fluorescència a quatre longituds d’ona diferents i tomografia d’emissió de positrons i 3) noves aproximacions per millorar l’acumulació cerebral de les nanocàpsules en ratolins i augmentar-ne la càrrega del secretoma encapsulat en les mateixes.<br>El desarrollo de sistemas nanoparticulados capaces de proporcionar las funcionalidades necesarias a las nuevas nanomedicinas ofreciendo la posibilidad de combinar la detección no invasiva de enfermedades con tratamientos individualizados están convirtiendo en realidad la medicina personalizada. Además, los progresos en teranóstica están configurando el progreso de la administración de fármacos guiados por imagen que mejoran la eficiencia del tratamiento visualizando su biodistribución, el efecto sobre las dianas moleculares y celulares específicas y los efectos terapéuticos correspondientes. Esta tesis tiene como finalidad el diseño y la síntesis de nano-biomateriales teranósticos dirigidos a la neuroreparación en el contexto de un ictus isquémico con el objetivo de estimular la angiogénesis en la zona de afectación. Para ello, se han encapsulado factores de crecimiento secretados por las células progenitoras endoteliales (EPCs-secretoma), con demostrado potencial para inducir angiogénesis, en nanocápsulas magnéticas biocompatibles y biodegradables de poli (D, L ácido co-glicólico) (PLGA). Por otra parte, las cápsulas de PLGA se han funcionalizado con varios agentes de contraste permitiendo tanto la retención magnética como su visualización in vitro o in vivo. Los principales objetivos conseguidos en esta tesis son: 1) optimización de nanocápsulas magnéticas de PLGA para favorecer su retención en la zona a tratar y la encapsulación y liberación controlados de proteínas terapéuticas; 2) funcionalización modular de las nanocápsulas con agentes de contraste para: resonancia magnética de imagen, fluorescencia a cuatro longitudes de onda diferentes i tomografía de emisión de positrones y 3) nuevas aproximaciones para mejorar la acumulación cerebral de las nanocápsulas en ratones y aumentar la carga de secretoma encapsulado en las mismas.<br>Advancements in nanoparticulated systems capable of providing the necessary functionalities to new nanomedicines and offering the possibility to combine non-invasive disease detection with individualized treatments are facilitating personalized medicine to become a reality. Besides, the progress in theranostics is shaping the development of image-guided drug delivery improving the efficiency of pharmaceuticals by visualizing their biodistributions, effects on specific molecular and cellular targets, and the corresponding therapeutic effects. This thesis is devoted to engineering theranostic magnetic nano-biomaterials to address neurorepair in the context of an ischemic stroke by enhancing local angiogenesis. Growth factors secreted by endothelial progenitor cells (EPCs-secretome), with proved potential to induce angiogenesis, were encapsulated into magnetic poly(D,L lactic co glycolic acid) (PLGA) nanocapsules. Additionally, this PLGA-drug delivery system was functionalized with versatile imaging reporters allowing magnetic retention and in vitro/in vivo product tracking. The main accomplished objectives of the thesis are: 1) optimization of PLGA nanocapsules for magnetically targeted delivery and controlled encapsulation and release of proteins, 2) modular functionalization of PLGA nanocapsules with versatile imaging reporters: magnetic resonance imaging, fluorescence at four different wavelengths and positron emission tomography and 3) improved approaches to enhance mice brain accumulation of the nanocapsules and to increase EPCs-secretome loading.
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Kohli, Neha. "Amelioration of Amyloid Burden in Advanced Human and Mouse Alzheimer's Disease Brains by Oral Delivery of Myelin Basic Protein Bioencapsulated in Plant Cells." Master's thesis, University of Central Florida, 2012. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/5380.
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One of the pathological hallmarks of Alzheimer's disease (AD) is the amyloid plaque deposition in aging brains by aggregation of amyloid-? (A?) peptides. In this study, the effect of chloroplast derived myelin basic protein (MBP) fused with cholera toxin subunit B (CTB) was investigated in advanced diseased stage of human and mouse AD brains. The CTB-fusion protein in chloroplasts facilitates transmucosal delivery in the gut by the natural binding ability of CTB pentameric form with GM1 receptors on the intestinal epithelium. Further, bioencapsulation of the MBP within plant cells confers protection from enzymes and acids in the digestive system. Here, 12-14 months old triple transgenic AD mice were fed with CTB-MBP bioencapsulated in the plant cells for 3 months. A reduction of 67.3% and 33.3% amyloid levels in hippocampal and cortical regions, respectively were observed by immunostaining of brain sections with anti- A? antibody. Similarly, 70% decrease in plaque number and 40% reduction of plaque intensity was observed through thioflavin S (ThS) staining that specifically stains amyloid in the AD brain. Furthermore, ex vivo 3xTg AD mice brain sections showed up to 45% reduction of ThS stained amyloid levels when incubated with enriched CTB-MBP in a concentration dependent manner. Similarly, incubation of enriched CTB-MBP with ex vivo postmortem human brain tissue sections with advanced stage of AD resulted up to 47% decrease of ThS stained amyloid plaque intensity. Lastly, lyophilization of plant material facilitates dehydration and long term storage of capsules at room temperature, in addition to increasing CTB-MBP concentration by 17 fold. These observations offer a low cost solution for treatment of even advanced stages of the AD by facilitating delivery of therapeutic proteins to central nervous system to address other neurodegenerative disease.<br>M.S.<br>Masters<br>Molecular Biology and Microbiology<br>Medicine<br>Biotechnology
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Munson, Jennifer Megan. "Novel nanocarriers for invasive glioma." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/41226.
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The invasive nature of glioblastoma (GBM) represents a significant challenge to the standard of care and contributes to poor clinical outcomes. Invasion of tumors into healthy brain restricts chemotherapeutic access and complicates surgical resection. The central hypothesis of the thesis is that an effective anti-invasive agent can enhance the standard chemotherapeutic response in invasive brain tumors. Through a screen of novel compounds, a new anti-invasive small molecule, Imipramine Blue (IB), was identified. This triphenylmethane compound inhibits invasion of highly invasive glioma in vitro and in vivo. To elicit a response in vivo, Imipramine Blue was liposomally encapsulated to yield better delivery to tumor. Using this formulation, it is shown that IB attenuates invasion of glioma in vivo leading to a more compact tumor in an aggressively invasive rodent glioma model. Further, it is shown that this novel compound binds NADPH oxidases and alters expression of actin regulatory elements to elicit this anti-invasive activity. To test our hypothesis that anti-invasive therapy coupled with chemotherapy will enhance efficacy, nano-IB therapy was followed by liposomally encapsulated doxorubicin (DXR) chemotherapy. Additionally, a co-encapsulated formulation of IB and DXR was developed and tested in vivo. This combination therapy significantly enhanced survival compared to IB or DXR alone, resulting in long-term survival in the syngeneic invasive rat astrocytoma model RT2. It was seen that sequential treatment was more effective than the co-encapsulated treatment indicating a benefit of pre-treating the tumor with the anti-invasive. This thesis demonstrates that novel anti-invasive IB mediated 'containment' of diffuse glioma significantly enhances the efficacy of DXR chemotherapy compared to chemotherapy or anti-invasive therapy alone.
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Attarhaie, Tehrani Mahtab. "Anatomical Expression and Functional Role of the G-Protein Coupled Estrogen Receptor 1 in the Song System of Zebra Finches (Taeniopygia guttata)." Kent State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent152416406994131.
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Haraszti, Reka A. "Engineered Exosomes for Delivery of Therapeutic siRNAs to Neurons." eScholarship@UMMS, 2018. https://escholarship.umassmed.edu/gsbs_diss/971.
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Extracellular vesicles (EVs), exosomes and microvesicles, transfer endogenous RNAs between neurons over short and long distances. We have explored EVs for siRNA delivery to brain. (1) We optimized siRNA chemical modifications and siRNA conjugation to lipids for EV-mediated delivery. (2) We developed a GMP-compatible, scalable method to manufacture active EVs in bulk. (3) We characterized lipid and protein content of EVs in detail. (4) We established how protein and lipid composition relates to siRNA delivering activity of EVs, and we reverse engineered natural exosomes (small EVs) into artificial exosomes based on these data.
We established that cholesterol-conjugated siRNAs passively associate to EV membrane and can be productively delivered to target neurons. We extensively characterized this loading process and optimized exosome-to-siRNA ratios for loading. We found that chemical stabilization of 5'-phosphate with 5'-E-vinylphosphonate and chemical stabilization of all nucleotides with 2'-O-methyl and 2'-fluoro increases the accumulation of siRNA and the level of mRNA silencing in target cells. Therefore, we recommend using fully modified siRNAs for lipid-mediated loading to EVs. Later, we identified that α-tocopherol-succinate (vitamin E) conjugation to siRNA increases productive loading to exosomes compared to originally described cholesterol.
Low EV yield has been a rate-limiting factor in preclinical development of the EV technology. We developed a scalable EV manufacturing process based on three-dimensional, xenofree culture of mesenchymal stem cells and concentration of EVs from conditioned media using tangential flow filtration. This process yields exosomes more efficient at siRNA delivery than exosomes isolated via differential ultracentrifugation from two-dimensional cultures of the same cells.
In-depth characterization of EV content is required for quality control of EV preparations as well as understanding composition–activity relationship of EVs. We have generated mass-spectrometry data on more than 3000 proteins and more than 2000 lipid species detected in exosomes (small EVs) and microvesicles (large EVs) isolated from five different producer cells: two cell lines (U87 and Huh7) and three mesenchymal stem cell types (derived from bone marrow, adipose tissue and umbilical cord Wharton’s jelly). These data represent an indispensable resource for the community. Furthermore, relating composition change to activity change of EVs isolated from cells upon serum deprivation allowed us to identify essential components of siRNA-delivering exosomes. Based on these data we reverse engineered natural exosomes into artificial exosomes consisting of dioleoyl-phosphatidylcholine, cholesterol, dilysocardiolipin, Rab7, AHSG and Desmoplakin. These artificial exosomes reproduced efficient siRNA delivery of natural exosomes both in vitro and in vivo. Artificial exosomes may facilitate manufacturing, quality control and cargo loading challenge that currently impede the therapeutic EV field.
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Thomas, Sean Casey. "A Developed and Characterized Orthotopic Rat Glioblastoma Multiforme Model." Thesis, Virginia Tech, 2020. http://hdl.handle.net/10919/100772.
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This thesis project serves to fill experimental gaps needed to advance the goal of performing pre-clinical trials using an orthotopic rat glioblastoma model to evaluate the efficacy of high-frequency electroporation (H-FIRE) and QUAD-CTX tumor receptor-targeted cytotoxic conjugate therapies, individually and in combination, in selectively and thoroughly treating glioblastoma multiforme. In order to achieve this, an appropriate model must be developed and characterized. I have transduced F98 rat glioma cells to express red-shifted firefly luciferase, which will facilitate longitudinal tumor monitoring in vivo through bioluminescent imaging. I have characterized their response to H-FIRE relative to DI TNC1 rat astrocytes. I have demonstrated the presence of the molecular targets of QUAD in F98 cells. The in vitro characterization of this model has enabled preclinical studies of this promising glioblastoma therapy in an immunocompetent rat model, an important step before advancing ultimately to clinical human trials.<br>Master of Science<br>Treating glioblastoma multiforme (GBM), a form of cancer found in the brain, has not been very successful; patients rarely live two years following diagnosis, and there have been no major breakthrough advances in treatment to improve this outlook for decades. We have been working on two treatments which we hope to combine. The first is high-frequency electroporation (H-FIRE), which uses electrical pulses to kill GBM cells while leaving healthy cells alive and blood vessels intact. The second is QUAD-CTX, which combines a toxin with two types of protein that attach to other proteins that are more common on the surface of GBM cells than healthy cells. We have shown these to be effective at disproportionately killing human GBM cells growing in a lab setting. Before H-FIRE and QUAD-CTX may be tested on humans, we need to show them to be effective in an animal model, specifically rats. I have chosen rat glioma cells that will behave similarly to human GBM and a rat species that will not have an immune response to them. I have made these cells bioluminescent so that we may monitor the tumors as they grow and respond to our treatments. I have also shown that QUAD-CTX kills these rat glioma cells, as does H-FIRE. Because of this work, we are ready to begin testing these two treatments in rats.
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Beccaria, Kévin. "Evaluation de la diffusion intracérébrale des drogues antinéoplasiques après ouverture de la barrière hémato-encéphalique induite par ultrasons : Application aux gliomes malins de l’enfant Brainstem Blood-Brain Barrier Disruption and Enhanced Drug Delivery with an Unfocused Ultrasound Device – A Preclinical Study in Healthy and Tumor-Bearing Mice Ultrasound-Induced Blood-Brain Barrier Disruption for the Treatment of Gliomas and other Primary CNS Tumors Blood-Brain Barrier Disruption with Low-Intensity Pulsed Ultrasound for the Treatment of Pediatric Brain Tumors: A Review and Perspectives." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS044.
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Les gliomes de haut grade représentent près de 15% de l’ensemble des tumeurs cérébrales de l’enfant. Aucun progrès thérapeutique n’a été fait depuis 30 ans et leur pronostic reste effroyable. La barrière hémato-encéphalique (BHE) est l’une des causes de l’échec des traitements médicaux car elle limite le passage de la majorité des molécules vers le cerveau, empêchant la plupart des drogues antinéoplasiques d’atteindre le tissu tumoral. L’ouverture de la BHE par les ultrasons pulsés de faible intensité en association avec des microbulles injectées par voie intraveineuse est une technique qui permet d’ouvrir transitoirement la BHE de manière localisée et sécurisée. Dans cette étude, nous avons confirmé la capacité d’un nouvel agent de contraste (microbulles) à ouvrir la BHE avec des ultrasons. Nous avons par ailleurs montré qu’il était possible d’ouvrir la BHE dans le tronc cérébral avec un dispositif ultrasonore non focalisé (SonoCloud®), à la fois sur des souris saines et des modèles murins de DIPG. Nous avons pu augmenter la distribution de l’irinotécan et du panobinostat dans le tronc cérébral de souris saines et de modèles de DIPG après ouverture de la BHE, sans cependant améliorer la survie de notre modèle de DIPG. Des études préliminaires ont été réalisées avec des inhibiteurs de chekpoints et des cellules natural killer, qui n’ont pas permis d’améliorer la survie d’un modèle murin de gliome malin sus-tentoriel. Enfin, nous avons mis au point le premier essai clinique pédiatrique qui visera, dès le premier semestre 2020, à évaluer la faisabilité et la tolérance de l’ouverture de la BHE avec le dispositif SonoCloud® chez l’enfant et l’adolescent<br>High-grade gliomas represent about 15% of pediatric brain tumors. No progress has been made in the treatment of these tumors during the last decades, and their prognosis remains dismal. The blood-brain barrier (BBB) plays a major role in the failure of medical treatments since it prevents most molecules to reach the brain, thus limiting the delivery of antineoplastic drugs to brain tumors. Disruption of the BBB (BBBD) with low intensity pulsed ultrasound in association with intravenous microbubbles is a technique that allows for safe, transient, and localized opening of the BBB. In this thesis, we confirmed the capacity of a new microbubble contrast agent to induce BBBD with ultrasound. We showed that opening of the BBB in the brainstem is possible with a nonfocused ultrasound device (SonoCloud®), in both healthy mice and a murine model of DIPG. We were able to increase irinotecan and panobinostat delivery in the brainstem of both healthy and tumor-bearing mice after BBBD, but we did not observe increased in overall survival. Preliminary studies have also been performed with checkpoints inhibitors and natural killer cells in a murine model of supra-tentorial high-grade glioma, but we were not able to increase survival in these models anymore. Finally, we prepared the first clinical trial that will evaluate the feasibility and tolerance of ultrasound-induced BBBD with the SonoCloud® device in the pediatric population. This trial will begin during the first semester of 2020
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Critchley, Helen. "Intranasal drug delivery." Thesis, University of Nottingham, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236046.
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Irwin, Michael Garnet. "Patient maintained drug delivery." Thesis, Click to view the E-thesis via HKUTO, 2003. http://sunzi.lib.hku.hk/hkuto/record/B31981847.
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