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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Crosslinked microspheres as drug delivery system for liver cancer

Nguyen, Thi Lam Uyen Nguyen, Centre for Advanced Macromolecular Design, Faculty of Engineering, UNSW January 2008 (has links)
It has been demonstrated that 1,25 dihydroxy vitamin D3 (1,25 (OH)2VD3) can inhibit the proliferation of cancer cells including colorectal and hepatocellular cells which are mainly responsible for liver cancer. However, the use of 1, 25 (OH)2VD3 is hampered due to the development of hypercalcaemia. Current treatment using hepatic arterial delivery of drug solution is inconvenient since repetitive invasive treatments are required. This work aims to tackle this problem by utilizing crosslinked microspheres prepared by suspension polymerization as a carrier to control the release of 1, 25 (OH)2VD3 or hydrophobic drug in general at targeted sites over a long period. Poly(vinyl neodecanoate crosslinked ethyleneglycol dimethacrylate) microspheres in the size range of 35 m were prepared via suspension polymerization. Different parameters in suspension polymerization such as temperature, concentration and crosslinker percentage were studied in details. The effect of stabilizer on the formation of spheres was carefully investigated by using RAFT polymerization to produce various structures of the stabilizer, poly (vinyl pyrrolidone). Core- shell microspheres were also produced to enhance the hydrophilicity of the surface of microspheres. Hydrophobic drugs were loaded to these microspheres after reaction by the evaporation method. These microspheres were then used for drug loading and drug release study. Release study has shown that up to 10% of drug was released after 40 days. Cytotoxicity test reveals the suitability of this polymer for application in biomedical field. The MTT assay of Clofazimine loaded microspheres on the colorectal cancer cell lines HT29 has shown that the cell number was decreased about 50% after drug treatment.
2

Crosslinked microspheres as drug delivery system for liver cancer

Nguyen, Thi Lam Uyen Nguyen, Centre for Advanced Macromolecular Design, Faculty of Engineering, UNSW January 2008 (has links)
It has been demonstrated that 1,25 dihydroxy vitamin D3 (1,25 (OH)2VD3) can inhibit the proliferation of cancer cells including colorectal and hepatocellular cells which are mainly responsible for liver cancer. However, the use of 1, 25 (OH)2VD3 is hampered due to the development of hypercalcaemia. Current treatment using hepatic arterial delivery of drug solution is inconvenient since repetitive invasive treatments are required. This work aims to tackle this problem by utilizing crosslinked microspheres prepared by suspension polymerization as a carrier to control the release of 1, 25 (OH)2VD3 or hydrophobic drug in general at targeted sites over a long period. Poly(vinyl neodecanoate crosslinked ethyleneglycol dimethacrylate) microspheres in the size range of 35 m were prepared via suspension polymerization. Different parameters in suspension polymerization such as temperature, concentration and crosslinker percentage were studied in details. The effect of stabilizer on the formation of spheres was carefully investigated by using RAFT polymerization to produce various structures of the stabilizer, poly (vinyl pyrrolidone). Core- shell microspheres were also produced to enhance the hydrophilicity of the surface of microspheres. Hydrophobic drugs were loaded to these microspheres after reaction by the evaporation method. These microspheres were then used for drug loading and drug release study. Release study has shown that up to 10% of drug was released after 40 days. Cytotoxicity test reveals the suitability of this polymer for application in biomedical field. The MTT assay of Clofazimine loaded microspheres on the colorectal cancer cell lines HT29 has shown that the cell number was decreased about 50% after drug treatment.
3

Studies of PLGA Nanoparticles for Pharmaceutical Applications

Sun, Yanqi 08 1900 (has links)
PLGA have already been successfully applied for controlled drug delivery systems by the pharmaceutical industry due to its biocompatibility, biodegradability and ease of processing. It has recently further been developed and formulated into a form of nanoparticle. The single emulsion evaporation method was used to prepare nanoparticles in this study. By varying different parameters such as the concentration of regents, the type of surfactant and emulsion method, different particle sizes and size distribution of PLGA nanoparticles could be obtained. The stability of PLGA nanoparticles was further investigated by assessing their thermal property over a certain period of time using DSC. The decrease of Tg confirmed the hydration and degradation of PLGA polymers and nanoparticles. The changes of surface morphology showed that the nanoparticles were in spherical shape and maintained smooth surface before the storage, whereas they started to lose their original shapes as well as agglomerate to each other after 2-week storage. These results suggested that there was an erosion and degradation of PLGA nanoparticles during storage. Ibuprofen-loaded PLGA nanoparticles have been successfully prepared by o/w single emulsion evaporation method. During the stability study, a faster degradation rate compared to non-loaded PLGA nanoparticles was exhibited, showing that Ibuprofen increased the degradation rate of PLGA nanoparticles. According to the results of drug releasing study, PLGA nanoparticles exhibiting a slower drug release rate than pure drug which proved that drug-nanoparticule system could effectively increase the stability of drugs. PLGA polymer is a potential material for drug delivery system.
4

EVALUATION OF THE PHYSICOCHEMICAL PROPERTIES AND STABILITY OF SOLID LIPID NANOPARTICLES DESIGNED FOR THE DELIVERY OF DEXAMETHASONE TO TUMORS

Howard, Melissa 01 January 2011 (has links)
Pre-clinical and clinical trials suggest that pre-treatment with dexamethasone (Dex) may facilitate enhanced uptake of subsequently administered chemotherapeutic agents. To reduce the side effects associated with systemic administration of Dex, solid lipid nanoparticles (SLNs) containing dexamethasone palmitate (Dex-P) were prepared as a means of achieving tumor-targeted drug delivery. These studies were aimed at evaluating the physicochemical properties and both the physiological and storage stability of the SLNs. SLNs were prepared using nanotemplate engineering technology. Stearyl alcohol (SA) was used as the lipid phase with Brij® 78 and Polysorbate 60 as surfactants and PEG6000 monostearate as a long-chain PEGylating agent. Both formulations exhibited a small particle size, ellipsoidal shape, and low polydispersity. 1H-NMR spectroscopy confirmed that SLNs have the expected solid core and PEGylated surface. Analysis of the bulk materials indicated that a number of complex interactions are present among the SLN components, including a eutectic between SA and Brij® 78. Dex-P could be incorporated in SLNs at 10-30% w/w SA with encapsulation efficiencies >85%. A preferential interaction with the SA-Brij® 78 eutectic was identified, indicating a possible interfacial localization. For comparison, SLNs were also prepared with ascorbyl palmitate (AP) and curcumin. Higher drug loads were achieved with both palmitate-containing prodrugs than curcumin, though all appeared to align differently within the SLNs. SLNs undergo a concentration-dependent particle size growth when incubated at physiological temperature. However, they appear to remain intact with over 85% of the added Dex-P retained at 24 h in conditions mimicking human plasma. In the presence of carboxylesterase, SLNs became turbid and showed a reduction in particle size as compared to controls. This instability was shown to be a result of the hydrolysis of PEG6000 monostearate and Polysorbate 60. To enhance storage stability, a lyophilization protocol designed to minimize changes in the physicochemical properties of SLNs was developed. During a 3 month period, lyophilized SLNs stored at 4°C demonstrated the greatest stability, showing a consistent particle size and an encapsulation efficiency >80%. Overall, these results indicate that Dex-P loaded SLNs possess the physicochemical properties and stability desirable for development as a tumor-targeted drug delivery system.
5

Příprava biodegradovatelných polymerních nanočástic / Biodegradable polymeric nanoparticles preparation

Bacskaiová, Silvia January 2018 (has links)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of: Pharmaceutical technology Consultant: PharmDr. Ondřej Holas, Ph.D. Student: Silvia Bacskaiová Title of Thesis: Biodegradable polymeric nanoparticles preparation The present scientific progress in an important rate conduces to nanomedicine development, which aims to reengineering of cancer pharmacotherapy and other substantial diseases. The main intention of this graduation thesis is the study of surface-active chemical's effects on the final properties of nanoparticles. The theoretical part is focused on the nanoparticles likedrugs vehicles, synthesis of biodegradable nanoparticles, themselves applications in the cancer therapy, diseases accompanied by inflammations, vaccination and for another different purposes. The theoretical part also contents characterization of active and passive goal- directed distribution by diseases, microencapsulations, synthesis of nanoparticles by polymerization and from previously synthesized polymers and definition of physical- chemical properties of nanoparticles. The experimental part is more extensive and concerned with the optimalization of reaction conditions of nanoparticles synthesis, with selection of advisable concentracion and type of surfactant. In the experimental part were...
6

CD81-guided cell-secreted EV sub-populations for targeted anticancer strategies

Gurrieri, Elena 19 July 2023 (has links)
Extracellular Vesicles (EVs) are small membranous particles secreted by the cells. They play an important role in intercellular communication and can transport a variety of biomolecules, including proteins, lipids, and nucleic acids, to target cells. The scientific community recently considered EVs attractive candidates for developing targeted drug delivery systems (DDSs), given their biocompatibility, low immunogenicity, stability in biofluids, and capability to cross biological barriers. Most studies have shown the feasibility of incorporating desired moieties at the EV surface through the genetic modification of EV-producing cells, exploiting the fusion with proteins enriched at the EV membrane. Tetraspanins are transmembrane proteins enriched in EVs, already exploited for EV isolation or tracking upon fusion with fluorescent reporters. CD81 is a well-characterized tetraspanin with ubiquitous protein expression, overexpression tolerance and a limited number of encoded protein isoforms with respect to other EV-associated tetraspanins. Here, I have explored a CD81-based approach for EV targeting. CD81, in full-length or truncated form, was used to guide the expression into EVs of an anti-HER2 moiety, namely the light chains of trastuzumab, within three different constructs, including turbo-GFP (tGFP) as a reporter: CD81-tGFP as master control, CD81-antiHER2-tGFP and CD81delta-antiHER2-tGFP. The first part of the project was dedicated to the characterization of chimeric proteins at cellular and vesicular levels. CD81-based constructs were successfully expressed in HEK239T cells with a preferential enrichment in organelle fractions, underlying the expected involvement in the intracellular vesicular trafficking. Next, chimeric proteins were also found in the derived EVs, with a similar expression trend, corroborated by imaging flow cytometry. Nanoparticle tracking analysis and cryogenic electron microscopy acquisitions confirmed that CD81-fusion proteins boosted EV release without altering the size distribution. Subsequently, I tested the binding capacity of the chimeric proteins to HER2 receptor through orthogonal techniques, such as AlphaLISA and immunoprecipitation. Confocal imaging, also on live cells, confirmed EV internalization into breast cancer cells, depending on the recipient cell type and the presence of HER2 receptor. Moreover, chimeric EVs loaded with doxorubicin were able to mediate a concentration-dependent cytotoxic effect on recipient breast cancer cells. Of note, messenger RNA provided a valuable readout of the in vivo delivery capability of the CD81-engineered EVs, since detected by digital droplet PCR in breast cancer tumour xenografts from mice treated with chimeric EVs. The results presented in this thesis highlighted the feasibility of using CD81 fusion proteins for cell targeting and cargo delivery, ultimately opening new perspectives for the development of EV-based therapeutics.
7

Block Copolymer Solutions: Transport and Dynamics, Targeted Cargo Delivery, and Molecular Partitioning and Exchange

Li, Xiuli 23 January 2020 (has links)
Block copolymers have been extensively applied in diverse fields including packaging, electrolytes, delivery devices, and biosensors. Multiple investigations have been carried out on polymeric materials for cargo delivery purpose to understand how they behave over time. Block copolymer micelles (BCMs) have demonstrated superiority to deliver cargo, especially in drug delivery due to their encapsulation of hydrophobic agents. This dissertation will mainly study BCMs for potential applications in cargo delivery. Methods to study BCMs, including NMR spectroscopy, relaxometry and diffusometry, can provide valuable molecular information, such as chemical structure, translational motion, inter- or intramolecular interaction, dynamics, and exchange kinetics. Therefore, this dissertation describes applications of versatile NMR methods to reveal the fundamental behaviors of block copolymer self-assemblies, such as their dynamic stability, cargo partitioning, polymer chain exchange, and chain distribution in solution. We have investigated two BCM systems. Poly(ethylene oxide)-b-(ε-caprolactone) (PEO-PCL) is a model system to study BCM dynamic stability. PEO-PCL can self-assemble into spherical micelles at 1% w/v in D2O-THF-d8 mixed solvents. We used NMR diffusometry to quantify diffusion coefficients and populations of micelles and unimers (i.e. free polymer chains in solution) over a range of temperature (21 – 50 °C) and solvent composition (10 – 100 vol % THF-d8). By mapping the micelle-unimer coexistence phase diagrams, we are able to enhance our ability to understand and design micelle structure and dynamics. Moreover, we can also probe the chain exchange kinetics between micelles using a new technique we developed – time-resolved NMR spin-lattice relaxation (T1) or TR-NMR. This technique is an analog to time-resolved small-angle neutron scattering (TR-SANS), which can monitor specific signal intensity changes caused after mixing of isotope-labeled micelle solutions. A second system, Pluronic® F127 (PEO99PPO69PEO99) is a test system to study BCM structure and dynamic changes upon drug uptake. Pluronic® F127 is a commercial copolymer that can solubilize different hydrophobic drugs in micelles. We successfully encapsulated three model drugs into Pluronic® F127 BCMs and investigated the effects of polymer concentration and drug composition on drug partitioning fractions. Also, we proposed to design and synthesize a series of block copolymers with varied glass transition temperatures in core-forming blocks. Using NMR diffusometry, we have measured the existing unimer concentrations in micellar solutions and correlated these results with chain mobility and internal chemical composition. Lastly, we have extended our expertise in NMR and polymers into the study of ion-containing polymer systems (polyelectrolytes). A critical problem in polymer science is the inability to reliably measure the molecular weight of polyelectrolytes. We are developing methods to solve this problem by using NMR diffusometry, rheology, scattering, and scaling theories to accomplish general molecular weight measurements for polyelectrolytes. In short, this dissertation describes studies to provide more perspectives on structural and dynamic properties at various time and length scales for polymeric materials. NMR measurements, in combination with many other advanced techniques, have given us a better picture of soft matter behaviors and provided guidance for synthesis and processing efforts, especially in block copolymer micelles for delivery purposes. / Doctor of Philosophy / Block copolymers have been extensively applied in diverse fields in packaging, electrolytes and nano-scale drug delivery carriers. In the area of cancer treatment, only a limited number of drug nanocarriers have been approved for clinical applications. Therefore, it is very important to understand the principles behind drug delivery for targeted purposes. There have been many studies on polymeric delivery carriers but their behaviors have not been completely understood. Therefore, we have tremendous interest in unraveling the mysteries in those polymeric systems. Among a multitude of techniques to study block copolymer materials, the NMR method serves as a potent tool for its non-destructive, chemical-specific and isotope-selective merits. NMR can provide basic information about block copolymer self-assembly and other polymeric properties, such as chemical structure, molecular interactions and diffusion coefficients of species of interests. Chapters 3, 4, 5, 6, and 7 have investigated different classes of polymeric materials, mainly block copolymer micelles, for their structure and stability, exchange kinetics of polymer chains or cargo, and translational properties. Greater understanding about the fundamental properties of these polymeric systems, is essential for enabling new applications and new research areas.
8

Pharmaceutical technologies for improving drug loading in the formulation of solid dispersions

O'Donnell, Kevin Patrick 03 July 2013 (has links)
It is estimated that 90% of new chemical entities in development pipelines exhibit poor aqueous solubility. For compounds not limited by biological membrane permeability, this poor aqueous solubility is the limiting factor in bioavailability. Therefore, the formulation of such drugs has primarily been centered on improving dissolution properties. Traditional approaches for overcoming poor aqueous solubility include salt formation of the active ingredient, complexation, the use of surface active agents, formulation into oil based systems, particle size reduction, or a combination of these methods. More recently amorphous solid dispersions have been explored. Currently, the drug loading within solid dispersions is limited resulting in large quantities of the formulation being required for a therapeutically relevant dose. In the frame of the work herein, Thin Film Freezing was utilized to generate high drug loaded amorphous solid dispersions of the poorly water soluble drug phenytoin utilizing a hydrophilic polymer or an amphiphilic graft copolymer for system stabilization. Additionally a new solvent removal technique, atmospheric freeze drying, was investigated for removal of the solvents used during Thin Film Freezing. The Thin Film Freezing materials were subsequently incorporated into a polymeric carrier for solid dispersion formulation by a novel fusion production technique termed Kinetisol® dispersing. Studies of the solid dispersions produced by Thin Film Freezing revealed an amorphous system had been obtained for both stabilizing polymers. The formulation containing a hydrophilic carrier was capable of achieving supersaturation. Conversely, the amphiphilic graft copolymer demonstrated a phenytoin-polymer interaction resulting in poor dissolution. Atmospheric freeze drying of the Thin Film Freezing product demonstrated that the alternative drying technique generated powders with significantly improved handling properties as a result of reduced electrostatic interactions due to the increased pore size, reduced surface area, larger particle size, and higher, though acceptable, residual solvent levels. The use of Thin Film Freezing powders during Kinetisol Dispersing resulted in a single phase amorphous system while solid dispersions produced from physical mixtures of bulk materials were amorphous two-phase systems. This indicates that the use of amorphous drug compositions during solid dispersion production may increase drug loading in the final system while remaining single phase in nature. / text
9

Uso do espalhamento de luz para o estudo do efeito de uréia sobre agregados supramoleculares e monitoramento do peso molecular em reações de polimerização / Use of light scattering to study the effect of urea about supramolecular aggregates and monitoring of the molecular weight in polymerization reactions

Florenzano, Fábio Herbst 18 June 1999 (has links)
Nesta tese, dois projetos distintos que usaram a técnica do Espalhamento de Luz foram desenvolvidos. Estudou-se a influência de soluções concentradas de uréia sobre agregados supramoleculares de anfifilicos (ASA\'s), através de condutimetria, supressão de fluorescência e espalhamento de luz. A uréia causou aumento da concentração micelar crítica (CMC) em todos os sistemas micelares estudados. A uréia diminuiu a seletividade da ligação iônica entre cloreto e brometo em micelas de haleto de cetil-trimetil-amônio, estudada através de supressão de fluorescência. Este aditivo causou também aumento na segunda CMC de brometo de tetradeciltrimetil- amônio (TTAB) e diminuição do peso molecular das micelas em bastão formadas. Concluiu-se, desta primeira parte, que a uréia tende a interferir nas transições de fase apresentadas em sistemas micelares, provavelmente através da combinação dos mecanismos direto e indireto. A uréia apresenta potencial para uso como aditivo para modulação das propriedades estruturais de sistemas micelares. Na segunda parte da tese desenvolveu-se um sistema, baseado em espalhamento de luz, capaz de monitorar o peso molecular de polímeros durante a polimerização. O sistema foi eficiente no monitoramento da polimerização da N-vinil-pirrolidinona, mostrando que o peso molecular do polímero formado é constante durante a maior parte da reação. As teorias atuais de cinética de polimerização não foram capazes de explicar esse comportamento. / Light scattering techniques (static and dynamic) were used to detenninate the effect of urea on supramolecular aggregates and to monitor on-line molar mass ofpolymerization reactions. For the first set of investigation it was already established that urea increases the CMC and the dissociation degree (α) of ionic micelles (CTABr, TTABr, and SDS). From fluorescence suppression studies it was found that urea diminishes the ionic binding in zwitterionic and cationic micelles as well as in cationic vesicles. Bromide and chloride ionic selectivity in cationic micelles was found to nearly disappear in the presence of urea. Light scattering (static) detenninations showed that the weight averaged molecular weight (Mw) ofboth SDS and CTABr are invariant by the presence of the denaturant. A slight increase in the excluded volume tenn (A2) was detected for CTABr in the presence of 3M urea. In parallel both A2 and the radius of gyration (γ) of two polyelectrolytes (PAA and Hyaluronic acid) were not affected by the presence of urea. Sphere-to-rod concentration transitions (2nd CMC) of TIABr micelles increased in the presence of urea and the MW of rod particles were observed to decrease. For the insoluble mixture of CTABr/Polystyrenesulfonate solubilization was achieved in the presence of 3M urea. These set of results were explained as a result of the dual effect of urea, that is, the indirect effect by changing the properties of the solvent and the direct effect by solvating the hydrophilic domain of the aggregates and contributing with a stronger dipole moment. The second set of experiments was directed towards the real-time, on-line monitoring of Mw of polymerization reactions. This new approach could be succeeded by the coupling a light scattering detector, an UV photometer and a differential refractometer on line with a HPLC system. Mw growth formed in the polymerization of N-vynil-pirrolidone was accomplished with a small inherent error. Within the studied conditions Mw reached a plateau at early polymerization stages, after that only an increase in the number of polymer kinetic chains was observed. Current kinetic models were unable to predict the observed Mw growth pattern. This system is of great importance in basic and technological applications by virtue of its on-line capability.
10

Uso do espalhamento de luz para o estudo do efeito de uréia sobre agregados supramoleculares e monitoramento do peso molecular em reações de polimerização / Use of light scattering to study the effect of urea about supramolecular aggregates and monitoring of the molecular weight in polymerization reactions

Fábio Herbst Florenzano 18 June 1999 (has links)
Nesta tese, dois projetos distintos que usaram a técnica do Espalhamento de Luz foram desenvolvidos. Estudou-se a influência de soluções concentradas de uréia sobre agregados supramoleculares de anfifilicos (ASA\'s), através de condutimetria, supressão de fluorescência e espalhamento de luz. A uréia causou aumento da concentração micelar crítica (CMC) em todos os sistemas micelares estudados. A uréia diminuiu a seletividade da ligação iônica entre cloreto e brometo em micelas de haleto de cetil-trimetil-amônio, estudada através de supressão de fluorescência. Este aditivo causou também aumento na segunda CMC de brometo de tetradeciltrimetil- amônio (TTAB) e diminuição do peso molecular das micelas em bastão formadas. Concluiu-se, desta primeira parte, que a uréia tende a interferir nas transições de fase apresentadas em sistemas micelares, provavelmente através da combinação dos mecanismos direto e indireto. A uréia apresenta potencial para uso como aditivo para modulação das propriedades estruturais de sistemas micelares. Na segunda parte da tese desenvolveu-se um sistema, baseado em espalhamento de luz, capaz de monitorar o peso molecular de polímeros durante a polimerização. O sistema foi eficiente no monitoramento da polimerização da N-vinil-pirrolidinona, mostrando que o peso molecular do polímero formado é constante durante a maior parte da reação. As teorias atuais de cinética de polimerização não foram capazes de explicar esse comportamento. / Light scattering techniques (static and dynamic) were used to detenninate the effect of urea on supramolecular aggregates and to monitor on-line molar mass ofpolymerization reactions. For the first set of investigation it was already established that urea increases the CMC and the dissociation degree (α) of ionic micelles (CTABr, TTABr, and SDS). From fluorescence suppression studies it was found that urea diminishes the ionic binding in zwitterionic and cationic micelles as well as in cationic vesicles. Bromide and chloride ionic selectivity in cationic micelles was found to nearly disappear in the presence of urea. Light scattering (static) detenninations showed that the weight averaged molecular weight (Mw) ofboth SDS and CTABr are invariant by the presence of the denaturant. A slight increase in the excluded volume tenn (A2) was detected for CTABr in the presence of 3M urea. In parallel both A2 and the radius of gyration (γ) of two polyelectrolytes (PAA and Hyaluronic acid) were not affected by the presence of urea. Sphere-to-rod concentration transitions (2nd CMC) of TIABr micelles increased in the presence of urea and the MW of rod particles were observed to decrease. For the insoluble mixture of CTABr/Polystyrenesulfonate solubilization was achieved in the presence of 3M urea. These set of results were explained as a result of the dual effect of urea, that is, the indirect effect by changing the properties of the solvent and the direct effect by solvating the hydrophilic domain of the aggregates and contributing with a stronger dipole moment. The second set of experiments was directed towards the real-time, on-line monitoring of Mw of polymerization reactions. This new approach could be succeeded by the coupling a light scattering detector, an UV photometer and a differential refractometer on line with a HPLC system. Mw growth formed in the polymerization of N-vynil-pirrolidone was accomplished with a small inherent error. Within the studied conditions Mw reached a plateau at early polymerization stages, after that only an increase in the number of polymer kinetic chains was observed. Current kinetic models were unable to predict the observed Mw growth pattern. This system is of great importance in basic and technological applications by virtue of its on-line capability.

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