Дисертації: "Functional delivery"

1

Alexander, Shirin. "Multi functional polymers for drug delivery." Thesis, University of Bristol, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.566691.

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Amphiphilic block and graft copolymers have been studied because of the possibility of tailoring their complex and fascinating chemical properties. Potential applications include wetting agents, foaming agents, plastic modifiers as well as biomedical applications in drug delivery, owing to their biocompatible and low toxic nature. This thesis describes the study of a series of amphiphilic block copolymers, known as Pluronics, and their aqueous interaction with a hydrophobic drug, flurbiprofen. Synthesis and characterisation of novel graft copolymers with interesting associative behaviour that is less influenced by concentration is also another major aspect of the work described in this thesis. Pulsed-field gradient stimulated-echo nuclear magnetic resonance (pFGSE- NMR) and surface tension measurements have been used to show that the addition of flurbiprofen promotes micellisation of Pluronic triblock copolymers (PI03, P123, and L43). Structural changes in the micelles ofPluronics PI03 and P123, as a function of temperature, eo-solvent (ethanol, 10 wt/vol %), and the addition of the hydrophobic drug flurbiprofen were also investigated by small- angle neutron scattering (SANS). Flurbiprofen was shown to be released from micelles by increasing the solution pH. At higher pH, the drug is ionised and the fraction of polymer in micelles reduces. Synthesis of novel graft copolymers was carried out using a "grafting onto" method. In this approach, the functional group of a hydrophobic backbone will react with the functional group of the copolymer chains. The graft copolymers composed of either hydrophilic Pluronics or sulfonated poly(ethylene oxide) chains and hydrophobic backbones, displayed formation of core-shell micelles in selective solvents. The Pluronic graft copolymers showed the potential for solubilising hydrophobic drug molecules in aqueous solution even at low polymer concentrations. These graft copolymers and their interactions with flurbiprofen were characterised by PFGSE-NMR and SANS.

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2

Siva, Sahithi Pokala. "Design and delivery : functional colour web pages." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343620.

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3

Zhang, Chengxiang. "Functional Conjugates for Drug and Gene Delivery." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu158703024326976.

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4

Kilsby, Samuel. "Functional polyesters for drug delivery and 3D printing." Thesis, Loughborough University, 2016. https://dspace.lboro.ac.uk/2134/20177.

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Funtional εCL monomers have been successfully synthesised utilising a primary amine (protected as a CBZ or BOC carbamate) and also a protected ketone (using an acetal protecting group). Amine derivatives were synthesised from the commercially available trans-4-aminocyclohexanol. The acetal protected ketone was synthesised from the commercially available 1,4-cyclohexanedione monoethylene acetal. The subsequent exposure of these monomers to ring opening polymerisation conditions (using stannous octanoate) in the presence of εCL, yielded random copolymers with a functionalised polyester backbone. The acetal copolymer was successfully deproteceted and reduced to yield an alcohol pendant. A polymer-drug composite was successfully synthesised through the use of this alcohol polymer reacting with ciprofloxacin. A polymer-drug conjugate was also successfully synthesised using surface chemistry on PCL and PLA films. PCL and PLA films were cast as films and subsequently aminolysed using 1,6-hexamethylene diamine in aqueous media at pH = 11.5. These aminolysed films were then treated with both ciprofloxacin and penicillin G, together with amide coupling chemistry to synthesise biologically active surfaces. Ciprofloxacin and penicillin G were successfully attached to the PCL surface with ciprofloxacin being attached to the PLA variant. A functional PCL monomer was also successfully synthesised from the commercially available PCL diol. Both methacrylate and acrylate varients were synthesised through acid chloride chemistry. The acrylate and methacrylate analogue were UV cured using both type I (Irgacure 2959) and II (DETX/EDB) photoinitiators. The relative ratios of these initiators were changed along with the composition of the curing material to investigate curing parameters, to aid in 3D printing conditions. To achieve viscocity criteria for 3D printing a ratio of 70:30 (PCL DMA:PEG DA) was used, utilising PEG DA as a reactive diluent. A ratio of 3 wt% DETX and 3 wt% EDB was found to give the best UV curing results and were successfully applied on a jetting machine to yield 3D printed constructs.

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5

Bansode, Ratnadeep Vitthal. "Functional ionic liquids in crystal engineering and drug delivery." Thesis, University of Bradford, 2016. http://hdl.handle.net/10454/14563.

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The objective of this research is to explore the use of ionic liquds in crystal engineering and drug delivery. Ionic liquids have a wide range of applications in pharmaceutical field due to their unique physicochemical propertie ssuch as chemical, thermal stability, low melting point, nonvolatility, nonflamability, low toxicity and recyclability which offer unique and interesting potential for pharmaceuitcal applications. Currently, many research groups are working on the development of ionic liquids to use in this field but there is need to develop systematic understanding about new techniques for synthesis and applications of ionic liquids to obtain new crystal form and potential of drug ionic salts. The synthesis of fifteen phosphonium ionic liquids under microwave irradiation and their physicochemical properties was investigated. The reaction time was significantly reduced compared to conventional methods, and higher yields were reported. The crystallisation of pharmaceutical drugs such as sulfathiazole, chlorpropamide, phenobarbital and nifedipine were investigated using imidazolium ionic liquids. The supramolecular complex of sulfathiazole and phenobarbital with imidazolium ionic liquids and polymorphic change in chlorpropamide was achieved. The ionic liquids provides unique environment for the crystallisation. The imidazolium salts of ibuprofen and diclofenac were synthesised and evaluated for physicochemical properties and their pharmaceutical performances especially transdermal absorption. The investigation of physicochemcal properties and pharmaceutical performance of imidazolium drug salts indicated opportunity to optimise lipophilicity and other physicochemical properties such as molecular size, osmolality, viscosity to achieve desired skin deposition and permeation. This study will provide a new approach to design of new drug salts develop using the interdisciplinary knowledge of chemical synthesis and drug delivery.

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6

Bansode, Ratnadeep V. "Functional ionic liquids in crystal engineering and drug delivery." Thesis, University of Bradford, 2016. http://hdl.handle.net/10454/14563.

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The objective of this research is to explore the use of ionic liquds in crystal engineering and drug delivery. Ionic liquids have a wide range of applications in pharmaceutical field due to their unique physicochemical propertie ssuch as chemical, thermal stability, low melting point, nonvolatility, nonflamability, low toxicity and recyclability which offer unique and interesting potential for pharmaceuitcal applications. Currently, many research groups are working on the development of ionic liquids to use in this field but there is need to develop systematic understanding about new techniques for synthesis and applications of ionic liquids to obtain new crystal form and potential of drug ionic salts. The synthesis of fifteen phosphonium ionic liquids under microwave irradiation and their physicochemical properties was investigated. The reaction time was significantly reduced compared to conventional methods, and higher yields were reported. The crystallisation of pharmaceutical drugs such as sulfathiazole, chlorpropamide, phenobarbital and nifedipine were investigated using imidazolium ionic liquids. The supramolecular complex of sulfathiazole and phenobarbital with imidazolium ionic liquids and polymorphic change in chlorpropamide was achieved. The ionic liquids provides unique environment for the crystallisation. The imidazolium salts of ibuprofen and diclofenac were synthesised and evaluated for physicochemical properties and their pharmaceutical performances especially transdermal absorption. The investigation of physicochemcal properties and pharmaceutical performance of imidazolium drug salts indicated opportunity to optimise lipophilicity and other physicochemical properties such as molecular size, osmolality, viscosity to achieve desired skin deposition and permeation. This study will provide a new approach to design of new drug salts develop using the interdisciplinary knowledge of chemical synthesis and drug delivery.
Social Justice Department, Government of Maharashtra, India.

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7

Wright, Ruvimbo Pearl. "Soysomes and Other Functional Biomaterials from Sucrose Soyate Derivatives." Diss., North Dakota State University, 2019. https://hdl.handle.net/10365/29872.

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Biomaterials serve as interventional tools in medicine to treat, improve or replace diseased tissues, organs or function of the body. Although several polymeric biomaterials already exist, they often present challenges, at material level, such as non-biodegradability, degradation into acidic by-products or tissue incompatibility, or at functional level such as failure to sustain prolonged release of therapeutic payload for a desired period. Research has been focused on investigating new polymeric candidates to address these problems of current systems. The use of renewable resources to generate smart polymers for biomedical and pharmaceutical purposes presents a new and exciting avenue for biomaterials. As part of these efforts, a new set of biomaterials were developed from plant-derived high molecular weight (~3.0 kDa) compounds. The advantages of biobased materials include availability for large-scale synthesis, facile post-synthetic modification, biocompatibility, improvement of functional properties and affordability. In this project we used sucrose soyates, i.e. octa-esters obtained from conjugation of sucrose molecules and multiple soybean oil fatty acid chains, to prepare three groups of functional biomaterials namely: a). self-assembled soy-based nano-constructs, b). blended soy-based free-standing films and c). three-dimensional cross-linked soy-based soft matrices. Here, we will discuss the fabrication and physical, chemical and mechanical characterization of these biomaterials prepared from soy-based compounds, as well as, the assessment of their functional performance in biological environment.
National Science Foundation ND EPSCoR Grant No. IIA1355466 through Center of Sustainable Materials Science

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8

Haag, Shannon S. "Effects of response-independent stimulus delivery and functional communication training." Morgantown, W. Va. : [West Virginia University Libraries], 2002. http://etd.wvu.edu/templates/showETD.cfm?recnum=2613.

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Thesis (M.A.)--West Virginia University, 2002.
Title from document title page. Document formatted into pages; contains viii, 38 p. : ill. Includes abstract. Includes bibliographical references (p. 33-37).

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9

Probert, John Michael. "Functional nano-particles derived from dendrimer derivatisation and self-assembly." Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266664.

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10

Li, Zhenqing. "Development of Multi-functional Stem Cell Delivery Systems for Cardiac Therapy." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1337223886.

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11

NAIRI, VALENTINA. "Functional ordered mesoporous silica in nanomedicine: target and drug delivery systems." Doctoral thesis, Università degli Studi di Cagliari, 2018. http://hdl.handle.net/11584/255981.

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Ordered mesoporous materials (OMMs) are characterized by high surface area (up to 1000 m2/g), high pore volume (1-3 cm3/g) and narrow pore size (2-30 nm) distribution. Recently, mesoporous silica nanoparticles (MSNs), a subclass of OMMs, have had great development as nanocarriers for drug delivery, particularly for cancer treatment. The research activity of my PhD work was aimed to study SBA-15 and MCM-41 mesoporous silica samples for biomedical applications. The texture and the structure of the synthesized materials were characterized through N2 adsorption/desorption isotherms, SAXS, and TEM. The functionalization of the mesoporous silica samples was verified by means of Fourier-transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA). DLS and ELS were used to determinate hydrodynamic diameter and zeta potential of the studied systems under different conditions. The PhD thesis focused on different aspects of the use of OMMs, particularly MSNs, as drug nanocarriers. In the first paper how different features of OMMs (surface area, pore size and surface charge) can affect the adsorption and release of drugs was investigated. Ampicillin, a penicillin-like -lactam antibiotic was loaded on MCM-41, SBA-15, and amino-functionalized SBA-15, then its release in simulated physiological conditions was studied. This study demonstrated that to obtain a sustained drug release, the chemical nature of the matrix’s surface plays a role which is more important than its textural features. SBA-15-NH2 matrix is a suitable candidate as depot system for local sustained release of ampicillin. Common target systems have the disadvantage that the targeting molecule can be recognized by several receptors. A possible strategy to solve this issue was investigated in the second paper. The targeting molecule was hidden by preparing a double sequential targeting system. To this purpose a double target system was synthesized. Alendronate was used as a tissue target to recognize a diseased bone, and an encrypted cellular target, Arg-Gly-Asp (RGD) was used to improve the internalization in human osteosarcoma cells (collaboration with Universidad Complutense de Madrid). This preliminary study showed the efficacy of the double target systems. The next step could be the functionalization of MSNs with the previously described systems for the synthesis of a smart target systems usable as a carrier for anticancer drugs against bone cancer. In the third paper, the effect of surface charge on the internalization of MCM-41-type MSNs, functionalized with chitosan (CHIT) and hyaluronic acid (HA) biopolymers, on 3T3 mouse fibroblast cells was then investigated. The opposite surface charge of the biopolymer-functionalized MSNs (negative for MSN-HA and positive for MSN-CHIT) gave a different interaction with BSA, used as a model protein to investigate the formation of the protein corona (forth paper). Finally, in the fifth paper, MSNs were functionalized with HA samples having three different molecular weights (HAS, HAM, and HAL). The effect of HA molecular weight on the internalization of HA-MSNs particles on HeLa cells was evaluated. These last studies showed the importance of the external functionalization on the interaction between MSNs and the components of body fluids, that change their surface properties. These changes as well as the polymer’s features (i.e. the molecular weight) are able to modulate the cellular uptake. The obtained results highlight the importance of the physico-chemical phenomena occurring at the nano-biointerface for the future use of functionalized OMMs and MSNs in nanomedicine. The present findings confirm that these nanocarriers are very promising matrices for the obtainment of targeting drug delivery systems for cancer treatment.

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12

Wang, Qi. "Synthesis of multi-functional dendrimers for targeted delivery of nucleic acids." Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM4068/document.

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Nous avons démontré que structurellement flexibles poly(amidoamine) (PAMAM) dendrimères sont efficaces système de livraison de siRNA in vitro et in vivo récemment. Nous voulons mener une enquête plus approfondie sur la livraison de siRNA ciblés en utilisant des dendrimères conjugués avec des ligands spécifiques ou d'anticorps, qui peuvent reconnaître les récepteurs correspondants ou des protéines exprimées à la surface des cellules. De cette façon, le siRNA peuvent être livrés spécifiquement aux cellules d'intérêt, conduisant à une délivrance ciblée, ce qui peut améliorer l'efficacité livraison et de réduire la toxicité en évitant les interactions non spécifiques et à des doses plus faibles. À cette fin, nous avons développé des dendrimères portant une chaîne PEG long et un dendron individu polyvalent. La chaîne PEG est de libérer l'encombrement stérique entre dendrimère et ligand / anticorps, tandis que le dendron multivalent fournit une plate-forme d'une conjugaison contrôlable de ligands. Par ailleurs, nous avons également conçu et synthétisé une autre dendrimères PEGylées portant un groupe thiol libre pour la préparation des anticorps / dendrimère conjugués
We have demonstrated that structurally flexible poly(amido)amine (PAMAM) dendrimers are efficient siRNA delivery system in vitro and in vivo recently. We would like to undertake further investigation on targeted siRNA delivery using dendrimers conjugated with specific ligands or antibodies, which can recognize the corresponding receptors or proteins expressed on the cell surface. In this way, siRNA can be delivered specifically to the cells of interest, leading to targeted delivery, which can further improve the delivery efficiency and reduce the toxicity by avoiding non-specific interactions and at lower doses. To this end, we have developed dendrimers bearing a long PEG chain and an individual multivalent dendron. The PEG chain is to release the steric congestion between dendrimer and ligand/antibody, whereas the multivalent dendron provides a platform of a controllable conjugation for ligands. Besides, we also designed and synthesized another PEGylated dendrimers bearing a free thiol group for the preparation of antibody/dendrimer conjugates

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13

Wang, Qi. "Synthesis of multi-functional dendrimers for targeted delivery of nucleic acids." Electronic Thesis or Diss., Aix-Marseille, 2012. http://www.theses.fr/2012AIXM4068.

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Nous avons démontré que structurellement flexibles poly(amidoamine) (PAMAM) dendrimères sont efficaces système de livraison de siRNA in vitro et in vivo récemment. Nous voulons mener une enquête plus approfondie sur la livraison de siRNA ciblés en utilisant des dendrimères conjugués avec des ligands spécifiques ou d'anticorps, qui peuvent reconnaître les récepteurs correspondants ou des protéines exprimées à la surface des cellules. De cette façon, le siRNA peuvent être livrés spécifiquement aux cellules d'intérêt, conduisant à une délivrance ciblée, ce qui peut améliorer l'efficacité livraison et de réduire la toxicité en évitant les interactions non spécifiques et à des doses plus faibles. À cette fin, nous avons développé des dendrimères portant une chaîne PEG long et un dendron individu polyvalent. La chaîne PEG est de libérer l'encombrement stérique entre dendrimère et ligand / anticorps, tandis que le dendron multivalent fournit une plate-forme d'une conjugaison contrôlable de ligands. Par ailleurs, nous avons également conçu et synthétisé une autre dendrimères PEGylées portant un groupe thiol libre pour la préparation des anticorps / dendrimère conjugués
We have demonstrated that structurally flexible poly(amido)amine (PAMAM) dendrimers are efficient siRNA delivery system in vitro and in vivo recently. We would like to undertake further investigation on targeted siRNA delivery using dendrimers conjugated with specific ligands or antibodies, which can recognize the corresponding receptors or proteins expressed on the cell surface. In this way, siRNA can be delivered specifically to the cells of interest, leading to targeted delivery, which can further improve the delivery efficiency and reduce the toxicity by avoiding non-specific interactions and at lower doses. To this end, we have developed dendrimers bearing a long PEG chain and an individual multivalent dendron. The PEG chain is to release the steric congestion between dendrimer and ligand/antibody, whereas the multivalent dendron provides a platform of a controllable conjugation for ligands. Besides, we also designed and synthesized another PEGylated dendrimers bearing a free thiol group for the preparation of antibody/dendrimer conjugates

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14

Fernandes, Alinda. "Lentiviral-mediated gene delivery to investigate the functional role of neuropsychiatric genes." Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/lentiviralmediated-gene-delivery-to-investigate-the-functional-role-of-neuropsychiatric-genes(b6392e47-e94b-4e64-b343-e7eafd696b26).html.

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Genetic studies have led to the identification of several candidate genes, some novel and others established, that may contribute to the risk of developing neuropsychiatric disorders. For example, dopamine receptor genes are established candidates for a number of psychiatric disorders such as Parkinson’s Disease, alcohol addiction and mood disorders. On the other hand, a gene of unknown function, AUTS2 (Autism susceptibility candidate 2), has recently been associated with alcohol consumption in a GWAS meta-analysis performed by our group. Interestingly, it has been associated with a broad range of neuropsychiatric disorders including autism, epilepsy and schizo-affective disorders. This thesis looked to address two broad aims: to establish lentiviral-mediated gene delivery technique in vivo by delineating the role of two well characterised Dopamine receptors D2R and D3R and to functionally characterise the role of AUTS2. By successfully establishing lentiviral mediated gene manipulation in vitro and in vivo, this thesis presents data for a similar role of nucleus accumbens D2R and D3R in novelty-induced locomotion while these receptors have a differential function in the regulation of light-induced locomotor behaviour in rats. Additionally, using molecular biology and in silica methods, this thesis demonstrates that AUTS2 is a nuclear protein and presents indications of its function as a neurodevelopmental gene with a potential role in neural migration, although its specific role has yet to be corroborated. Collectively, findings from this thesis will increase our understanding of the genetic link with brain function and behavioural traits. This will therefore have implications for overall neuropsychiatric research, as it will help understand molecular mechanisms underlying these conditions and possibly direct in the identification of potential therapeutic targets.

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15

Levy, Charlotte Luanne Victoria. "Nanoporous calcium carbonate-based substrates for the controlled delivery of functional materials." Thesis, University of Plymouth, 2017. http://hdl.handle.net/10026.1/9288.

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The overall aim of this project was to study 'functionalised' calcium carbonates (FCCs) for use as a carrier for the controlled release of 'actives,' by permeation and diffusion, and is being proposed as an environmentally friendly and non-toxic pharmaceutical excipient, nutraceutical, and flavour carrier. The delivery of a drug to its target site in the appropriate amount and time-frame in order for it to have a controlled release effect whilst achieving the maximum therapeutic effect remains a topic of design and development for novel drug delivery systems. FCCs encompass a family of new pharmaceutical excipients in which the conditions of manufacture follow strict process regulations with respect to the grade of reagents that are employed and the microbiological environment under which they are produced, and include freedom from organic polymers. Adjustments to the FCC production process can be used to produce a wide range of different morphologies, and raise the possibility of tailoring the void structures of the particles to provide controlled release delivery vehicles for actives across many fields, including drugs and flavours. However, such tailoring can only be fully optimised by a fundamental characterisation of the way in which a drug, loaded into an FCC, then flows and diffuses out over a period of time to provide the delayed release. It was found that adsorption on the FCC surface is selective, for example, saccharin does not become adsorbed from 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES) buffer solution, and neither does anethole from ethanol. FCC also does not adsorb the cationic probe benzyltrimethylammonium bromide (BTMAB) or the anionic probe sodium 2-naphthalenesulphonate (Na2NS). However, it was found that vanillin adsorbs onto the FCC in an amount of 2.00 ± 0.59 mg g^-1. Aspirin and vanillin adsorption from ethanolic solutions with various additions of water onto FCC TP was investigated and fitted with the Tóth isotherm. It was estimated that vanillin adsorbed onto around 17 %, and aspirin onto around 39 %, of the overall FCC TP surface area without the addition of any water. An equation was formulated in order to approximate the adsorption as a function of the FCC's surface coverage by the water. This is discussed in Chapter 4 and has also been published in a peer-reviewed academic journal (Levy et al., 2017). Chapter 5 discusses the preliminary steps of the loading of vanillin and saccharin into FCC, and the results were inconclusive for a majority of samples, concluding that the loading and analysis methods need refining. The modelling of the diffusion profiles of vanillin loaded FCC S07 and S10 was successful, and resulted in diffusion coefficients of 231.9 x 10^-16 m^2 s^-1 and 248.44 x 10^-16 m^ s^-1, respectively. This is outlined in Chapter 6. Chapter 7 describes the 'zero length column' (ZLC) technique, which was used as a way to characterise the diffusivity of the intraparticle pores of each FCC grade. However, it was established that there are many experimental artefacts present with such a method. This work outlines the development of the novel 'finite length column' (FLC), which was developed as a means to overcome the limitations of the ZLC (Levy et al., 2015). Effective diffusivity coefficients in the long-term region of the diffusion curves of the FCC samples range from 1.06-106 x 10 ^-16 m ^2 s^-1. The FLC was then used in preliminary trials to dilute FCC with an inert solid in order to further refine the ZLC technique, and is discussed in Chapter 8. Two mathematical methods were also developed to aid in the refinement. The reported effective diffusivity coefficient for FCC 03 in the long-term region of the diffusion curve is 49.5 x 10^-16 m^2 s^-1. In conclusion, this work confirms that FCC has potential for use as a carrier for the controlled release of 'actives' by diffusion. The utilisation of mathematical modelling in conjunction with experimental methods in the study of drug release and delivery is steadily increasing due to its enormous future potential; it will enable the optimisation of novel dosage forms and the elucidation of release mechanisms at a major reduction in cost and time compared with the number of experimental studies required to do so.

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16

Keshwan, Abdulmohsin. "Utilising cross-functional teams to achieve marketing/operations integration for delivery priority." Thesis, University of Salford, 2016. http://usir.salford.ac.uk/40450/.

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In today's manufacturing environment, due to the complexity of products, and the progress of technology, organisations are forced to be more responsive to the pressure of the dynamic market by developing, producing and delivering products quickly and before competitors (Bendoly et al., 2012; Gattiker, 2007). As a result, the integration between marketing and operations as core functions of a manufacturing organisation (Slack et al., 2013) has increasingly received attention from many academics and practitioners (e.g., Hausman et al., 2002; O’Leary-Kelly & Flores, 2002; Prabhaker, 2001; Swink & Song, 2007; Tang, 2010). This is because of the importance of the marketing and operations interface to achieve more rapid responsiveness to market demand through the fit between market requirements and operations capabilities (Slack et al., 2009). Despite the importance of this work, empirical research on how to achieve and develop this integration is still limited in comparison with conceptual work (Felekoglu et al., 2013; Paiva, 2010; Sharma, 2013; Song et al., 2010). Therefore, this study is an attempt to narrow this gap by investigating why and how to manage the marketing and operations functional relationship effectively in order to become more market oriented. The framework of this research consists of four phases namely; the needs (reasons for integration), the methods (cross-functional teams), the development (potential problems), and the achievement (delivery priority). This framework represents a strategic imperative for developing the delivery performance of an organisation based on the fit between strategy (time-based strategy), organisational structure (cross-functional integration), and environment (the competitive position) (Lenz, 1980; Miller, 1988). Empirically, due to the need to develop the performance of Iraqi public industry sector, two Iraqi public textile organisations were chosen as case studies to conduct this project by using semi-structured interviews and direct observation to gather data. According to the findings of this research, it can be argued that this study would be an approach to implement market orientation in the Iraqi context albeit one which is difficult to execute.

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17

Nelson, Ashley M. "Design of Functional Polyesters for Electronic and Biological Applications." Diss., Virginia Tech, 2015. http://hdl.handle.net/10919/74914.

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Melt polymerization and novel monomers enabled the synthesis of polyesters for electronic and biological applications. Inspiration from nature and a passion for environmental preservation instigated an emphasis on the incorporation of renewable resources into polymeric materials. Critical analysis of current research surrounding bisphenol-A replacements and ioncontaining segmented polyurethanes aided in identifying benchmark polymers, including limitations, challenges, and future needs. Structure-property-morphology relationships were investigated to evaluate the polymers for success in the proposed applications as well as to improve understanding of polyester compositions to further design and develop sophisticated polymers for emerging applications. Aiming to utilize the reported [2 + 2] cycloaddition of the known mesogen 4,4’-dimethyltrans-stilbene dicarboxylate (SDE) to overcome ultraviolet (UV) induced degradation issues in electronic encasings, the synthesis of copolyesters containing SDE ensued. 1,6-Hexanediol (HD) and 1,4-butanediol comonomers in varying weight ratios readily copolymerized with SDE under melt transesterification conditions to afford a systematic series of copolyesters. Differential scanning calorimetry revealed all copolyesters exhibited liquid crystalline transitions and melting temperatures ranged from 196 °C – 317 °C. Additionally, melt rheology displayed shear thinning to facilitate melt processing. Compression molded films exhibited high storage moduli, a glassy plateau until the onset of flow, and tensile testing revealed a Young’s iii modulus of ~900 MPa for poly(SDE-HD). These properties enable a wide range of working temperatures and environments for electronic applications. Adding complexity to linear liquid crystalline copolyesters, copolymerization with oligomeric hydroxyl-functionalized polyethers afforded segmented liquid crystalline copolyesters. 4,4’-Biphenyl dicarboxylate (BDE), commercially available diols containing 4, 5, 6, 8, or 10 methylene units, and introducing poly(tetramethylene oxide) or a Pluronic® triblock oligoethers in varying weight % were used to synthesize multiple series of segmented copolyesters. Comparing melting transitions as a function of methylene spacer length elucidated the expected even-odd effect and melting temperatures ranged from 150 °C to 300 °C. Furthermore, incorporating the flexible soft segment did not prevent formation of a liquid crystalline morphology. Complementary findings between differential scanning calorimetry and small-angle X-ray scattering confirmed a microphase-separated morphology. Thermomechanical analysis revealed tunable plateau moduli and temperature windows based on both soft segment content and methylene spacer length, and tensile testing showed the strain at break doubled from 75 weight % to 50 weight % hard segment content. The same compositions Young’s moduli decreased from 107 ± 12 MPa at 75 weight % hard segment to 19 ± 1 MPa with 50 weight % hard segment, demonstrating the mechanical trade-off and range of properties possible with small compositional changes. These segmented copolyesters could find use in high-performance applications including electronic and aerospace industries. A two-step synthesis transformed caffeine into a novel caffeine-containing methacrylate (CMA). Conventional free radical copolymerization with a comonomer known to provide a low glass transition temperature (Tg), 2-ethylhexyl methacrylate (EHMA), allowed the investigation of the effect of small amounts of pendant caffeine on polymer properties. Thermal and iv thermomechanical testing indicated CMA incorporation dramatically increased the storage modulus, however, a microphase-separated morphology was not attained. Association of the pendant caffeine groups through non-covalent π-π stacking could present opportunities for novel thermoplastics and it is proposed that placing the pendant group further from the backbone, and potentially increasing the concentration, could aid in promoting microphase-separation. Alkenes are reactive sites for placing functional groups, particularly those required for polyester synthesis. Methyl 9-decenoate (9-DAME), a plant-based fatty acid, provided a platform for novel biodegradable, renewable, polyesters. A formic acid hydration reaction generated an isomeric mixture of AB hydroxyester or AB hydroxyacid monomers for melt polymerization. Thermal analysis elucidated the plant-based polyesters exhibited a single transition, a Tg of about -60 °C. Aliphatic polyesters commonly crystallize, thus the isomeric mixture of secondary alcohols seemed to introduce enough irregularity to prevent crystallization. These polyesters offer an amorphous, biodegradable, sustainable replacement for applications currently using semi-crystalline poly(ε-caprolactone), which is not obtained from renewable monomers and also exhibits a -60 °C Tg. Additional applications requiring low-Tg polymers such as pressure sensitive adhesives or thermoplastic elastomers could also benefit from these novel polyesters. 9-DAME also was transformed into an ABB’ monomer after an epoxidation and subsequent hydrolysis. Successful gelation under melt transesterification conditions provided evidence that the multifunctional monomer could perform as a renewable, biodegradable, branching and/or crosslinking agent. Novel copolyesters comprised of a bromomethyl imidazolium diol and adipic acid demonstrated potential as non-viral gene delivery vectors. Melt polycondensation produced water dispersible polyesters which bound deoxyribonucleic acid at low N/P ratios. The v polyplexes showed stability in water over 24 h and no cytotoxic effect on human cervical cancer cells (HeLa). A luciferase transfection assay revealed the copolyesters successfully underwent endocytosis and released the nucleic acid better than controls. The copolyesters with pendant imidazolium functionality also provided tunable Tgs, -41 °C to 40 °C, and the ability to electrospin into fibers upon blending with poly(ethylene oxide). These additional properties furthered potential applications to include pressure sensitive adhesives and biocompatible antibacterial bandages.
Ph. D.

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18

Shanbhag, Mihir S. Wheatley Margaret A. "Development of a multi-functional construct for central nervous system repair /." Philadelphia, Pa. : Drexel University, 2008. http://hdl.handle.net/1860/2906.

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19

Errico, Claudia. "Ultrasound sensitive agents for transcranial functional imaging, super-resolution microscopy and drug delivery." Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCC013.

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Cette thèse porte sur deux branches majeures de l'utilisation d'agents sensibles aux ultrasons: l'échographie ultrarapide du cerveau assistée par microbulles et la délivrance par ultrasons de médicaments pour la thérapie du cancer. Dans la première approche, des microbulles remplies de gaz fluoré ont été utilisés pour observer l'activation du cerveau à travers le crâne des rongeurs. Nous avons été en mesure de reconstituer de manière non invasive le réseau vasculaire du cerveau, puis de récupérer sa réponse hémodynamique avec une résolution spatio-temporelle élevée. La validation de cette approche d'imagerie fonctionnelle par échographie (FUS) a été facilitée par la grande sensibilité de la technique du Doppler ultrarapide ultrasensible. En effet, cette modalité d'imagerie permet de détecter les changements hémodynamiques dus au couplage neurovasculaire avec une grande résolution (1ms, 100pm). Ces résultats suggèrent que la combinaison des agents de contraste et l'imagerie ultrarapide peut aider à compenser entièrement l'atténuation par le crâne, et ce en préservant la résolution et en augmentant la profondeur de pénétration. L'injection d'agents de contraste ultrasonore a également conduit à des résultats remarquables en imagerie ultrasonore ultrarapide. La barrière de la diffraction a été contournée pour aller au-delà de la limite de demi-longueur d'onde de résolution. Nous avons démontré que des microvaisseaux cérébraux de 9pm de diamètre peuvent être distingués par microscopie échographie ultrarapide de localisation (uULM). Des millions de sources «clignotantes» sont localisées dans l'espace et dans le temps, conduisant à des images super-résolues (cartographie de densité de microbulles) de l'ensemble du réseau vasculaire du cerveau du rat avec une résolution spatiale de À / 10. En outre, les trajets des microbulles au cours du temps ont pu être relevés et ainsi permettre d'extraire les vitesses des flux sanguins avec une grande dynamique. Dans la seconde approche, nous avons exploité la manière dont nous pouvons contrôler, spatialement et temporellement, la vaporisation de micro gouttes composites de perfluorocarbone (PFC) lorsque leur activation est déclenchée par de courtes impulsions ultrasonore. Le concept de "chimie in-situ" est introduit dès lors que nous avons été en mesure de contrôler une réaction chimique spontanée in vitro. En outre, dans le cadre des applications in vivo de la chimie in situ, un nouveau dispositif microfluidique en verre a été proposé afin de permettre une production stable et rapide de gouttes monodisperses. Ce nouveau dispositif présente 128 générateurs en parallèles avec deux canaux sous pression. Finalement, de nouvelles séquences d'échographie de contrôle ultra-rapides ont été développées dans le but de contrôler et de surveiller la libération des gouttelettes composites
This thesis focuses on two main branches of the application of ultrasound contrast agents: microbubbles-aided ultrafast ultrasound imaging of the brain and ultrasound-triggered drug delivery for cancer therapy. At first, gas-filled microbubbles have been used to retrieve the brain activation through the skull in large animais. With this approach we have been able to non-invasively reconstruct the cerebral network of the brain, as well as retrieve its hemodynamic response to specific evoked tasks with high spatiotemporal resolution. The validation of this novel functional ultrasound (fUS) imaging approach was facilitated by the high sensitivity of the ultrasensitive Doppler technique able to detect subtle hemodynamic changes due to the neurovascular coupling. These resuits suggested that combining microbubbles injections with ultrafast imaging may help to fully compensate for the attenuation from the skull. Indeed, by combining both, we preserved resolution and increased penetration depth. The injection of ultrasound contrast agents has also lead to outstanding resuits in ultrafast ultrasound imaging by breaking the diffraction barrier and move beyond the half-wavelength limit in resolution. We have demonstrated that cerebral microvessels of 9pm in diameter can me distinguished via ultrafast ultrasound localization microscopy (uULM). Millions of blinking sources were localized in space and in time in few seconds in a higher dimensional space, leading to super-resolved images (microbubble density map) of the whole rat brain with a spatial resolution of À/10. Moreover, a displacement vector allowed microbubbles-tracking within frames yielding to in-plane velocity measurements retrieving a large dynamic of cerebral blood velocities. Next, we have exploited how we can spatiotemporally control the vaporization of composite perfluorocarbon (PFC) microdroplets when their activation is triggered by short ultrasound pulses. The concept 'chemistry in-situ' is introduced as we have been able to control a spontaneous chemical reaction in-vitro. Moreover, a new microfluidic device in glass has been proposed to robustly produce monodisperse droplets for future in-vivo applications of the chemistry in situ. This new device presents 128-parallel generators with two pressurized rivers. Eventually, new ultrafast ultrasound monitoring sequences have been developed in order to control and monitor the release of composite droplets

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20

Smith, Meghan Elisabeth. "Biologically Functional Scaffolds for Tissue Engineering and Drug Delivery, Produced through Electrostatic Processing." Cleveland, Ohio : Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1251224066.

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Thesis(Ph.D.)--Case Western Reserve University, 2010
Title from PDF (viewed on 2009-12-30) Department of Chemical Engineering Includes abstract Includes bibliographical references and appendices Available online via the OhioLINK ETD Center

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21

Huang, Wei-Pang. "Functional analysis of Aut7 in vacuolar delivery of aminopeptidase I in Saccharomyces cerevisiae /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2002. http://uclibs.org/PID/11984.

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22

CURTO, M. D. DEL. "ORAL DELIVERY SYSTEMS INTENDED FOR COLONIC RELEASE OF INSULIN AND SELECTED FUNCTIONAL ADJUVANTS." Doctoral thesis, Università degli Studi di Milano, 2009. http://hdl.handle.net/2434/152826.

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Abstract of the PhD thesis entitled “Oral delivery systems intended for colonic release of insulin and selected functional adjuvants” Colon delivery has gained increased attention as a potential approach to improve the oral bioavailability of peptides and proteins. In this respect, the suitability of a previously developed release platform (ChronotopicTM) was explored for the conveyance of insulin and selected functional adjuvants. The system consists of a drug core and a swellable/erodible hydroxypropyl methylcellulose (HPMC) release-controlling coating. When an outer enteric film is applied, colon delivery is obtained based on relatively consistent small intestinal transit time. Preliminarily, the compatibility of insulin with a protease inhibitor (camostat mesilate, CM) and an absorption enhancer (sodium glycocholate, NaGly) was assessed. Subsequently, differing insulin/adjuvants release patterns were pursued by properly modifying the system formulation. A concurrent liberation of these compounds was achieved after reproducible and programmable lag phases from devices in which the protein and enzyme inhibitor/absorption enhancer were included in the core unit. The possibility of timing the adjuvant release to occur prior to that of the protein, which might allow a more favorable environment to be established in advance, was then investigated. For this purpose, prototypes with a CM/NaGly interlayer enclosed between HPMC coatings with differing thicknesses were prepared that elicited flexible two-pulse release profiles.

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23

Yang, Xia. "Multi-functional Hyaluronan Based Biomaterials for Biomedical Applications." Doctoral thesis, Uppsala universitet, Polymerkemi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-224371.

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This thesis presents strategies for constructing multi-functional biomaterials based on hyaluronan (HA) derivatives for various biomedical applications, such as drug delivery, tissue regeneration, and imaging biomaterials. The aim of this study is to improve the functionalities of HA biomaterials as well as simplify the preparation procedures. Native HA polymer contains D-glucuronic acid residue with a carboxyl group per disaccharide unit that can be easily modified by carbodiimide-mediated amidation reaction. Therefore, we have designed a series of orthogonal groups (hydrazide, carbazate, aldehyde, and thiol) that can be linked to HA under mild conditions using the carbodiimide chemistry. Multiple functionalities can be introduced to the obtained HA derivatives via chemoselective “click”-type transformations. The modified HA derivatives were used for the preparation of either nanogel particles (NPs) or bulk hydrogels. Due to “click” character of the reactions used, structural HA transformations were performed with high fidelity on different scales including molecular (polymers), nanometer (NPs), and a visible scale (bulk hydrogels). By linking pyrene or camptothecin to hydrophilic HA backbone, amphiphilic polymers were obtained and utilized as drug delivery carriers or prodrugs, respectively. Subsequently, physically loaded drug (doxorubicin) could be released upon degradation of HA carriers, while the chemically linked camptothecin was released intact by a thiol-triggered cleavage reaction. Bisphosphonated HA (HA-BP) polymers were prepared to induce hydrogel scaffold bio-mineralization for bone regeneration application. Moreover, we could recruit strong binding capacity of bisphosphonate (BP) groups to calcium ions for the formation of physically crosslinked HA-BP gel upon simple mixing of the polymer and calcium phosphate nanoparticle components. This gel was more stable in vivo compared to hydrazone crosslinked HA gels. Furthermore, the hydrogel composed of fluorine-19 (19F) linked HA polymer was successfully observed by both 1H and 19F MR imaging. In conclusion, the presented herein study describes new approaches for building up multi-functional biomaterials from the HA-based blocks. The utilization of carbodiimide and click chemistries along with the enzymatic degradation of HA allowed simple and efficient interconversion between HA macromolecules, nanoparticles and macroscopic hydrogels. These HA-based biomaterials show high potential for use in the fields of drug delivery, bone regeneration, and imaging techniques.

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24

Dupont, Kenneth Michael. "Human stem cell delivery and programming for functional regeneration of large segmental bone defects." Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/39647.

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Large bone defects pose a significant clinical challenge currently lacking an adequate therapeutic solution. Bone tissue engineering (BTE) therapies aim to provide that solution by combining structural scaffolds, bioactive factors, and/or osteogenic cells. Cellular therapies are likely vital to repair severe defects in patients lacking sufficient endogenous cells. Stem cells are attractive cell choices due to their osteogenic differentiation and extensive proliferation abilities, but their therapeutic potential is still uncertain, as studies comparing stem cell sources and delivery methods have produced inconsistent results. In this thesis, we developed a challenging in vivo large bone defect model for quantitative comparison of human stem cell-based therapies and then evaluated the abilities of adult or fetal stem cell-seeded constructs to enhance defect repair, with or without added osteogenic cues. First, we showed that cellular construct treatment enhanced defect healing over acellular construct treatment, although there were no differences between adult or fetal cell sources. We next labeled stem cells with a fluorescent tracking agent, the quantum dot, to determine biodistribution of implanted cells during the repair process. While quantum dots effectively labeled cells in vitro, they were ineffective in vivo tracking agents due to false positive signals and detrimental effects on stem cell-mediated repair. Finally, we developed a novel gene therapy technique using virus-coated scaffolds to deliver the osteogenic factor bone morphogenetic protein 2 (BMP2) to defect sites, either by in vitro (BMP2 transduction of seeded stem cells pre-implantation) or in vivo (BMP2 transduction of defect-site host cells) means. While defect-site BMP2 delivery through gene therapy methods improved repair, in vivo therapy enhanced healing more than stem cell-based in vitro therapy. This finding does not rule out the potential of stem cell-based in vitro gene therapy treatment for functional bone repair, as increases in viral dose may improve stem cell-mediated healing, but it does present evidence of a novel acellular BTE therapy with potential off-the-shelf clinical application in large bone defect repair, as scaffolds could be virally coated with the gene for BMP2 expression and frozen until implantation.

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25

Manson, Joanne. "PLGA films containing poly(ethylene glycol) functional gold nanoparticles for potential drug delivery applications." Thesis, University of Ulster, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.557399.

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In this study novel composites comprising poly(ethylene glycol) functionalised gold nanoparticles (PEG-AuNP) dispersed within a poy(DL-Iactic-co-glycolic) (PLGA) film were produced via a solvent-casting technique and their effect on the degradation of PLGA investigated. In addition to the release profile of AuNPs during degradation was studied. The production of PLGA films containing PEG-AuNPs is a first step proof-of-principle concept for the aim of producing a composite capable of both targeted and sustained drug delivery. PLGA films were produced via solvent-casting using a number of molecular weight 50:50 PLGA polymers and three commonly reported solvents, namely dichloromethane, chloroform and acetone. The effect of molecular weight and solvent choice was investigated in regard to drying time required and subsequent residual solvent levels. Analysis reported a drying time of 14 days at 40°C, 400 mbar, with dichloromethane displaying the lowest residual solvent content after drying, PLGA 3A (0.58 dL/g) was found to be the most robust sample in terms of ease of handing. The mould material is one of the most important features of solvent-casting in terms of removing the sample after drying, to this end it was demonstrated that glass petri dishes pre-coated with RainX proved ideal. PEG functionalisation of the AuNP surface allows for successful drying and re- dispersion in a range of media (PBS, H20, PBS-BSA, and DCM). A PEG capping density of 16.8 μg/mL was found from UV-Vis, TGA and DLS to be the most suitable for successful incorporation into PLGA films via solvent-casting. A range of weight percentages of PEG-AuNPs were successfully incorporated into PLGA films namely, 0.2, 0.4, 0.6, 0.8, 1 and 2 wt%. The AuNP release profile of PLGA containing 1 and 2 wt% PEG functionalised AuNPs was studied using ICP-MS during degradation. Unfunctionalised AuNPs could not be successfully incorporated in PLGA films due to irreversible aggregation after drying. The incorporation of PEG-AuNPs into PLGA films was found to aid in the drying process and resulted in reduced levels of residual solvent. The addition of 1 and 2 wt% PEG functionalised AuNPs was found to increase the PLGA degradation time from 39 to 58 days. Release of PEG-AuNPs from PLGA films during degradation was investigated using ICP-MS and appeared to follow a relatively sustained release profile for both 1 and 2 wt% PEG-AuNPs over the 58 day degradation timeframe.

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26

Vabbilisetty, Pratima. "Functional Anchoring Lipids for Drug Delivery Carrier Fabrication and Cell Surface Re-Engineering Applications." Cleveland State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=csu1424175323.

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27

Nichols, Sarah, Nathan Justice, Anjali Malkani, and David Wood. "The Path(way) to a Clean Colon: Improving the Management of Functional Constipation." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/asrf/2020/presentations/42.

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Title: The path(way) to a clean colon: Improving the management of functional constipation Authors: Sarah Nichols, D.O. Pediatrics Resident, Nathan Justice, M.D. Pediatrics Hospital Medicine, Anjali Malkani, M.D. Pediatric Gastroenterology, David Wood, M.D., MPH General Pediatrics and Adolescent Medicine Purpose / Objectives: Hospitalization for the treatment of functional constipation is a leading cause among encounters that incur a financial loss at our institution. There are few resources that describe best practices or quality improvement efforts in the management of children who are hospitalized with functional constipation. A clinical pathway was implemented to promote interventions that improve hospital resource utilization for this group of children. Design / Methods: A clinical pathway was developed by a multidisciplinary team of stakeholders. The pathway emphasized interventions known to improve resource utilization and believed to facilitate a more effective and efficient cleanout. The inpatient arm of the pathway was implemented on a 24-bed medical/surgical unit; members of the medical and clinical staff of this unit received education with dissemination of the pathway. An electronic order set was implemented concurrently to facilitate practitioners’ application of pathway recommendations. Plan-Do-Study-Act (PDSA) cycles were used to monitor process measures and outcomes. Inpatient utilization was selected as the primary outcome for this effort’s first iteration; length of stay and frequency of readmissions were monitored as a secondary outcome and balancing measure, respectively. Results: Pathway utilization reached 65% within two periods of implementation. Adherence to selected process measures exceeded 80% within two periods. Inpatient utilization demonstrated initial improvement, increasing from 20% at baseline to 50% post-implementation; however, it subsequently fell below baseline performance after third-party payers revised admission criteria during period 6. Length of stay and frequency of readmissions remained unchanged post-intervention. Conclusion / Discussion: A clinical pathway for the treatment of functional constipation was quickly adopted by clinicians within two periods of implementation (spanning two months). The pathway was effective at promoting interventions that improved inpatient utilization; however, these improvements could not be sustained in the face of an unanticipated, external force. Future improvement cycles will be directed at reducing the length of stay to improve hospital resource utilization.

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28

Clemente, Ilaria. "Compartmentalized algal-based nanocarriers as vectors for antioxidants: structural and functional characterization." Doctoral thesis, Università di Siena, 2022. http://hdl.handle.net/11365/1193669.

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The delivery of poorly water-soluble natural drugs is a longtime challenge that has led to the development of several solubilizing and encapsulating carrier systems, to administrate hydrophobic molecules for biomedical, pharmaceutical, food and cosmetics applications. Among the most popular soft matter nanocarriers, lipid-based vectors are particularly favored thanks to the advantageous properties of lipids used as versatile and biocompatible building blocks. Indeed, lipids are the class of bio-macromolecules with the richest polymorphism and spontaneous self-assembly character, that result in a broad variety of hierarchical structures. Several aggregates with various interfacial curvatures and symmetries can be obtained, mainly depending on the lipid class and packing parameter, and they can be differentiated in lamellar and nonlamellar mesophases. Lamellar aggregates are characterized by the presence of one or multiple bilayers which possess vesicular morphology at larger scale (um). Nonlamellar mesophases with exotic symmetries, such as cubic and hexagonal, are lyotropic liquid crystalline systems with specific inner ordering, and among the most interesting nonlamellar structures are the bicontinuous cubic phases. When these systems are in excess water conditions, dispersed nanosystems are obtained and termed liposomes and cubosomes, respectively. The versatility and biodegradability of these nanosystems makes them particularly suitable as carriers for orally administered drugs. Moreover, lipids to be used for formulation development can be obtained from a variety of natural sources and biomasses, to obtain nanovectors for bioactive molecules with high carrier-cargo and carrier-target compatibility. In this thesis work, lipid nanovectors were designed and prepared as biocompatible and biodegradable drug carriers for a commercially valuable antioxidant drug i. e. curcumin, whose therapeutic application is typically hindered by its poor water solubility, that was chosen as the designated natural antioxidant of interest for this investigation. Two other antioxidants i. e. α-tocopherol and piperine were used as adjuvants for curcumin since they are known to facilitate incorporation and co-administration by acting synergistically as bio-enhancers. These three antioxidants were then encapsulated in newly formulated lipid nanocarriers to improve their biodistribution and bioavailability. The design strategy adopted for these formulations involved the use of natural-derived building blocks by lipid extraction from two biomasses of the marine microalga Nannochloropsis sp., containing mostly either phospholipids or triglycerides. Two dispersed nanovector series with different supramolecular structure were thus obtained i. e. liposomes and cubosomes, respectively. The high surface-to-volume ratio and loading efficiency granted successful encapsulation of the guest molecules. These nanoformulations were extensively characterized both from the physico-chemical and functional viewpoint. The structure and morphology was studied by combination of Dynamic Light Scattering, Small Angle X-Ray Scattering and Cryogenic Transmission Electron Microscopy. The guest-carrier and guest-guest interactions, stability and cargo entrapment were investigated by spectroscopic (UV–Vis, Nuclear Magnetic Resonance) and calorimetric (Isothermal Titration Calorimetry) techniques. Finally, the functionality was studied with both chemical and biological approaches, in an integrated structure-function perspective.

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29

Lee, Hyun-Jung. "Delivery of thermostabilized chondroitinase ABC enhances axonal sprouting and functional recovery after spinal cord injury." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/31734.

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Thesis (Ph.D)--Biomedical Engineering, Georgia Institute of Technology, 2010.
Committee Chair: Ravi V. Bellamkonda; Committee Member: Andreas Bommarius; Committee Member: Andrés J. García; Committee Member: Niren Murthy; Committee Member: Robert J. McKeon. Part of the SMARTech Electronic Thesis and Dissertation Collection.

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30

Xu, Zhenhua, and 许振华. "Functional characterization of cell cycle-related kinase in glioblastoma and development of gene delivery system." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47752658.

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Cell cycle-related kinase (CCRK) is a 42 KDa serine/threonine protein kinase homologous to Cdk1, 2 and 7. Previous work has shown that CCRK regulates cell cycle transition by phosphorylating Cdk2 and Rb. More importantly, it was found that CCRK was a candidate oncogene in both glioblastoma multiform (GBM) and human colorectal cancer. However, the mechanistic role of CCRK in tumorigenicity is still not completely understood. In the first part of this thesis, I found that casein kinas II beta (CKIIβ) was one of proteins that interact with CCRK using the high-throughput yeast-two-hybrid analysis. Then I confirmed their interaction by co-immunoprecipitation. CCRK phosphorylated CKIIβ at Ser-209 in a cell cycle-dependent manner. The phosphorylation of CKIIβ by CCRK enhanced the activity of CKII holoenzyme, protected CKIIβ against proteasome degradation, and facilitated CKIIβ translocation into the nucleus in U-87 MG and U-373 MG GBM cells. Importantly, CCRK de-sensitized GBM cells to the cytotoxic effect of three chemotherapy drugs, whereas knockdown of CCRK by siRNA reduced chemoresistance. Functionally, CKIIβ is responsible for CCRK-mediated inhibition of apoptosis, as suppression of CKIIβ by siRNA or CKIIβ inhibitor could re-sensitize cells to the cytotoxic effect of cisplatin in both wild type and CCRK-overexpressing U-87 MG cells. In vivo studies also showed that stable over-expression of CCRK increased tumor growth and decreased the anti-tumor efficacy of cisplatin in a nude mice GBM xenograft model. These results provide the first evidence that phosphorylation of CKIIβ is a new mechanism by which CCRK confers tumor growth and drug resistance to GBM cells. In the second part of this thesis I described a novel polymer, mPPS-FA, synthesized as a potential gene transfer vector. To complete mPPS-FA, folic acid was conjugated to a backbone (named mPPS) consisting of a copolymer of methyl PEG-2000, PEI-600 and sebacoyl chloride. 1H-NMR, FT-IR and UV spectroscopy were used to characterize the structure of mPPS-FA. It was revealed that mPPS-FA holds the ability to bind plasmid DNA yielding positively charged particles (polyplexes). Dynamic light scattering (DLS) and TEM techniques were used to study the size and morphology of the formed mPPS-FA/DNA nanocomplexes. Cytotoxicity of the mPPS-FA/DNA nanoparticles was also evaluated on B16-F0, U87MG, CHO-1 and Ho-8910 cells. The ability of mPPS-FA to deliver EGFP plasmid to melanoma B16-F0, U87, CHO-1, Ho-8910 and A549 cells was investigated in vitro as compared to the lipid-based transfection agent LipofectamineTM2000 and Linear PEI 22KDa (L-PEI 22KDa). I found that mPPS-FA/DNA complexes yielded the highest GFP transfection efficiency in B16-F0, U87, CHO-1 and Ho-8910 cells, which all highly express folate receptors (FR), at an mPPS-FA/DNA ratio (w/w) of 15. Furthermore, the transfection of mPPS-FA/DNA complexes in CHO-1 cells could be significantly competed and blocked by the free folic acid molecules. All together, mPPS-FA showed the highest efficiency in vitro and the potential to be developed as a nonviral gene carrier.
published_or_final_version
Chemistry
Doctoral
Doctor of Philosophy

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31

Gulfam, Muhammad. "Development of functional micelles from biodegradable amphiphilic block copolymers for drug delivery and tumour therapy." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/47106/.

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Drug delivery systems in the size range of ~ 10-250 nm are enabling tools for site-specific targeting and controlled release applications. To take advantage of these capabilities, various nanocarriers e.g., micelles, dendrimers, liposomes, nanoparticles, nanocapsules, nanotubes, and nanogels, have been designed for drug delivery. Specifically, micelle-based drug carrier systems have emerged as promising tools for site-specific delivery and controlled release applications. Despite several advantages over conventional drugs, some limitations of micelle-based drug delivery have also been reported. These drawbacks include low stability in vivo, poor penetration, modest accumulation in tumour tissues, and inadequate control over drug release. To overcome these limitations, stimuli-responsive or smart polymeric nanocarriers have been developed for drug delivery and tumour therapy, previously. The most well-known internal stimuli in cancerous regions include higher acidity associated with dysregulated metabolism in tumour tissues, elevated levels of glutathione in the cytosol and nucleus of cancer cells, and altered degradative enzymes in the lysosomes, and reactive oxygen species in the mitochondria. These intrinsic microenvironments can be exploited as internal stimuli to attain active drug release in the tumour tissues or cancer cells. In particular, the reducing potential inside the cancer cells is considerably higher than found in the extracellular environment and bloodstream. Such varying redox potential can be exploited for tumour-specific drug delivery and controlled release applications. Various types of redox-responsive micelles have been developed, previously. Generally, redox-responsive micelles have disulfide linkages that undergo rapid cleavage in the presence of reducing agents in the intracellular components, however, are stable at oxidising extracellular environment. The redox-responsive disulfide bridges can be incorporated into nanocarriers by placing multiple disulfide bonds in the hydrophobic backbone or by conjugating therapeutic agents to the side chain of the polymer via a disulfide linker. Another strategy to construct redox-responsive linkages is to crosslink the polymeric nanocarriers with a disulfide crosslinker. Studies have shown that polymeric micelles can dissociate, especially upon administration when they are diluted below their critical micelle concentration. The stability of polymeric micelles can be enhanced by chemical crosslinking. Various types of crosslinked micelles can be prepared subjected to the localisation of the crosslinking, e.g. shell crosslinked micelles, and core crosslinked micelles. Introducing redox-responsive bridges through disulfide crosslinkers may not only provide stability to nano-carriers against dilutions during circulation, but also render them responsive to reducing conditions. Specifically, redox-responsive core-crosslinked micelles have demonstrated good stability and better ‘stealth’ properties, nevertheless, the hydrophobic core of most of the existing core-crosslinked micelles have been based on non-degradable polymers such as polyacrylamide or polyacrylate. The non-degradable constituent of the block copolymer may cause complications in clinical applications. Therefore, reduction-responsive core-crosslinked micelles comprising entirely of biologically inert or biocompatible and biodegradable polymers would be better candidates for drug delivery and controlled release application. To overcome these limitations, micelles based on polyesters (a class of aliphatic biodegradable polymers) can used for drug delivery application. In the last few decades, various FDA approved aliphatic polyesters e.g. poly(lactic-co-glycolic acid) (PLGA), poly(ε-caprolactone), and poly(lactic acid), have been intensively studied to exploit their potential in drug, gene and protein delivery and controlled release applications. Nevertheless, most of these polyesters lack functional groups, making it difficult to incorporate redox-responsive linkages to core-crosslink their micelles. To address these issues, we have synthesised functional biodegradable and biocompatible block copolymers based on methoxypoly(ethyleneglycol)-b-poly(-caprolactone-co--azido--caprolactone) (mPEG-b-poly(CL-co-N3CL)). The pendent chloro groups of the block copolymer were converted into azides using nucleophilic substitution reaction to obtain mPEG-b-poly(CL-co-N3CL) block copolymer as a precursor of reactive polymeric micelles. The synthesised polymers were characterised by NMR, FT-IR and size exclusion chromatography (SEC). Micelles were prepared using the dialysis method and methotrexate (an anticancer drug) was loaded into the hydrophobic core of the reactive micelles. Micelles were subsequently crosslinked by a redox-responsive bis-alkyne ethyl disulfide crosslinker. The size distributions and morphology of core-crosslinked micelles were assessed using dynamic light scattering (DLS) and transmission electron microscopy. The drug release studies were performed under simulated non-reducing and reducing conditions. Cellular uptake studies in human breast cancer cells (MCF7 cells) were performed using Oregon-green loaded core-crosslinked micelles. The MTX-loaded core-crosslinked micelles were assessed for their cytotoxicity in human breast cancer cells by MTT assays. The apoptosis inducing potential of MTX-loaded core-crosslinked micelles was analysed using Hoechst/PI assays and was further probed by annexin-V/PI assays. The data from these studies indicate that drug release from these crosslinked micelles can be controlled and that redox-responsive micelles are more effective carriers for MTX than non-cross-linked analogues in the cell lines tested. In another strategy, a multifunctional amphiphilic block copolymer based on -amine-PEG-b-poly(CL-co-N3CL) was synthesised and subsequently was used to conjugate methotrexate on the hydrophilic block for receptor mediated targeting of breast cancer cells. Cellular uptake studies revealed 2.3-fold higher uptake of MTX-conjugated micelles as compared with un-conjugated micelles. The blank micelles showed low cytotoxicities in breast cancer cells, however, MTX-conjugated micelles exhibited greater antitumor activity in contrast to the free-MTX. We hypothesise that these functional micelles could be potentially powerful nanocarriers for stimuli-responsive controlled release, active tumour targeting, and cancer therapy.

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32

Riddle, Ryan T. "Maximizing sulforaphane delivery and sensory acceptability of a novel soy-tomato-broccoli sprout beverage." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1323373292.

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33

Liang, Ya Palmese Giuseppe R. Lowman Anthony M. "Functional polymer-polymer composites by nano/meso-fiber encapsulation : applications in drug delivery systems and polymer toughening /." Philadelphia, Pa. : Drexel University, 2010. http://hdl.handle.net/1860/3316.

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34

McKee, Deloyce A. "Assessing the background and training for delivery of functional behavior assessment at the application level in Kansas /." Search for this dissertation online, 2006. http://wwwlib.umi.com/cr/ksu/main.

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35

He, Wei. "Dual-functional polyurea microcapsules for chronic wound care dressings: sustained drug delivery and non-leaching infection control." John Wiley and Sons, 2012. http://hdl.handle.net/1993/8443.

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A new design of dual-functional polyurea microcapsules was proposed for chronic wound dressings to provide both non-leaching infection control and sustained topical drug delivery functionalities. Quaternary ammonium functionalized polyurea microcapsules (MCQs) were synthesized under mild conditions through an interfacial crosslinking reaction between branched polyethylenimine (PEI) and 2,4-toluene diisocyanate (TDI) in a dimethylformamide/cyclohexane emulsion. An in-situ modification method was developed to endow non-leaching surface antimicrobial properties to MCQs via bonding antimicrobial surfactants to surface isocyanate residues on the polyurea shells. The resultant robust MCQs with both non-leaching antimicrobial properties and sustained drug releasing properties have potential applications in medical textiles, such as chronic wound dressings, for infection control and drug delivery.

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36

Schneider, Anselm Fabian Lowell [Verfasser]. "Novel Cell-Penetrating Peptides in the Delivery of Functional Protein Conjugates Into Living Cells / Anselm Fabian Lowell Schneider." Berlin : Freie Universität Berlin, 2021. http://d-nb.info/1229917306/34.

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37

Lee, Cen Ying. "Integrative Trust-Based Functional Contracting: A Complementary Contractual Approach to BIM-Enabled Oil And Gas EPC Project Delivery." Thesis, Curtin University, 2019. http://hdl.handle.net/20.500.11937/75059.

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The research has successfully bridged the gap between contractual and technological practices for the Engineering, Procurement and Construction (EPC) contracts in oil and gas projects. It has identified the related Building Information Modelling (BIM) uses and developed an integrative trust-based functional contracting that complement to EPC contracts. The research contributes to new functional perspectives of contracting and also provides significant insights into the proper use contract functions for improving BIM-enabled projects’ performance.

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38

Uesaka, Akihiro. "Precise Structural and Functional Control of Molecular Assemblies Composed of Amphiphilic Peptides Having a Hydrophobic Helical Block." 京都大学 (Kyoto University), 2015. http://hdl.handle.net/2433/199273.

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39

Myers, Meredith R. Myers. "Comparison of Consumer Acceptance, Physico-chemical Properties, and Bioactive Delivery of Blueberry Extract and Whole Blueberry Powder Confections." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1531490769497695.

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40

Khan, Md Arif. "NANOHARVESTING AND DELIVERY OF BIOACTIVE MATERIALS USING ENGINEERED SILICA NANOPARTICLES." UKnowledge, 2019. https://uknowledge.uky.edu/cme_etds/110.

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Анотація:

Mesoporous silica nanoparticles (MSNPs) possess large surface areas and ample pore space that can be readily modified with specific functional groups for targeted binding of bioactive materials to be transported through cellular barriers. Engineered silica nanoparticles (ESNP) have been used extensively to deliver bio-active materials to target intracellular sites, including as non-viral vectors for nucleic acid (DNA/RNA) delivery such as for siRNA induced interference. The reverse process guided by the same principles is called “nanoharvesting”, where valuable biomolecules are carried out and separated from living and functioning organisms using nano-carriers. This dissertation focuses on ESNP design principles for both applications. To investigate the bioactive materials loading, the adsorption of antioxidant flavonoids was investigated on titania (TiO2) functionalized MSNPs (mean particle diameter ~170 nm). The amount of flavonoid adsorbed onto particle surface was a strong function of active group (TiO2) grafting and a 100-fold increase in the adsorption capacity was observed relative to nonporous particles with similar TiO2 coverage. Active flavonoid was released from the particle surface using citric acid-mediated ligand displacement. Afterwards, nanoharvesting of flavonoids from plant hairy roots is demonstrated using ESNP in which TiO2 and amine functional groups are used as specific binding sites and positive surface charge source, respectively. Isolation of therapeutics was confirmed by increased pharmacological activity of the particles. After nanoharvesting, roots are found to be viable and capable of therapeutic re-synthesis. In order to identify the underlying nanoparticle uptake mechanism, TiO2 content of the plant roots was quantified with exposure to nanoparticles. Temperature (4 or 23 °C) dependent particle recovery, in which time dependent release of ESNP from plant cells showed a similar trend, indicated an energy independent process (passive transport). To achieve the selective separation and nanoharvesting of higher value therapeutics, amine functionalized MSNPs were conjugated with specific functional oligopeptides using a hetero-bifunctional linker. Fluorescence spectroscopy was used to confirm and determine binding efficiency using fluorescently attached peptides. Binding of targeted compounds was confirmed by solution depletion using liquid chromatography–mass spectrometry. The conjugation strategy is generalizable and applicable to harvest the pharmaceuticals produced in plants by selecting a specific oligopeptide that mimic the appropriate binding sites. For related gene delivery applications, the thermodynamic interaction of amine functionalized MSNPs with double-stranded (ds) RNA was investigated by isothermal titration calorimetry (ITC). The heat of interaction was significantly different for particles with larger pore size (3.2 and 7.6 nm) compared to that of small pore particles (1.6 nm) and nonporous particles. Interaction of dsRNA also depended on molecular length, as longer RNA (282 base pair) was unable to load into 1.6 nm particles, consistent with previous confocal microscopy observations. Calculated thermodynamic parameters (enthalpy, entropy and free energy of interaction) are essential to design pore size dependent dsRNA loading, protection and delivery using MSNP carriers. While seemingly diverse, the highly tunable nature of ESNP and their interactions with cells are broadly applicable, and enable facile nano-harvesting and delivery based on a continuous uptake-expulsion mechanism.

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41

Burberry, Diane. "LOW COST PRODUCTION OF PROINSULIN IN TOBACCO AND LETTUCE CHLOROPLASTS FOR INJECTABLE OR ORAL DELIVERY OF FUNCTIONAL INSULIN AND." Master's thesis, University of Central Florida, 2010. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/2148.

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Current treatment for type I diabetes includes delivery of insulin via injection or pump, which is highly invasive and expensive. The production of chloroplast-derived proinsulin should reduce cost and facilitate oral delivery. Therefore, tobacco and lettuce chloroplasts were transformed with the cholera toxin B subunit fused with human proinsulin (A, B, and C peptides) containing three furin cleavage sites (CTB-PFx3). Transplastomic lines were confirmed for site-specific integration of transgene and homoplasmy. Old tobacco leaves accumulated proinsulin up to 47% of total leaf protein (TLP). Old lettuce leaves accumulated proinsulin up to 53% TLP. Accumulation was so stable that up to ~40% proinsulin in TLP was observed even in senescent and dried lettuce leaves, facilitating their processing and storage in the field. Based on the yield of only monomers and dimers of proinsulin (3 mg/g leaf, a significant underestimation), with a 50% loss of protein during the purification process, one acre of tobacco could yield up to 20 million daily doses of insulin per year. Proinsulin from tobacco leaves was purified up to 98% using metal affinity chromatography without any His-tag. Furin protease cleaved insulin peptides in vitro. Oral delivery of unprocessed proinsulin bioencapsulated in plant cells or injectable delivery into mice showed reduction in blood glucose levels similar to processed commercial insulin. C-peptide should aid in longterm treatment of diabetic complications including stimulation of nerve and renal functions. Hyper-expression of functional proinsulin and exceptional stability in dehydrated leaves offer a low cost platform for oral and injectable delivery of cleavable proinsulin.
M.S.
Burnett School of Biomedical Sciences
Medicine
Biotechnology MS

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42

Theune, Loryn Elisabeth [Verfasser]. "Thermo-Responsive Nanogels as Versatile Platform for Smart Drug Delivery Systems and Multi-Functional Photothermal Agents / Loryn Elisabeth Theune." Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1212031814/34.

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43

Boehm, Michael. "EXPERIMENTAL INVESTIGATION OF TWO-PHASE PENETRATING FLOW OF NEWTONIAN AND NON-NEWTONIAN POLYMERIC FLUIDS AND DEVELOPMENT OF PRACTICAL APPLICATIONS IN DRUG/GENE DELIVERY." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1253548237.

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44

Mindemark, Jonas. "Functional Cyclic Carbonate Monomers and Polycarbonates : Synthesis and Biomaterials Applications." Doctoral thesis, Uppsala universitet, Polymerkemi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-169677.

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The present work describes a selection of strategies for the synthesis of functional aliphatic polycarbonates. Using an end-group functionalization strategy, a series of DNA-binding cationic poly(trimethylene carbonate)s was synthesized for application as vectors for non-viral gene delivery. As the end-group functionality was identical in all polymers, the differences observed in DNA binding and in vitro transfection studies were directly related to the length of the hydrophobic poly(trimethylene carbonate) backbone and the number of functional end-groups. This enabled the use of this polymer system to explore the effects of structural elements on the gene delivery ability of cationic polymers, revealing striking differences between different materials, related to functionality and cationic charge density. In an effort to achieve more flexibility in the synthesis of functional polymers, polycarbonates were synthesized in which the functionalities were distributed along the polymer backbone. Through polymerization of a series of alkyl halide-functional six-membered cyclic carbonates, semicrystalline chloro- and bromo-functional homopolycarbonates were obtained. The tendency of the materials to form crystallites was related to the presence of alkyl as well as halide functionalities and ranged from polymers that crystallized from the melt to materials that only crystallized on precipitation from a solution. Semicrystallinity was also observed for random 1:1 copolymers of some of the monomers with trimethylene carbonate, suggesting a remarkable ability of repeating units originating from these monomers to form crystallites. For the further synthesis of functional monomers and polymers, azide-functional cyclic carbonates were synthesized from the bromo-functional monomers. These were used as starting materials for the click synthesis of triazole-functional cyclic carbonate monomers through Cu(I)-catalyzed azide–alkyne cycloaddition. The click chemistry strategy proved to be a viable route to obtain structurally diverse monomers starting from a few azide-functional precursors. This paves the way for facile synthesis of a wide range of novel functional cyclic carbonate monomers and polycarbonates, limited only by the availability of suitable functional alkynes.

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45

Glanz, Maria. "Chemoselective conjugation of biological active peptides to functional scaffolds." Doctoral thesis, Humboldt-Universität zu Berlin, 2019. http://dx.doi.org/10.18452/20223.

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Peptide bilden eine einzigartige Klasse von Biomolekülen. Auf Grund ihrer komplexen Struktur sind sie in der Lage hochspezifisch an Zielmoleküle zu binden und können darüber hinaus bioaktive Eigenschaften aufweisen. In dieser Dissertation wurden verschiedene Anwendungen, für die biologisch aktive Peptide genutzt werden können untersucht und darüber hinaus die Konjugation ungeschützter Peptide an funktionelle Gerüstmoleküle betrachtet. Die spezifischen Bindungseigenschaften eines Hemagglutinin bindenden Peptids konnten durch deren multivalente Präsentation auf einem Polymer-Nanopartikel genutzt werden, um einen hochwirksamen Virus-Eintritts-Blocker zu synthetisieren. Außerdem wurde in dieser Dissertation eine neuartige chemoselektive Konjugation zwischen ungeschützten zyklischen Peptiden und Proteinen erforscht, basierend auf der Staudinger Phosphonite Reaktion. Die kovalente Bindung zwischen Proteinen und Peptiden ermöglichte die zellulären Aufnahme und zytosolische Verteilung des konjugierten Proteins. Die neuartige Staudinger induzierte Thiol Addition konnte darüber hinaus für die intramolekulare Makrozyklisierung von Peptiden eingesetzt werden, wodurch die biologische Aktivität der Peptide gesteigert wurde. Dies konnte anhand von zyklischen zellpenetrierenden Peptiden, als auch in der Stabilisierung der helikalen Struktur eines peptidischen Protein-Protein-Interaktions Inhibitors gezeigt werden. Des weiteren wurde eine bioreversible chemoselektive Konjugationsmethode untersucht, basierend auf der O-Alkylierung von Carbonsäuren, um eGFP mit zyklischen zellpenetrierenden Peptiden zu markieren. Erste Schritte zur Evaluierung der entstandenen Konjugate wurden unternommen. Zusammengenommen konnte die Vielfältigkeit bioaktiver Peptide in mehreren Anwendungen gezeigt werden, mit besonderem Augenmerk auf die Erweiterung der Konjugationsmethoden für ungeschützte Peptide an funktionale Trägermoleküle.
Synthetic peptides are a unique class of biomolecules. Due to their complex structure they can bind targets in a highly specific manner and can furthermore exhibit unique properties. Even though they are complex in structure, they are straightforward synthetically accessible. This thesis evolves around the many different aspects, in which biological active peptides can be used, from specific binders to cell penetration tags. Furthermore, the site specific and chemoselective conjugation of an unprotected peptide to a functional scaffold has been addressed. The binding properties of peptides could be used to generate a highly potent virus entry blocker from a viral-membrane-protein binding peptide, which was displayed multivalently on a polymeric nanoparticle. Furthermore, this thesis explored a novel chemoselective reaction, based on the Staudinger phosphonite reaction to conjugate cyclic peptides to eGFP. The covalent attachment of the peptidic ligand promoted efficiently the cellular uptake of protein and its cytosolic distribution. The novel Staudinger induced thiol addition cascade was further successfully used in an intramolecular reaction to macrocyclize peptides in order to induce bioactivity. This could be shown for the synthesis of cyclic cell penetrating peptides, as well as to stabilize the helical structure of a peptidic protein-protein interaction inhibitor. Furthermore, a bioreversible chemoselective conjugation based on a diazo building block, was used to label eGFP with cyclic cell penetrating peptides. First steps to evaluate the potency in vitro were undertaken. Taken together, the versatility of bioactive peptides was demonstrated in multiple applications and the tools to conjugate unprotected peptides to functional scaffolds was extended by the Staudinger induced thiol addition.

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46

Villar, Gabriel. "Aqueous droplet networks for functional tissue-like materials." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:602f9161-368c-48c0-9619-7974f743f2f2.

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An aqueous droplet in a solution of lipids in oil acquires a lipid monolayer coat, and two such droplets adhere to form a bilayer at their interface. Networks of droplets have been constructed in this way that function as light sensors, batteries and electrical circuits by using membrane proteins incorporated into the bilayers. However, the droplets have been confined to a bulk oil phase, which precludes direct communication with physiological environments. Further, the networks typically have been assembled manually, which limits their scale and complexity. This thesis addresses these limitations, and thereby enables prospective medical and technological applications for droplet networks. In the first part of the work, defined droplet networks are encapsulated within mm-scale drops of oil in water to form structures called multisomes. The encapsulated droplets adhere to one another and to the surface of the oil drop to form interface bilayers that allow them to communicate with each other and with the surrounding aqueous environment through membrane pores. The contents of the droplets can be released by changing the pH or temperature of the surrounding solution. Multisomes have potential applications in synthetic biology and medicine. In the second part of the work, a three-dimensional printing technique is developed that allows the construction of complex networks of tens of thousands of heterologous droplets ~50 µm in diameter. The droplets form a self-supporting material in bulk oil or water analogous to biological tissue. The mechanical properties of the material are calculated to be similar to those of soft tissues. Membrane proteins can be printed in specific droplets, for example to establish a conductive pathway through an otherwise insulating network. Further, the networks can be programmed by osmolarity gradients to fold into designed shapes. Printed droplet networks can serve as platforms for soft devices, and might be interfaced with living tissues for medical applications.

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47

Kasper, Marc-André. "Chemoselective synthesis of functional drug conjugates." Doctoral thesis, Humboldt-Universität zu Berlin, 2020. http://dx.doi.org/10.18452/20870.

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In der vorliegenden Arbeit wird eine modulare Reaktionssequenz von zwei aufeinanderfolgenden chemoselektiven Umwandlungen vorgestellt: Es wird gezeigt, dass Vinyl- und Ethynylphosphonamidate chemoselektiv mit Cysteinen von Proteinen und Antikörpern reagieren. Weiterhin wird gezeigt, dass elektrophile Phosphonamidate durch eine vorhergehende chemoselektive Staudinger-Phosphonit Reaktion zwischen Aziden und ungesättigten Phosphoniten in das gewünschte Molekül eingebaut werden können. Hierbei wird ein elektronenreiches Phosphonit in ein elektronenarmes Phosphonamidat umgewandelt, welches somit für die nachfolgende Thiol-Addition aktiviert wird. Die beschriebene Methode erweitert das bestehende Repertoire von Biokonjugationen durch die Einführung eines neuen Konzepts: Eine chemoleselektive Reaktion, die Reaktivität für eine nachfolgende Biokonjugation induziert. Da Phosphonamidat-Konjugationen an Cysteine herausragende Eigenschaften, wie hohe Selektivität für Cysteine, saubere Reaktionsprodukte und eine hervorragende Stabilität mitbringen, wird im zweiten Teil beschrieben wie Phosphonamidate für die Anbindung von zytotoxischen Wirkstoffen an tumor-bindende Antikörper genutzt werden können um Antikörper-Wirkstoff-Konjugate (ADCs) herzustellen. Ein einfaches Syntheseprotokoll für die Herstellung, ausgehend von einem nicht gentechnisch veränderten Antikörper mit nur geringen Überschüssen des Wirkstoffs wird vorgestellt. Phosphonamidat-verbundene ADCs zeigen im direkten Vergleichen zum zugelassenen, Maleimid-verbundenen Adcetris überlegende Eigenschaften, wie eine erhöhte Stabilität in Serum und eine erhöhte in vivo Wirksamkeit in einem Tumor Mausmodel. Zusammenfassend verbindet die hier vorgestellte Methode einen einfachen synthetischen Zugang mit hoher Selektivität, überragender Konjugat-Stabilität und der Möglichkeit hochwirksame Wirkstoffkonjugate herzustellen und wird daher aller Voraussicht nach einen großen Beitrag zum Gebiet der zielgerichteten Therapie leisten.
The present work introduces a modular reaction sequence of two chemoselective manipulations in a row. It is shown that vinyl- and ethynylphosphonamidates react selectively with cysteine residues on proteins and antibodies. Most importantly, those electrophilic phosphonamidates can be incorporated into a given molecule in another preceding chemoselective Staudinger-phosphonite reaction (SPhR) from unsaturated phosphonites and azides. During this reaction, an electron-rich phosphonite is transformed into an electron-deficient phosphonamidate that is thereby activated for the subsequent thiol addition. The described technique thereby extends the existing repertoire of bioconjugations by introducing a new concept in protein synthesis: A chemoselective reaction that induces reactivity for a subsequent bioconjugation. Since phosphonamidate conjugations to cysteine hold outstanding features such as high selectivity for cysteine, clean reaction products and excellent stability of the protein adducts in biological environments, it is described in the second part of the present work how ethynylphosphonamidates can be employed for the conjunction of tumor-sensing antibodies and cytotoxic drugs to generate Antibody-Drug-Conjugates (ADCs). A simple synthetic protocol starting from unengineered antibodies, using only a slight excess of the desired drug in a one-pot synthesis protocol is introduced. In a direct comparison to the maleimide containing FDA-approved Adcetris, phosphonamidate linked ADCs show a superior behaviour in terms of linkage stability in serum, combined with an increased in vivo efficacy in a tumor xenograft mouse model. Taken together, the method described herein combines simple synthetic access with high selectivity, superior conjugate stability and the possibility to synthesize highly efficacious drug conjugates and is therefore likely to have a great contribution to the field of targeted therapeutics.

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48

Yang, Xin. "Evaluation of neurochemical and functional effects of glial cell-derived neurotrophic factor gene delivery using a tetracycline-regulatable adeno-associated viral vector." Doctoral thesis, Universite Libre de Bruxelles, 2011. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209984.

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Gene transfer to the brain is a promising therapeutic strategy for a variety of neurodegenerative disorders including Parkinson‟s disease (PD). PD is the second most common neurodegenerative disease. Although many drugs have been developed and introduced into the market to provide symptomatic treatment, there is still no cure for PD. Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for injured nigrostriatal dopamine neurons and is currently being evaluated as a potential treatment for PD. Gene therapy allows localized, long-term and stable transgene expression after a single intervention to obtain a therapeutic effect. Regulatable promoters for transgene expression furthermore allow optimizing GDNF concentration to avoid undesirable biological activity and clinical side effects. In the first part of the study, an autoregulatory tetracycline-inducible recombinant adeno-associated viral vector (rAAV-pTetbidiON) utilizing the rtTAM2 reverse tetracycline transactivator (rAAV-rtTAM2) was used to conditionally express the human GDNF cDNA. Eight weeks after a single intrastriatal injection of the rAAV-rtTAM2-GDNF vector encapsidated into AAV serotype 1 capsids (rAAV2/1), the GDNF protein level was respectively 15 fold higherand undistinguishable from the endogenous level in doxycycline(Dox) treated and untreated animals. However, a residual GDNF expression in the uninduced animals was evidenced by a sensitive immunohistochemical staining. As compared to rAAV2/1-rtTAM2-GDNF, the rAAV2/1-rtTAM2-WPRE-GDNF vector harboring a woodchuck hepatitis post-transcriptional regulatory element, which increases and stabilizes the transgene transcript, expressed a similar concentration of GDNF in the induced state but a basal level ~2.5-fold higher than the endogenous striatal level. However, the distribution of GDNF in the striatum in induced state was more widespread using the rAAV2/1-rtTAM2-WPRE-GDNF vector as compared to rAAV2/1-rtTAM2- GDNF. As a proof for biological activity, for both vectors, downregulation of tyrosine hydroxylase (TH) was evidenced in dopaminergic terminals of Dox-treated but not untreated animals. In the second part of my study, functional (behavioural) and neurochemical changes mediated by delayed intrastriatal GDNF gene delivery in the partial Parkinson‟s disease rat model were investigated. The rAAV2/1-rtTAM2-WPRE-GDNF vector (3.5 108 viral genomes) was administered unilaterally in the rat striatum 5 weeks after intrastriatal injection of 6-hydroxydopamine (6-OHDA) which produces a partial and progressive lesion of the nigro-striatal dopaminergic pathway. Rats were treated with Dox or untreated from the day of vector injection until sacrifice at 4 or 14 weeks (continuous treatment). A sub-group was Dox-treated for 7 weeks (temporary treatment) then untreated until 14 weeks. In the absence of Dox, the GDNF tissue concentration was found to be equivalent to the endogenous level in 6-OHDA-lesioned rats. In the presence of Dox, it was ~10-fold higher. Dox-dependent behavioral improvements were demonstrated 4 weeks post-vector injection. At later time points, spontaneous partial recovery was observed in all rats, but no further improvement was found in Dox-treated animals. Moreover GDNF gene delivery only transiently improved dopaminergic function. Over the long term, TH was more abundant, but not functional, and the increase was lost when GDNF gene expression was switched off. The third part of my study consisted in the evaluation of the respective dose-range of therapeutical and undesirable effects of GDNF. Functional effects appeared after delivery of 3.5 108 viral particles which produced 200-300 pg/mg protein of GDNF in the lesioned rat striatum (see above). In order to evaluate the viral dose producing undesirable effects, we compared two different doses of vector: 3.5x108 and 4.4x109 viral genome. In the low dose group, the GDNF concentration in the striatum was ~300 pg/mg protein in the Dox-treated animals and equivalent to the endogenous level in untreated animals (~20 pg/mg protein). In contrast, in the high dose group, GDNF levels reached ~1200 pg/mg protein in induced animals but up to ~300 pg/mg protein in uniduced animals. In the low dose group, Dox-dependent downregulation of TH but no asymetrical behaviour was evidenced. In the high dose group, TH downregulation was observed in both Dox+ and Dox-rats. In addition, amphetamine-induced rotational behaviour was evidenced in Dox+ but not in Dox-rats. These data suggest that low doses of virus are sufficient to induce therapeutically-relevant but not undesirable functional effects of GDNF. Nevertheless,a neurochemical effect of GDNF (TH down-regulation) did appear at low dose. In order to understand the GDNF-induced motor asymmetry, we investigated the anatomical pattern of TH down regulation in striatum. Strikingly, there was a greater loss of TH labeling in striosomes than in the surrounding matrix. Receptors which are known to be differentially expressed in the striosomes i.e. µ-opioid receptor(MOR-1) and N-methyl-D-aspartic acid (NMDA) receptor 1 (NR1) as compared to the matrix were analyzed in the high-dose group of animals. MOR-1 was not affected by GDNF gene delivery. In contrast, NR1 was down regulated. The potential relationship between TH and NR1 down-regulation as well as other previously described neurochemical effects of GDNF (as enhancement of DA release and metabolism, of DA neurons excitability or of TH phosphorylation) and behavioural asymmetry remains to be clarified. As summary, our data suggest that behavioural and neurochemical effects of striatal delivery of GDNF can be controlled by Dox by using the autoregulatory rAAV2/1-TetON- GDNF vector, provided the dose range of gene delivery is carefully adjusted.
Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished

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49

Diarrassouba, Fatoumata. "Interactions between ß-lactoglobulin and nutraceutical ligands riboflavin, vitamin D3 and lysozyme Formation, physico-chemical and biological characterization of functional delivery scaffolds." Thesis, Université Laval, 2013. http://www.theses.ulaval.ca/2013/30500/30500.pdf.

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Анотація:

La protéine majeure du lactosérum, la β-lactoglobuline (βlg) est bien reconnue pour ses propriétés structurales intéressantes lui permettant d’établir des interactions avec des ligands de taille et de caractéristiques différentes. La riboflavine (RF) et la vitamine D3 (D3) ont été sélectionnées comme modèles de petits nutraceutiques amphiphiles et hydrophobes, respectivement, et le lysozyme (Lyso), comme ligand protéique de plus grande taille. La capacité de la βlg à lier la RF a été étudiée par des méthodes spectroscopiques. La βlg et la RF forment le complexe βlg-RF dont la photoactivation génère une activité antiproliférative contre les cellules cancéreuses de la peau, démontrée en utilisant le protocole du NCI/NIH Developmental Therapeutics Program. La cytotoxicité serait probablement due à la génération d’espèces oxydatives réactives résultant de l’interaction entre la RF et la βlg. L’impact de la formation du βlg-D3 sur la solubilité et stabilité de la D3 a été étudié en utilisant des méthodes spectroscopiques et de chromatographie. Les résultats ont démontré que le complexe βlg-D3 était stable aux pHs gastrique et intestinal et augmentait la solubilité de la D3. De plus, une matrice protéique appelée coagulum enrichie en D3 (94.5 ± 1.8 % de taux d’encapsulation) été formée à partir du complexe βlg-D3 grâce à l’aptitude de la βlg à s’auto-associer. Les images de microscopie électronique ont montré que les interactions électrostatiques entre la βlg et Lyso ont pour leur part, abouti à la formation de microsphères pouvant encapsuler la D3 à un taux élevé (90.8 ± 4.8 %). La capacité des matrices à base de βlg à transporter, protéger et à améliorer la solubilité, la stabilité et la biodisponibilité de la D3 a été évaluée en effectuant des expériences in vitro et in vivo chez des modèles animaux. Les matrices protéiques à base de βlg ont significativement augmenté la solubilité, stabilité et biodisponibilité de la D3 (p < 0.001). Ces études prouvent que la βlg, grâce à ses caractéristiques suturales, pourrait former des matrices protéiques compatibles avec une administration orale et les aliments, tout en préservant l’activité biologique de la RF, de la D3 et donc possiblement d’autres molécules bioactives
The major whey protein, β-lactoglobulin (βlg) is well recognized for its interesting structural properties and ability to interact with ligands with varying size and characteristics. Riboflavin (RF) and vitamin D3 (D3) were selected as small amphiphilic and hydrophobic nutraceutical models, respectively, and Lysozyme, as a larger size ligand model. Spectroscopic methods were used to demonstrate interaction between βlg and RF. βlg and RF form a complex, which was irradiated according to the NCI/NIH Developmental Therapeutics Program. The βlg-RF complex exhibited an important anti-proliferative activity against skin melanoma cancer cell lines, probably due to the generation of reactive oxygen species as the result of the interaction between RF and βlg. The impact of the βlg-D3 complex on the solubility and stability of the D3 was studied using spectroscopic methods and chromatography. The findings indicate that the βlg-D3 complex is stable at the gastric and intestinal pHs and increases the solubility of the vitamin. A βlg-based scaffold, named coagulum, enriched with D3 (94.5 ± 1.8 % of encapsulation efficiency) was prepared by using the capacity of βlg to self-aggregate. Electronic microscopy images showed that microspheres, with high D3 encapsulation efficiency (90.8 ± 4.8 %), were formed as the result of electrostatic interactions between βlg and Lyso. The efficiency of βlg-based scaffolds to improve the solubility, stability and bioavailability of the D3 was evaluated by performing in vitro and in vivo experiments using animal model. The βlg-based scaffolds significantly increased the solubility, stability bioavailability of D3 (p < 0.001). Overall, the present study showed that βlg, due to its structural properties, can be used to form protein-based matrices compatible with a food and an oral administration while preserving the biological activity of RF, D3 and possibly other bioactive molecules.

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50

Diarrassouba, Fatoumata. "Interactions between ß-lactoglobulin and nutraceutical ligands riboflavin, vitamin D₃ and lysozyme : formation, physico-chemical and biological characterization of functional delivery scaffolds." Doctoral thesis, Université Laval, 2013. http://hdl.handle.net/20.500.11794/22672.

Повний текст джерела

Анотація:

La protéine majeure du lactosérum, la β-lactoglobuline (βlg) est bien reconnue pour ses propriétés structurales intéressantes lui permettant d’établir des interactions avec des ligands de taille et de caractéristiques différentes. La riboflavine (RF) et la vitamine D3 (D3) ont été sélectionnées comme modèles de petits nutraceutiques amphiphiles et hydrophobes, respectivement, et le lysozyme (Lyso), comme ligand protéique de plus grande taille. La capacité de la βlg à lier la RF a été étudiée par des méthodes spectroscopiques. La βlg et la RF forment le complexe βlg-RF dont la photoactivation génère une activité antiproliférative contre les cellules cancéreuses de la peau, démontrée en utilisant le protocole du NCI/NIH Developmental Therapeutics Program. La cytotoxicité serait probablement due à la génération d’espèces oxydatives réactives résultant de l’interaction entre la RF et la βlg. L’impact de la formation du βlg-D3 sur la solubilité et stabilité de la D3 a été étudié en utilisant des méthodes spectroscopiques et de chromatographie. Les résultats ont démontré que le complexe βlg-D3 était stable aux pHs gastrique et intestinal et augmentait la solubilité de la D3. De plus, une matrice protéique appelée coagulum enrichie en D3 (94.5 ± 1.8 % de taux d’encapsulation) été formée à partir du complexe βlg-D3 grâce à l’aptitude de la βlg à s’auto-associer. Les images de microscopie électronique ont montré que les interactions électrostatiques entre la βlg et Lyso ont pour leur part, abouti à la formation de microsphères pouvant encapsuler la D3 à un taux élevé (90.8 ± 4.8 %). La capacité des matrices à base de βlg à transporter, protéger et à améliorer la solubilité, la stabilité et la biodisponibilité de la D3 a été évaluée en effectuant des expériences in vitro et in vivo chez des modèles animaux. Les matrices protéiques à base de βlg ont significativement augmenté la solubilité, stabilité et biodisponibilité de la D3 (p < 0.001). Ces études prouvent que la βlg, grâce à ses caractéristiques suturales, pourrait former des matrices protéiques compatibles avec une administration orale et les aliments, tout en préservant l’activité biologique de la RF, de la D3 et donc possiblement d’autres molécules bioactives
The major whey protein, β-lactoglobulin (βlg) is well recognized for its interesting structural properties and ability to interact with ligands with varying size and characteristics. Riboflavin (RF) and vitamin D3 (D3) were selected as small amphiphilic and hydrophobic nutraceutical models, respectively, and Lysozyme, as a larger size ligand model. Spectroscopic methods were used to demonstrate interaction between βlg and RF. βlg and RF form a complex, which was irradiated according to the NCI/NIH Developmental Therapeutics Program. The βlg-RF complex exhibited an important anti-proliferative activity against skin melanoma cancer cell lines, probably due to the generation of reactive oxygen species as the result of the interaction between RF and βlg. The impact of the βlg-D3 complex on the solubility and stability of the D3 was studied using spectroscopic methods and chromatography. The findings indicate that the βlg-D3 complex is stable at the gastric and intestinal pHs and increases the solubility of the vitamin. A βlg-based scaffold, named coagulum, enriched with D3 (94.5 ± 1.8 % of encapsulation efficiency) was prepared by using the capacity of βlg to self-aggregate. Electronic microscopy images showed that microspheres, with high D3 encapsulation efficiency (90.8 ± 4.8 %), were formed as the result of electrostatic interactions between βlg and Lyso. The efficiency of βlg-based scaffolds to improve the solubility, stability and bioavailability of the D3 was evaluated by performing in vitro and in vivo experiments using animal model. The βlg-based scaffolds significantly increased the solubility, stability bioavailability of D3 (p < 0.001). Overall, the present study showed that βlg, due to its structural properties, can be used to form protein-based matrices compatible with a food and an oral administration while preserving the biological activity of RF, D3 and possibly other bioactive molecules.

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