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Development of Multi‐purpose Lipid Coated PNIPAM Microgels and Techniques for Characterizing Lateral Diffusion in BilayersSaleem, Qasim 01 September 2014 (has links)
The pursuit of a greater understanding of the biological membrane has led to the development of a number of mimetics and probing techniques. This thesis contributes to both of these efforts.
Towards the development of mimetics, poly(N-isopropylacrylamide) (pNIPAM) microgels were explored as membrane supports. PNIPAM microgels are “smart” materials that experience a volume phase transition (VPT) at ~32°C, where they undergo a severe loss in volume. The core-shell microgels were synthesized with a low crosslinked pNIPAM core covered by a highly crosslinked pNIPAM shell that was functionalized with exploitable carboxylates.
It was shown that a lipid bilayer could be coated on these microgels using either liposomes or bicelles. Specifically, lipid bilayer enclosed microgels made with liposomes (“Lipogels”) were created by using hydrophobically modified microgels, which possessed the ability to sequester liposomes that could ultimately be fused into a continuous bilayer. It was also found that above the VPT temperature, surface decoupled lipid protrude into highly curved structures. Hence, the VPT property could be used to control the curvature of the Lipogel bilayer. These particles could be useful platforms for conducting biophysical membrane studies as well as drug delivery vehicles.
Bicelles were also explored as lipid sources for microgel coating, resulting in the creation of “Bicellogels”. Electrostatic attraction between cationic bicelles and unmodified anionic core-shell pNIPAM microgels resulted in the coating of the latter. Astonishingly, the resulting bilayer was made up of only the long chain bicellar lipid. Due to the simplicity of this method, it could be extended to easily coat all types of soft material.
The last development on the pNIPAM front involved the coupling of intact liposomes to microgels to create “VESCOgels”. These complexes offer two distinct cargo holds through which temporally distinct release can be achieved. Hence, they could be very useful for applications in tandem release.
Lastly, the 31P CODEX NMR technique was adapted to study the lateral diffusion of phospholipids in large liposomes. This technique allows for the measurement of lateral diffusion coefficients of multiple phospholipids simultaneously. This could prove useful for the study of such biologically relevant phenomena as domain formations and drug-lipid interactions.
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Lateral Diffusion of Phospholipids Measured using 31P Centreband-only Detection of Exchange Nuclear Magnetic ResonanceLai, Angel 20 November 2012 (has links)
Lateral diffusion of phospholipids is a process essential to membrane function, and can be measured by nuclear magnetic resonance (NMR). This project will use CODEX (Centerband-Only Detection of Exchange), the most highly-evolved NMR experiment combining magic angle spinning with exchange sensitivity, to measure lateral diffusion.
31P CODEX NMR measurements were performed on phospholipids in small unilamellar vesicles (SUV) in a high viscosity solution to slow the rotational tumbling of the SUV and minimize its influence on the CODEX decay. For SUV composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), alone or mixed with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) or cholesterol (CHOL), 31P CODEX spectra showed well-resolved resonances for POPC and POPG, with monoexponential decays for both, from which the correlation time for molecular motion could be extracted. The lateral diffusion coefficients were determined, and fell in the range of 1.0 - 3.3 x 10-12 m2s-1 at 10°C, which agree with established literature values for POPC and POPG.
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Lateral Diffusion of Phospholipids Measured using 31P Centreband-only Detection of Exchange Nuclear Magnetic ResonanceLai, Angel 20 November 2012 (has links)
Lateral diffusion of phospholipids is a process essential to membrane function, and can be measured by nuclear magnetic resonance (NMR). This project will use CODEX (Centerband-Only Detection of Exchange), the most highly-evolved NMR experiment combining magic angle spinning with exchange sensitivity, to measure lateral diffusion.
31P CODEX NMR measurements were performed on phospholipids in small unilamellar vesicles (SUV) in a high viscosity solution to slow the rotational tumbling of the SUV and minimize its influence on the CODEX decay. For SUV composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), alone or mixed with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) or cholesterol (CHOL), 31P CODEX spectra showed well-resolved resonances for POPC and POPG, with monoexponential decays for both, from which the correlation time for molecular motion could be extracted. The lateral diffusion coefficients were determined, and fell in the range of 1.0 - 3.3 x 10-12 m2s-1 at 10°C, which agree with established literature values for POPC and POPG.
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Computational nanoscience and molecular modelling of shock wave interactions with biological membranesSourmaidou, Damiani January 2011 (has links)
Lateral diffusion of membrane components (lipids and proteins) is an important membrane property to measure since the essential process of absorption of anti-cancer and other drugs -some of which are not soluble in lipids and therefore would not be able to penetrate the cell membrane through passive diffusion- lies on it. In particular, the procedure of diffusion into the cell cytoplasm is reliant on free volumes in the membrane (passive diffusion) as well as carrier proteins (facilitated diffusion). By enhancing the mobility of lipids and/or proteins, the possibility of the carrier protein to "encapsulate" pharmacological components maxim- izes, as a "scanning" of the proteins gets performed due to the fluid phase of a biological membrane. At the same time, the increased mobility of the lipids facilitates the passage of lipid-soluble molecules into the cell. Thus, given that the success of anticancer treatments heavily depends on their absorption by the cell, a significant enhancement of the cell mem- brane permeability (permeabilisation) is rendered vital to the applicability of the technique. For this reason, there is augmented interest in combined methods such as Nanotechnology based drug delivery that is focused on the development of optimally designed therapeutic agents along with the application of shock waves to enhance the membrane permeability to the agents. This study examines the impact of shock waves on a numerical model of a biological membrane. Cont/d.
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Computational nanoscience and molecular modelling of shock wave interactions with biological membranesSourmaidou, Damiani January 2011 (has links)
Lateral diffusion of membrane components (lipids and proteins) is an important membrane
property to measure since the essential process of absorption of anti-cancer and other drugs
-some of which are not soluble in lipids and therefore would not be able to penetrate the cell
membrane through passive diffusion- lies on it. In particular, the procedure of diffusion into
the cell cytoplasm is reliant on free volumes in the membrane (passive diffusion) as well as
carrier proteins (facilitated diffusion). By enhancing the mobility of lipids and/or proteins,
the possibility of the carrier protein to "encapsulate" pharmacological components maxim-
izes, as a "scanning" of the proteins gets performed due to the fluid phase of a biological
membrane. At the same time, the increased mobility of the lipids facilitates the passage of
lipid-soluble molecules into the cell. Thus, given that the success of anticancer treatments
heavily depends on their absorption by the cell, a significant enhancement of the cell mem-
brane permeability (permeabilisation) is rendered vital to the applicability of the technique.
For this reason, there is augmented interest in combined methods such as Nanotechnology
based drug delivery that is focused on the development of optimally designed therapeutic
agents along with the application of shock waves to enhance the membrane permeability
to the agents. This study examines the impact of shock waves on a numerical model of a
biological membrane. Cont/d.
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Improving the Mechanistic Understanding of Zinc Pyrithione Bioavailability in Skin through Lateral and Transverse Diffusion MeasurementsRush, Allison K. 11 September 2015 (has links)
No description available.
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The Preformulation and Formulation Development for Transungual Delivery of Antifungal Drug Ciclopirox olaminePalliyil, Biji January 2013 (has links)
Onychomycosis also known as dermatophytic onychomycosis is the fungal infection of the toenails and fingernails, characterized by discoloration and thickening of the nail and involves the nail plate, nail bed and nail folds. The disease is more than a cosmetic problem, as it severely impacts the patient's quality of life. Onychomycosis is an opportunistic infection in special subpopulations of patients suffering from diabetes, psoriasis, HIV/AIDS etc. The current treatment strategies involve systemic delivery of oral antifungal agents including azoles (e.g. itraconazole) and allylamines (e.g. terbinafine hydrochloride) which are delivered to the nail plate from the nail bed. More recently, topical delivery of drugs including amorolfine and bifonazole/urea (available outside the United States) and Penlac® nail lacquer (ciclopirox) topical solution, 8%, available in the US are an alternative treatment option to the oral antifungal agents. Topical delivery of antifungal agents through the human nail offer several advantages over oral therapy including lower incidence of adverse events and lower potential for drug-drug interaction with drugs used to treat diabetes, HIV/AIDS and psoriasis. The objectives of this project were to: 1) To determine the critical factors affecting the delivery of ciclopirox olamine across the human nail, 2) To screen and select penetration enhancer(s) specific for ciclopirox olamine delivery into the target tissue(s) and 3) To develop a novel transungual formulation containing ciclopirox olamine (CPO) and penetration enhancer(s) for transungual delivery. Ciclopirox olamine, the salt form of the free acid of ciclopirox was used in the study to develop a novel transungual patch formulation and skin and nail permeation from the patch formulation was compared to Penlac® nail lacquer. Various factors such as drug partitioning into the healthy and infected toenail, drug-keratin binding, lateral diffusion, drug-epidermal binding and the formulation components, all play a role in achieving optimum drug penetration and permeation through the nail. Understanding the interplay of these factors helped in the development of an effective topical formulation which was observed to be superior to Penlac® nail lacquer in the in vitro studies. Most cases of onychomycosis show infection and inflammation of the nail folds (skin surrounding the nails). Therefore for an efficient treatment of OM, the antifungal drugs must be delivered to two target tissues - human nail and the nail folds. The major challenges in developing a topical formulation for treatment on OM are: a) Achieving antifungal drug minimum inhibitory concentration (MIC) in the epidermis of the nail folds. b) Enhancing penetration and permeation of the antifungal drug across the human nail to reach the nail bed and achieve the necessary MIC (tissue underneath the nail). Twelve chemical penetration enhancers (PEs) were screened for their ability to enhance ciclopirox olamine accumulation into the nail folds and permeation through the nail. Propylene glycol (PG) enhanced the levels of the drug in the epidermis of the skin while limiting its permeation across the skin. Thiourea (TU) was selected as the best enhancer to increase ciclopirox olamine penetration into the nail. The diffusion of the antifungal drug across the human nail was studied in vitro using human cadaver toenails mounted in Franz diffusion cells. Pressure sensitive adhesives (PSA) belonging to the polyisobutylene, polysiloxane and polyacrylate classes of adhesives were screened to develop a monolithic drug-in-adhesive-type nail patch. The in vitro release of CPO from the PSA patches were limited and did not improve in presence of hydrophilic plasticizer (propylene glycol) and hydrophobic plasticizers (triacetin and triethyl citrate). Increasing the concentration of TU from 1 % to 10 %, lead to its crystallization in the dry patches. Therefore a change in the patch design was recommended. Other hydrophilic polymers including Polyoxyethylene (POLYOX®) and hydroxyl propyl methyl cellulose (HPMC) were also screened to develop a modified drug-in-hydrophilic matrix patch design. The patch was designed to incorporate CPO, PG and TU in the polymer matrix overlaid on a non-occlusive backing membrane cast with polyacrylate PSA. The HPMC films showed the best drug release profile with 80 % release in 2 to 4 hours using a USP apparatus 5. These patches were characterized for drug penetration into the skin and nail permeation. Penlac® nail lacquer was used as the comparator control product. The prototype HPMC K15M patch containing 10 %w/w each of the drug and TU and 150 % w/w of PG showed 2.8 fold increase in CPO accumulation in epidermis compared to Penlac® nail lacquer in 24 hours. The skin permeation was found to be similar to that of Penlac®. The HPMC K15M patch formulation showed 2.7 fold increase in CPO concentration within the nail and 4.2 fold increase in transungual flux compared to Penlac®. The patch delivered higher levels of ciclopirox olamine into the target tissues with a lower permeation lag-time. The novel nail patch delivery system had the following properties: a) Ease of application, b) Contact with the nail surface, c) Increased concentration of drug in dissolved form within the patch, d) Presence of enhancers. The novel nail patch formulation has shown increased efficiency in topical and transungual drug delivery for treatment of OM, when compared to the commercial formulation, Penlac® nail lacquer in the in vitro studies. The physical characterization of the patch using Scanning Electron Microscopy, Polarized Light Microscopy, Optical Light Microscopy, Differential Scanning Calorimetry, X-Ray Diffractometer and Fourier Transform Infrared Spectroscopy show that ciclopirox olamine exists at a sub-saturation level in a non-crystalline form in the patch without any significant drug-polymer interaction. In conclusion, all the objectives of the study were met by successfully selecting penetration enhancers for CPO delivery into the nail folds and across the nail plate, evaluating the interaction between CPO and target tissues, developing a transungual patch system and characterizing the novel transungual patch. / Pharmaceutical Sciences
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NMR diffusion studies on lyotropic liquid crystalline systemsOrädd, Greger January 1994 (has links)
The pulsed field gradient fourier transform nuclear magnetic resonance (PFG-FTNMR) method to measure translational diffusion coefficients in multicomponent systems has been applied to amphiphilic molecules forming liquid crystalline phases. By analyzing the concentration dependence of the diffusion coefficients of water and amphiphile in a micellar system of N,N-dimethyldodecy lamine oxide (DDAO) in water it was possible to conclude that the micelles formed were polydisperse in size and shape. It was also shown that solubilization of small amounts of hydrophobic molecules into the micelles induces spherical micelles of a narrow size distribution. From the magnitude of the lateral diffusion coefficient in the cubic phase of DDAO/water it was concluded that this phase is built up of bicontinous aggregates. The lipid lateral diffusion in the cubic phase of monooleoylglycerol (MO)/water has been measured. The decrease in the lateral diffusion of MO in this phase, when the water was replaced by glycerol, was ascribed to changes in viscosity in the polar region. Measurements by electron spin resonance and time-resolved fluorescence spectroscopy showed that changes in viscosity of the solvent also affected the motions in the hydrocarbon region. The diffusion coefficients of all three components in the cubic phase located in the lowwater region of the ternary system of diacylglycerol (DAG)/soybean phosphatidylcholine (SPC)/water have been determined. Conclusive evidence was provided for that this cubic phase is built up of reversed micelles containing mainly SPC in a continous matrix of mainly DAG. The effect on the phase properties of DDAO upon incorporation of the peptide gramicidin D has been investigated. It was shown that gramicidin D induces a lamellar phase at all water contents. The change in the order parameter profile of the C-2H bonds in perdeuterated DDAO upon incorporation of gramicidin D is compatible with theoretical calculations for proteins exhibiting a positive hydrophobic mismatch. A method for using the PFG FTNMR technique in measurements of the transmembrane exchange rate of small molecules in vesicular suspensions is discussed and some preliminary data is shown. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1994, härtill 4 uppsatser</p> / digitalisering@umu
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Mathematical Modeling of the Disposition of Binary Solutions of Topically Applied Agents in the Stratum Corneum and Underlying Skin LayersYu, Fang 05 October 2021 (has links)
No description available.
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Etude de la régulation glutamate dépendante de la mobilité des récepteurs AMPA et de son rôle physiologique / Study of the glutamate dependant regulation of AMPA receptor mobility and of its physiological roleConstals, Audrey 23 October 2013 (has links)
Les récepteurs AMPA (rAMPA) sont les récepteurs ionotropiques du glutamate responsables de la majeure partie des courants excitateurs rapides dans la transmission synaptique rapide. Lors de la libération de glutamate, le rAMPA passe par 3 états conformationnels majoritaires : pore fermé/agoniste non lié, pore ouvert/agoniste lié et pore fermé/agoniste lié. Le contrôle du nombre et de l’organisation dans la synapse des rAMPA, via une combinaison de diffusion latérale et d’endo/exocytose, est essentiel à la régulation de l’intensité de la transmission synaptique. Les interactions existant entre les protéines de la densité post-synaptique et les protéines partenaires des récepteurs régulent la diffusion des récepteurs, contrôlant leur nombre et leur organisation à la post-synapse. Mon travail de thèse a consisté à étudier l’impact de l’activation des rAMPA sur leur mobilité et leur organisation à la post-synapse. En effet, la fixation de glutamate sur les récepteurs ainsi que leur désensibilisation entraînent des modifications structurales majeures affectant leurs interactions avec les protéines d’échafaudage et les protéines accessoires. L’impact de telles modifications sur les propriétés de diffusion et sur l’organisation sub-synaptique de ces rAMPA était jusqu’à présent inconnu. Mes travaux démontrent une mobilisation des rAMPA synaptiques consécutivement à leur activation par le glutamate. A l’échelle moléculaire, je propose que le passage de l’état activé à l’état désensibilisé des rAMPA entraîne un changement d’affinité de ces derniers pour une de leur protéine partenaire : la Stargazin. Cette régulation glutamate dépendante de la diffusion des rAMPA participe au maintien de la fidélité de la transmission synaptique rapide. / AMPA receptors (AMPAR) are ionotropic glutamate receptors which are responsible for the vast majority of fast excitatory synaptic currents in fast transmission. Upon release of glutamate, AMPAR undergo three main conformational states: pore closed/agonist unbound, pore open/agonist bound and pore closed/agonist bound. Controlling the number of AMPAR and their organization in the synapse, through a combination of lateral diffusion and endo/exocytosis, is essential to regulate the intensity of synaptic transmission. The interactions between proteins of the post-synaptic density and accessory receptor proteins regulate the distribution of receptors, controlling their number and organization in the post-synapse. During my PhD, I studied the impact of AMPAR activation on their mobility and organization in the post-synapse. Indeed, the binding of glutamate to AMPAR and their following desensitization lead to major structural changes on the receptor which impacts on their interactions with scaffolding proteins and accessory proteins. The impact of such modifications on the lateral diffusion and sub-synaptic organization of AMPAR was not known yet. My findings show a mobilization of synaptic AMPAR following their activation by glutamate. At the molecular level, I suggest that the transition from the activated state to the desensitized state of AMPAR leads to a change in affinity of the receptor for their partner protein: Stargazin. This glutamate dependent regulation of AMPAR diffusion participates in maintaining the fidelity of fast synaptic transmission.
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