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Nasal drug delivery of calcitonin with pheroid technology / Jeanéne Celesté KotzéKotzé, Jeanéne Celesté January 2005 (has links)
Advances in biotechnology and recombinant technologies have lead to the
production of several classes of new drugs such as peptide and protein drugs.
These compounds are mostly indicated for chronic use but their inherent
characteristics such as size, polarity and stability prevent them from
incorporation in novel dosage forms. The bioavailability of nearly all peptide
drugs is very low due to poor absorption from the administration site. Several
challenges confront the pharmaceutical scientist in developing effective and
innovative dosage forms for these classes of drugs. A lot of attention has
been given to the nasal route of drug administration for delivery of peptide
drugs. The availability of several promising classes of absorption enhancers
and new drug delivery technologies has also prompt scientists to develop new
delivery systems for nasal administration of peptide drugs.
It has been shown in recent years that N-trimethyl chitosan chloride (TMC), a
quaternary derivative of chitosan, is effective in enhancing the absorption of
several peptide drugs, both in the peroral route and in the nasal route of drug
administration. Early indications are that new drug delivery technologies such
as Pheroid technology will also be able to enhance peptide drug absorption in
the nasal route. The aim of this study was to evaluate and compare the
absorption enhancing abilities of TMC and Pheroid technology in the nasal
delivery of calcitonin, a peptide hormone with low bioavailability.
Pheroid vesicles and Pheroid microsponges were prepared and characterized
for their morphology and size distribution. Calcitonin was entrapped into these
vesicles and microsponges and TMC and TMO solutions (0.5 % w/v),
containing calcitonin, was also prepared. These formulations were
administered nasally to rats in a volume of 100 μl/kg body-weight to obtain a
final concentration of 10 IU/kg body-weight of calcitonin. Plasma calcitonin
and calcium levels were determined over a period of 3 hours.
The results of this study clearly indicated that both Pheroid formulations and
the TMC formulation increase the nasal absorption of calcitonin with a
resulting decrease in plasma calcium levels, indicating an increased
absorption of calcitonin. The highest increase in calcitonin absorption was
obtained with the TMC formulation and this was explained by the difference in
the mechanism of action in enhancing peptide absorption between TMC and
Pheroid technology. It was concluded that Pheroid technology is also a potent
system to enhance peptide drug delivery and that the exact mechanism of
action should be investigated further. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2006.
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Nasal delivery of recombinant human growth hormone with pheroid technology / Dewald SteynSteyn, Johan Dewald January 2006 (has links)
Over the past couple of years there has been rapid progress in the development and design of
safe and effective delivery systems for the administration of protein and peptide drugs. The
effective delivery of these type of drugs are not always as simple as one may think, due to
various inherent characteristics of these compounds.
Due to the hydrophilic nature and molecular size of peptide and protein drugs, such as
recombinant human growth hormone, they are poorly absorbed across mucosal epithelia,
both transcellularly and paracellularly. This problem can be overcome by the inclusion of
absorption enhancers in peptide and protein drug formulations but this is not necessarily the
best method to follow.
This investigation focussed specifically on the evaluation of the ability of the PheroidTM
carrier system to transport recombinant human growth hormone across mucosal epithelia
especially when administered via the nasal cavity. The PheroidTM delivery system is a
patented system consisting of a unique submicron emulsion type formulation. The PheroidTM
delivery system, based on PheroidTM technology, will for ease of reading be called Pheroid(s)
only throughout the rest of this dissertation.
The Pheroid carrier system is a unique microcolloidal drug delivery system. A Pheroid is a
stable structure within a novel therapeutic system which can be manipulated in terms of
morphology, structure, size and function. Pheroids consist mainly of plant and essential fatty
acids and can entrap, transport and deliver pharmacologically active compounds and other
useful substances to the desired site of action.
The specific objectives of this study can be summarised as follows:
a literature study on Pheroid technology;
a literature study on chitosan and N-trimethyl chitosan chloride;
a literature study on recombinant human growth hormone (somatropin);
a literature study on nasal drug administration;
formulation of a suitable Pheroid carrier;
entrapment of somatropin in the Pheroid carrier, and
in vivo evaluation of nasal absorption of somatropin in Sprague-Dawley rats. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.
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Intracellular vesicles induced by monotopic membrane protein in Escherichia coliEriksson, Hanna M. January 2009 (has links)
The monotopic membrane protein alMGS, a glycosyltransferase catalyzing glucolipid synthesis in Acholeplasma laidlawii, was overexpressed in Escherichia coli. Optimization of basic growth parameters was performed, and a novel method for detergent and buffer screening using a small size-exclusion chromatography was developed. This resulted in a tremendous increase in protein yields, as well as the unexpected discovery that the protein induces intracellular vesicle formation in E. coli. This was confirmed by sucrose density separation and Cryo-TEM of membranes, and the properties of the vesicles were analyzed using SDS-PAGE, western blot and lipid composition analysis. It is concluded that both alMGS and alDGS, the next enzyme in glucolipid pathway, have the ability to make the membrane bend and eventually form vesicles. This is likely due to structural and electrostatic properties, such as the way the proteins penetrate the membrane interface and thereby expand one monolayer. The highly positively charged binding surfaces of the glycosyltransferases may bind negatively charged lipids, such as Phosphatidylglycerol (PG), in the membrane and withdraw it from the general pool of lipids. This would increase the overall lipid synthesis, since PG is a pace-keeper, and the local concentration of nonbilayer prone lipids, such as Phosphatidylethanolamine, can increase and also induce bending of the membrane. The formation of surplus membrane inside the E. coli cell was used to develop a generic method for overexpression of membrane proteins. A proof-of-principle experiment with a test set of twenty membrane proteins from E. coli resulted in elevated expression levels for about half of the set. Thus, we believe that this method will be a useful tool for overexpression of many membrane proteins. By engineering E. coli mutants with different lipid compositions, fine-tuning membrane properties for different proteins is also possible. / At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Manuscript.
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Sorting nexin 9 in clathrin-mediated endocytosis /Lundmark, Richard, January 2004 (has links)
Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 3 uppsatser.
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Exosomes in immune regulation and allergy /Admyre, Charlotte, January 2007 (has links)
Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.
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FRAP measurements of synaptic vesicle mobility in motor nerve terminals /Gaffield, Michael A. January 2007 (has links)
Thesis (Ph.D. in Neuroscience) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 84-93). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
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Characterization of the fusogenic properties of COPI vesicles a role for PI(4,5) P₂ /Laporte, Frédéric. January 1900 (has links)
Thesis (Ph.D.). / Written for the Dept. of Biochemistry. Title from title page of PDF (viewed 2009/06/09). Includes bibliographical references.
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The expression and role of Tmed2/TMED2 during the development of the murine embryo and placentaAchkar, Tala. January 1900 (has links)
Thesis (M.Sc.). / Written for the Dept. of Human Genetics. Title from title page of PDF (viewed 2009/06/18). Includes bibliographical references.
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Vésicules lipidiques biomimétiques décorées par un assemblage multicouche nanocristaux de cellulose/xyloglucane : élaboration et caractérisation mécanique / Biomimetitc lipidic vesicles coated with a cellulose nanocrystals/xyloglucan multilayer assembly : elaboration and mechanical characterizationRadavidson, Harisoa 15 December 2016 (has links)
Contrairement à leurs homologues animales, les cellules végétales sont entourées d’une fine enveloppe de polysaccharides appelée paroi primaire, dont la principale structure portante est un réseau de microfibrilles de cellulose reliées entre elles par des hémicelluloses. L’objectif de ce travail est de mettre au point des capsules biomimétiques de la paroi végétale qui puissent servir de système modèle dans l’étude des propriétés mécaniques de ce matériau naturel. Pour ce faire, des vésicules géantes unilamellaires d’un diamètre moyen de 20 µm ont été utilisées comme support de dépôts couche-par-couche de nanocristaux de cellulose (les sous-éléments des microfibrilles) et de xyloglucane (l’hémicellulose la plus répandue) jusqu’à une dizaine de bicouches, les capsules ainsi obtenues ayant été caractérisées par microscopie confocale. Leur comportement en déformation en réponse à une pression osmotique a pu être observé : leur dégonflement a donné lieu à l’apparition de diverses morphologies dont certaines sont similaires aux formes de coques minces de matériau isotrope dégonflées, tandis que leur comportement en gonflement est comparable à la réponse d’un matériau viscoélastique. Enfin, des expériences de nano-indentation par microscopie à force atomique ont été effectuées pour mesurer la rigidité de la paroi des capsules. Leur module d’Young a pu être déduit des courbes de force-déformation et s’avère être compris entre 6 et 18 MPa, ce qui est du même ordre de grandeur que les valeurs obtenues par des mesures similaires effectuées sur des parois végétales naturelles. / Unlike their animal counterparts, plant cells are surrounded by a thin polysaccharide-rich envelop called the primary wall, in which the main load-bearing structure is a network of cellulose microfibrils tethered by hemicellulose. This work aims at designing plant cell wall mimicking capsules that could be used as a model system in the mechanical characterization of this natural material. To do so, we used giant unilamellar vesicles with an average diameter of 20 µm as a template for the layer-by-layer deposition of cellulose nanocrystals (the microfibrils sub-elements) and xyloglucan (the most common hemicellulose) up to ten bilayers, the resulting capsules being characterized by confocal microscopy. Their deformation behaviour under osmotic stress could be observed : deflation of the capsules led to various morphologies, some of them similar to what is observed for thin deflated shells of isotropic material, while their response to swelling resembled that of a viscoelastic material. Nano-indentation experiments were eventually performed using an atomic force microscope to probe the stiffness of the capsules wall. Their Young’s modulus could be deduced from the force-depth curves and found to be in the 6-18 MPa range, which is in the same order of magnitude of values obtained with similar measurements done on natural plant cell walls.
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Activity-dependent bulk endocytosis : control by molecules and signalling cascadesNicholson-Fish, Jessica January 2017 (has links)
Synaptic vesicle (SV) recycling in the presynapse is essential for the maintenance of neurotransmission. During mild stimulation clathrin-mediated endocytosis (CME) dominates, however during intense stimulation activity-dependent bulk endocytosis (ADBE) is the dominant form of membrane retrieval. The aim of this thesis was to determine how the signalling molecule GSK3 controlled ADBE, with the hypothesis that this enzyme was required at multiple stages of this endocytosis mode. I also hoped to identify a specific cargo for ADBE. I found that during intense action potential stimulation, a localised calcium increase is necessary for the activation of Akt, which inhibited GSK3. This activation was mediated via a phosphatidylinositol 3-kinase (PI3K)-dependent mechanism. Furthermore, I found that phosphatidylinositol 4-kinaseIIα (PI4KIIα), a molecule whose abundance is regulated by GSK3, had a key role in ADBE. Specifically, I found that the absence of PI4KIIα accelerated CME but inhibited ADBE and that PI4KIIα controls CME and ADBE via distinct mechanisms. The PI4KIIα study revealed potential cross-talk between CME and ADBE. To determine whether modulation of either endocytosis mode impacts on the other, the retrieval of genetically-encoded reporters of SV cargo was monitored during intense stimulation during inhibition of either CME or ADBE. The recovery of almost all SV cargo was unaffected by ADBE inhibition but was arrested by abolishing CME. In contrast, VAMP4-pHluorin retrieval was perturbed by inhibiting ADBE and not by blocking CME. Knockdown of VAMP4 also arrested ADBE, indicating that in addition to being the first identified ADBE cargo, it is also essential for this endocytosis mode to proceed.
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