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1
Vellore, Janarthanan Mohanraj. "Formulation of chitosan-based nanoparticles for delivery of proteins and peptides." Thesis, Curtin University, 2003. http://hdl.handle.net/20.500.11937/1224.
Повний текст джерелаАнотація:
Delivery of complex molecules such as peptides, proteins, oligonucleotides and plasmids is an intensively studied subject, which has attracted considerable medical and pharmaceutical interest. Encapsulation of these molecules with biodegradable polymers represents one way of overcoming various problems associated with the conventional delivery of macromolecules, for example instability and short biological half-life. The use of carriers made of hydrophilic polysaccharides such as chitosan, has been pursued as a promising alternative for improving the transport of biologically active macromolecules across biological surfaces. The development of nanoparticles as a delivery system also has major advantages of achieving possible drug protection, controlled release and drug targeting by either a passive or an active means. The aim of this study was to develop a simple and effective method to formulate biodegradable nanoparticles for the delivery of a model protein-bovine serum albumin (BSA) and an angiogenesis inhibitor, arginine-rich hexapeptide (ARE peptide). Major factors which determine nanoparticle formation and loading of the protein and the peptide as well as the underlying mechanisms controlling their incorporation and release characteristics were investigated. The preparation technique, based on the complex coacervation process, is extremely mild and involves the mixture of two aqueous solutions (chitosan and dextran sulfate) at room temperature. The formation of nanoparticles is dependent on the concentrations of chitosan (CS) and dextran sulfate (DS); particles with size, of 257 to 494nm can be obtained with 0.1%w/v solutions of CS and DS. Zeta potential of nanoparicles can be modulated conveniently from -34.3mV to +52.7mV by varying the composition of the two ionic polymers.Both bovine BSA and the ARH peptide were successfully incorporated into CS-based nanoparticles, mainly via an electrostatic interaction, with entrapment efficiency up to 100% and 75.9% for the protein and peptide respectively. Incorporation of both the protein and peptide into nanoparticles resulted in an increase in size suggesting their close association with the nanoparticle matrix material. The difference in sign and magnitude of zeta potential of empty and macromolecules-loaded nanoparticles supports the hypothesis that protein and peptide association with nanoparticles can be modulated by their ionic interaction with the oppositely charged ionic polymer (DS) in the nanoparticles. The release of BSA from the nanoparticles was very slow in water compared to that in l0mM phosphate buffer pH 7.4; whereas, ARH peptide showed extremely low level of release in water at the low ratio of DS but at the high ratio of DS, its release was in biphasic fashion, with an initial burst effect followed by an almost constant but very slow release up to 7 days in both water and 1 OmM phosphate buffer (pH 7.4). It was found that, unlike ARH peptide, the percentage of BSA released was relatively slower for the nanoparticles with a high ratio of DS. It is speculated that this difference in the release behaviour of BSA and ARH peptide, could be due to the effect of molecular size of the compounds and their interaction with the polymer matrix of the nanoparticle. The results of this study suggest that these novel CS/DS nanoparticulate system, prepared by a very mild ionic crosslinking technique, have potential to be a suitable carrier for the entrapment and controlled release of peptides and proteins.
2
Abdulrazzaq, Fadi. "Aquasomes as a drug delivery system for proteins and peptides." Thesis, Aston University, 2016. http://publications.aston.ac.uk/30080/.
Повний текст джерелаАнотація:
Aquasomes are nanocarrier systems consist of three distinctive layers; an inner core, a polyhydroxy carbohydrate layer and an outer layer of an API (Kossovsky et al., 1991). Aquasomes have a unique structure and ability to carry active molecules through a non-covalent bounding and provide superior stability, especially for proteins and peptides (Masatoshi and Yongning, 1998; Kim and Kim, 2002; Khopade et al., 2002). Different core and coating materials were used to prepare aquasomes under different conditions to investigate the relationship between preparation conditions and loading efficiency. In terms of loading efficiency, hydroxyapatite aquasomes, with either lactose or trehalose as a coating material, had the highest BSA loading (40%-60%) when compared to DSPA aquasomes. While DCPA aquasomes, with either lactose or trehalose as a coating material, had the lowest BSA loading (8%-16%). To investigate the interaction of the three layers of aquasomes, Surface analysis, docking and MD simulations were performed. Surface analysis performed by Discovery Studio showed that HA and trehalose interact by hydrogen bonding with the later acting as a hydrogen acceptor, while BSA displayed almost complete SAS and that there are numerous targets for trehalose attachments (no specific active site). MD simulations of BSA performed by AMBER 12 showed a stable MD simulation of BSA for 5 ns. Total energy analysis of BSA on the two conditions performed (300K and 280K) support the experimental data of lower BSA loadings of aquasomes prepared at 400C compared to those manufactured at 250C (p < 0.05). This could be related to that BSA might have either started to denature/unfold or breaking up which eventually resulted in low BSA loadings obtained experimentally. The high loading efficiency highlights aquasomes as a promising carrier for the delivery of proteins and peptides. Following formulation Optimisation, two routes of delivery were investigated, pulmonary and oral routes. For pulmonary delivery of aquasomes, BSA-loaded aquasomes were successfully formulated as pMDI and DPI formulations. Both pMDI and DPI formulations were investigated to identify lung distribution of BSA-loaded aquasomes using NGI. In vitro release studies on the selected size fractions from NGI show a sustained release of BSA over a period of 6 hr. In order to complement the in vitro release data, cell culture studies were performed to demonstrate the controlled release effect of aquasomes with BEAS-2B cell lines. The release of salbutamol sulphate (model drug) from aquasomes post 2 hr started to slow gradually until it reached its highest difference at 6 hr (p<0.05) when compared to the control. For oral delivery of aquasomes, BSA-loaded aquasome tablets were successfully formulated with MCC as multifunctional excipient and talc as a lubricant. Various powder blends of varying aquasomes amounts (25, 37.5, 50, 62.5 and 75%) were prepared and compressed at increasing compression forces (0.5, 1, 2 and 3 tons). It was noticed that under high compression forces of 2 and 3 tons, BSA spreads out of BSA-loaded aquasomes as was presented with confocal microscopy images. Tablets compressed under 1 ton of compression force was therefore chosen for coating as it showed desirable tablet characteristics (hardness, disintegration etc.). Acrylic based coating was used to spray coat the tablets. The coated tablets were found to disintegrate in pH >5.5 and steadily release for 6 hr. Cell culture studies were conducted to demonstrate the controlled release effect of aquasomes using Caco-2 cell lines. The release of metronidazole (model drug) from aquasomes post 2 hr started to slow gradually until it reached its highest difference at 6 hr (p<0.05) when compared to the control.
3
Soane, Robert J. "Bioadhesive polymers as intranasal drug delivery systems for peptide and protein drugs." Thesis, University of Nottingham, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298078.
Повний текст джерела
4
Vellore, Janarthanan Mohanraj. "Formulation of chitosan-based nanoparticles for delivery of proteins and peptides." Curtin University of Technology, School of Pharmacy, 2003. http://espace.library.curtin.edu.au:80/R/?func=dbin-jump-full&object_id=14517.
Повний текст джерелаАнотація:
Delivery of complex molecules such as peptides, proteins, oligonucleotides and plasmids is an intensively studied subject, which has attracted considerable medical and pharmaceutical interest. Encapsulation of these molecules with biodegradable polymers represents one way of overcoming various problems associated with the conventional delivery of macromolecules, for example instability and short biological half-life. The use of carriers made of hydrophilic polysaccharides such as chitosan, has been pursued as a promising alternative for improving the transport of biologically active macromolecules across biological surfaces. The development of nanoparticles as a delivery system also has major advantages of achieving possible drug protection, controlled release and drug targeting by either a passive or an active means. The aim of this study was to develop a simple and effective method to formulate biodegradable nanoparticles for the delivery of a model protein-bovine serum albumin (BSA) and an angiogenesis inhibitor, arginine-rich hexapeptide (ARE peptide). Major factors which determine nanoparticle formation and loading of the protein and the peptide as well as the underlying mechanisms controlling their incorporation and release characteristics were investigated. The preparation technique, based on the complex coacervation process, is extremely mild and involves the mixture of two aqueous solutions (chitosan and dextran sulfate) at room temperature. The formation of nanoparticles is dependent on the concentrations of chitosan (CS) and dextran sulfate (DS); particles with size, of 257 to 494nm can be obtained with 0.1%w/v solutions of CS and DS. Zeta potential of nanoparicles can be modulated conveniently from -34.3mV to +52.7mV by varying the composition of the two ionic polymers.Both bovine BSA and the ARH peptide were successfully incorporated into CS-based nanoparticles, mainly via an electrostatic interaction, with entrapment efficiency up to 100% and 75.9% for the protein and peptide respectively. Incorporation of both the protein and peptide into nanoparticles resulted in an increase in size suggesting their close association with the nanoparticle matrix material. The difference in sign and magnitude of zeta potential of empty and macromolecules-loaded nanoparticles supports the hypothesis that protein and peptide association with nanoparticles can be modulated by their ionic interaction with the oppositely charged ionic polymer (DS) in the nanoparticles. The release of BSA from the nanoparticles was very slow in water compared to that in l0mM phosphate buffer pH 7.4; whereas, ARH peptide showed extremely low level of release in water at the low ratio of DS but at the high ratio of DS, its release was in biphasic fashion, with an initial burst effect followed by an almost constant but very slow release up to 7 days in both water and 1 OmM phosphate buffer (pH 7.4). It was found that, unlike ARH peptide, the percentage of BSA released was relatively slower for the nanoparticles with a high ratio of DS. It is speculated that this difference in the release behaviour of BSA and ARH peptide, could be due to the effect of molecular size of the compounds and their interaction with the polymer matrix of the nanoparticle. The results of this study suggest that these novel CS/DS nanoparticulate system, prepared by a very mild ionic crosslinking technique, have potential to be a suitable carrier for the entrapment and controlled release of peptides and proteins.
5
Capriotti, Lisa A. "Surface-induced peptide folding." Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 347 p, 2009. http://proquest.umi.com/pqdweb?did=1824967161&sid=6&Fmt=2&clientId=8331&RQT=309&VName=PQD.
Повний текст джерела
6
Ali, Stuart Alvaro. "Transferrin trojan horses : a novel approach for drug delivery?" Thesis, Brunel University, 1999. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285047.
Повний текст джерела
7
Lei, Xia. "Study of Zwitterionic Functionalized Materials for Drug Delivery and Protein Therapeutics." University of Akron / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=akron1555511296878391.
Повний текст джерела
8
Qian, Ziqing. "Developments and Applications of Cyclic Cell Penetrating Peptides." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1405340891.
Повний текст джерела
9
Mozaffari, Saghar. "Amphiphilic Cell-Penetrating Hybrid Cyclic-Linear Peptides as a Drug Delivery System." Chapman University Digital Commons, 2019. https://digitalcommons.chapman.edu/pharmaceutical_sciences_dissertations/2.
Повний текст джерелаАнотація:
A number of cyclic peptides containing a positively charged ring composed of arginine residues attached to hydrophobic tail made of tryptophan residues through a lysine linker namely [R5K]W5, [R6K]W5, [R5K]W6, [R7K]W5, [R5K]W7, [R6K]W6, and [R7K]W7 were synthesized and evaluated as molecular transporters. The peptides were evaluated for their ability to deliver, fluorescence-labeled cell-impermeable negatively charged phosphopeptide (F′-GpYEEI), and fluorescent labeled anti-HIV drugs (F′-FTC and F′-d4T). The results indicated that the presence of positively charged arginine residues on the ring and hydrophobic tryptophan residues in a sequential linear outside the ring was an optimal approach to improve the intracellular uptake of cargo molecules through non-covalent interactions. Some of these peptides were also evaluated for their efficiency for intracellular delivery of siRNA to triple-negative breast cancer cell lines in the presence and absence of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). [R6K]W6 and [R5K]W5 were found to be very efficient in the delivery of siRNA. Furthermore, co-formulation of peptides with lipid DOPE significantly enhanced the efficiency of siRNA delivery compared to peptide alone. Silencing of kinesin spindle protein (KSP) and Janus kinase 2 (JAK2) was evaluated in MDA-MB-231 cells in the presence of the peptides. The addition of DOPE significantly enhanced the silencing efficiency for all selected peptides.
A chemotherapeutic drug, doxorubicin (Dox) was covalently conjugated to the cyclic peptide [R5K]W7A and linear peptide R5KW7A, and the biological activity was evaluated in cell-based assays. Comparative antiproliferative assays between covalently conjugated peptide-Dox and the corresponding noncovalent physical mixtures of the peptides and Dox were performed. The conjugation of Dox with cyclic [R5K]W7A-Dox exhibited similar antiproliferative activity compared to Dox alone after 72 h incubation time in all cancer cell lines, such as leukemia, ovarian and gastric cancer cells. However, [R5K]W7A-Dox significantly reduced the cell cytotoxicity in normal cell lines such as normal heart muscle and normal kidney cells after 72 h when compared with Dox alone. These results revealed that this cyclic peptide prodrug can be used as a potential candidate for the treatment of cancer cells with reduced side effects against normal cells in the body.
10
Nadal, Bufi Ferran. "Peptide-based drugs to inhibit LDH5, a potential target for cancer therapy." Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/232526/1/Ferran_Nadal%20Bufi_Thesis.pdf.
Повний текст джерелаАнотація:
This thesis investigates novel strategies to target lactate dehydrogenase 5 (LDH5), a protein involved in cancer. After decades of research without success, this thesis reports the development of the first molecules able to inhibit the activity of LDH5 with an alternative mechanism of action: disrupting its structure. To do that, an emerging class of drugs called peptides are explored. The lead peptide of this work successfully kills breast cancer cells via LDH5 inhibition. The validation of this strategy is relevant because it can be applied to many other cancer targets that have been traditionally considered “undruggable”.
11
Albarran, Brian. "TAT-streptavidin : a novel drug delivery vector for the intracellular uptake of macromolecular cargo /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/8016.
Повний текст джерела
12
Barthold, Sarah [Verfasser], and Claus-Michael [Akademischer Betreuer] Lehr. "Nanotechnology enabled drug delivery of proteins and peptides to the lung / Sarah Barthold. Betreuer: Claus-Michael Lehr." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2016. http://d-nb.info/1104733315/34.
Повний текст джерела
13
Sen, Gulseren Petek. "Fabrication Of Poly (dl-lactic-co-glycolic Acid) Nanoparticles And Synthetic Peptide Drug Conjugate For Anti-cancer Drug Delivery." Master's thesis, METU, 2010. http://etd.lib.metu.edu.tr/upload/12611405/index.pdf.
Повний текст джерелаАнотація:
Cancer is a group of diseases in which normal cells are converted to cells capable of autonomous growth and invasion. In the chemotherapeutic control of cancer, drugs are usually given systemically so they reach toxic levels in healthy cells as well as cancer cells. This causes serious side effects. Another important problem with chemotherapy is resistance developed to cytotoxic drugs (multi drug resistance).
Doxorubicin (Dox) occupies a central position in the treatment of breast cancer. However doxorubicin induced cardiac toxicity is associated with a high incidence of morbidity and mortality. Resistance of malignant tumors to Dox is another important cause of treatment failure in patients with cancer.
One approach to overcome Dox-related toxicity is to use polymeric drug carriers, which direct the Dox away from heart tissue, and allow usage of lower dosages. In this present study two different anti-cancer drug delivery methods were evaluated. Dox was encapsulated in PLGA microparticles by single and double microemulsion solvent evaporation techniques. The highest entrapment of doxorubicin within PLGA microspheres obtained by optimization of process parameters. A sustained release of doxorubicin was obtained for 20 days.
Several protein transduction domains are known to have the ability to pass through biological membranes. One such peptide is HIV-1 TAT. In this study TAT was evaluated for its ability to carry Dox into Dox resistant MCF-7 tumor cells. Dox peptide conjugate was more potent than free drug. The concentration of drug in resistant cancer cells was increased indicating a partial reversal of drug resistance.
14
Alsoraj, Monerah. "siRNA depletion of endocytic proteins and pathways for analysing the cellular uptake of cell penetrating peptides as vectors for drug delivery." Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/54430/.
Повний текст джерелаАнотація:
Cell-penetrating peptides (CPPs) have the potential to deliver a host of macromolecular therapeutics into cells including peptides, proteins, and nucleotides. The mechanism by which they are internalised has been hotly-disputed but is important if improvements are to be made in their delivering capacities. Endocytosis is thought to be of significant importance but identifying the exact uptake mechanism has been difficult due predominantly to a lack of specific tools. Multiple pathways have been reported to contribute to uptake, including macropinocytosis and those regulated by clathrin and cavaeolin-1. The aim of this thesis was to utilise siRNA-depletion to develop cell models with defects in specific endocytic proteins and pathways that could then be utilised to study the uptake of drug delivery vectors such as CPPs. Targeted pathways were those regulated by clathrin heavy chain, dynamin-2, caveolin-1, flotillin-1 and P21-activated kinase (PAK-1). Significant variation between cell lines emerged in the expression of these proteins and the ease with which they could be depleted. Single siRNA sequences were, however, discovered that effectively depleted these proteins and using a variety of endocytic probes the effects of depletion could be determined. Eventually, model cell lines were generated that were measurably defective in at least one of the five different endocytic pathways and these were tested to determine routes utilised by two well characterised CPPs, HIV-Tat and octaarginine. Only cells depleted of pak-1 protein and thus macropinocytosis were defective in CPP uptake. Further analysis revealed defective actin organisation in these cells that could have caused the effects and support data presented here and elsewhere on actin disruption with cytochalasin D. With comparative studies using pharmacological inhibitors of endocytic pathways these methods provide new tools to study drug delivery systems as shown here for CPPs and also for polyplexes through a collaboration with the University of Ghent, Belgium.
15
Haraszti, Reka A. "Engineered Exosomes for Delivery of Therapeutic siRNAs to Neurons." eScholarship@UMMS, 2018. https://escholarship.umassmed.edu/gsbs_diss/971.
Повний текст джерелаАнотація:
Extracellular vesicles (EVs), exosomes and microvesicles, transfer endogenous RNAs between neurons over short and long distances. We have explored EVs for siRNA delivery to brain. (1) We optimized siRNA chemical modifications and siRNA conjugation to lipids for EV-mediated delivery. (2) We developed a GMP-compatible, scalable method to manufacture active EVs in bulk. (3) We characterized lipid and protein content of EVs in detail. (4) We established how protein and lipid composition relates to siRNA delivering activity of EVs, and we reverse engineered natural exosomes (small EVs) into artificial exosomes based on these data.
We established that cholesterol-conjugated siRNAs passively associate to EV membrane and can be productively delivered to target neurons. We extensively characterized this loading process and optimized exosome-to-siRNA ratios for loading. We found that chemical stabilization of 5'-phosphate with 5'-E-vinylphosphonate and chemical stabilization of all nucleotides with 2'-O-methyl and 2'-fluoro increases the accumulation of siRNA and the level of mRNA silencing in target cells. Therefore, we recommend using fully modified siRNAs for lipid-mediated loading to EVs. Later, we identified that α-tocopherol-succinate (vitamin E) conjugation to siRNA increases productive loading to exosomes compared to originally described cholesterol.
Low EV yield has been a rate-limiting factor in preclinical development of the EV technology. We developed a scalable EV manufacturing process based on three-dimensional, xenofree culture of mesenchymal stem cells and concentration of EVs from conditioned media using tangential flow filtration. This process yields exosomes more efficient at siRNA delivery than exosomes isolated via differential ultracentrifugation from two-dimensional cultures of the same cells.
In-depth characterization of EV content is required for quality control of EV preparations as well as understanding composition–activity relationship of EVs. We have generated mass-spectrometry data on more than 3000 proteins and more than 2000 lipid species detected in exosomes (small EVs) and microvesicles (large EVs) isolated from five different producer cells: two cell lines (U87 and Huh7) and three mesenchymal stem cell types (derived from bone marrow, adipose tissue and umbilical cord Wharton’s jelly). These data represent an indispensable resource for the community. Furthermore, relating composition change to activity change of EVs isolated from cells upon serum deprivation allowed us to identify essential components of siRNA-delivering exosomes. Based on these data we reverse engineered natural exosomes into artificial exosomes consisting of dioleoyl-phosphatidylcholine, cholesterol, dilysocardiolipin, Rab7, AHSG and Desmoplakin. These artificial exosomes reproduced efficient siRNA delivery of natural exosomes both in vitro and in vivo. Artificial exosomes may facilitate manufacturing, quality control and cargo loading challenge that currently impede the therapeutic EV field.
16
Squire, Marie A. "Protein-based drug delivery systems." Thesis, University of Canterbury. Chemistry, 2004. http://hdl.handle.net/10092/6518.
Повний текст джерелаАнотація:
The targeted delivery of drugs is one of the most actively pursued goals in anti-HIV and anti-cancer chemotherapy. This project takes a proof-of-concept approach to the development of protein-based drug delivery systems - delivery systems that would package, target, and deliver cytotoxins to diseased cells.
Primarily, this project explores the use of the potent anti-HN protein, cyanovirin-N (CV-N), to actively target and deliver cytotoxic natural products to HN-infected cells. This project also investigates the use of human serum albumin (HSA), a 66 kDa protein, as a macromolecular carrier to passively target and deliver cytotoxic natural products to cancerous cells.
To facilitate release of the toxin within infected cells, an enzymatically-cleavable tetra peptide was incorporated in the conjugates. Maleimido-activated tetra peptide toxin constructs were prepared in readiness for selective reaction with proteins carrying thiol functionalities. Release of the toxin, norhomohalichondrin B, was demonstrated in vitro.
Native CV -N conjugates were prepared by thiolation of the lysine ε-amino groups, and the subsequent reaction with maleimido-activated compounds. Reaction across all lysine residues was demonstrated. A singly-substituted tyrosinamide conjugate of CV-N was prepared. Two recombinantly produced mutant CV-N proteins allowed for the production of selectively modified, double- and single-norhomohalichondrin B conjugates of CV-N. The conjugates retained the anti-HN activity of the parent protein.
Homohalichondrin B, doxorubicin, and tyrosinamide conjugates of HSA were prepared. The syntheses exploited the availability of a free thiolmoiety at cysteine-34 of HSA, and the specific and selective reaction of this thiol with the maleimido-activated tetra peptide derivatives.
All toxin conjugates demonstrate excellent cell toxicity. Further research to investigate whether this is targeted toxicity is currently underway.
17
SOLLAMI, DELEKTA SZYMON. "Hexosomes as Drug Delivery Vehicles for Antimicrobial Peptides." Thesis, KTH, Skolan för kemivetenskap (CHE), 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-172360.
Повний текст джерелаАнотація:
This master thesis project was carried out at SP Technical Research Institute of Sweden within the FORMAMP project which goal is to increase the efficiency and stability of antimicrobial peptides (AMPs) by exploring and developing a number of innovative formulation strategies for the drug delivery of those systems. In view of the growing problem of bacterial resistance to traditional antibiotics, AMPs represent one of the most promising alternatives as therapeutics against infectious diseases: besides having a fast and non-specific mechanism of action, they are less prone to bacterial resistance. In this project, the goal was to develop an efficient method for the formulation of hexagonal lyotropic phase nanodispersions (called hexosomes) as drug delivery vehicles for the AP114, DPK-060 and LL-37 AMPs. Then, these formulations were characterized through size measurements, zeta potential measurements, SAXS, cryo-TEM and UPLC and their stability was assessed. Lastly, the interaction of these systems with model bacterial membranes was tested through QCM-D and ellipsometry. The relevant samples were found to have a hexagonal structure with the lattice parameter being larger when peptide was loaded. The systems were observed to be sufficiently stable and the peptide loading efficiency was found to be higher than 90% in most cases. The hexosomes loaded with LL-37 were observed to preserve the effectiveness of the peptide when interacting with the model membrane through QCM-D.
18
Easley, Christina A. "Electrically-assisted enhancement of transdermal drug delivery using magainin peptides." Thesis, Georgia Institute of Technology, 2002. http://hdl.handle.net/1853/21419.
Повний текст джерела
19
Mitra, Deboleena. "Light Mediated Drug Delivery Using Photocaged Molecules and Photoswitchable Peptides." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3618.
Повний текст джерелаАнотація:
There are many different types of targeted therapy for cancer treatment. The method of light mediated targeted therapy that we have developed uses photocaged molecules and photoswitchable peptides.
In photocaging, a biologically active molecule is made inactive by the attachment of a photocleavable blocking group. On exposure to UV radiation the photocleavable entity is removed and the biologically active molecule is released. Using this concept we have designed a prodrug that consists of a cell impermeable hydrophilic molecule attached to a photocaged doxorubicin. Upon irradiation with UV light the photosensitive group is removed and cytotoxic doxorubicin is released at the tumor site. This concept has been further modified by attaching receptor binding molecules to the photocaged entity to increase its specificity.
A peptide which consists of an azobenzene photoswitch has been used which, in the dark state is randomly coiled and cell impermeable but upon illumination becomes helical and cell permeable and can be used to deliver drugs into the cells. Upon illumination with UV light of suitable wavelength the azobenzene linker will change from a trans to a cis form and this will convert the randomly coiled cell impermeable peptide into an α helical permeable form. Thus a series of peptides have been designed with different arginine mutations which develop an arginine patch in the helical form. This arginine patch would help in cell permeability by interacting with cell surface glycans. The method could potentially be used to deliver drugs into cells in presence of light.
20
Mawad, Damia Graduate School of Biomedical Engineering Faculty of Engineering UNSW. "Development of Novel hydrogels for protein drug delivery." Awarded by:University of New South Wales. Graduate School of Biomedical Engineering, 2005. http://handle.unsw.edu.au/1959.4/25221.
Повний текст джерелаАнотація:
Introduction: Embolic agents are used to block blood flow of hypervascular tumours, ultimately resulting in target tissue necrosis. However, this therapy is limited by the formation of new blood vessels within the tumour, a process known as angiogenesis. Targeting angiogenesis led to the discovery of anti-angiogenic factors, large molecular weight proteins that can block the angiogenic process. The aim of this research is development of poly (vinyl alcohol) (PVA) aqueous solutions that cross-link in situ to form a hydrogel that functions as an embolic agent for delivery of macromolecular drugs. Methods: PVA (14 kDa, 83% hydrolysed), functionalised by 7 acrylamide groups per chain, was used to prepare 10, 15, and 20wt% non-degradable hydrogels, cured by UV or redox initiation. Structural properties were characterised and the release of FITCDextran (20kDa) was quantified. Degradable networks were then prepared by attaching to PVA (83% and 98 % hydrolysed) ester linkages with an acrylate end group. The effect on degradation profiles was assessed by varying parameters such as macromer concentration, cross-linking density, polymer backbone and curing method. To further enhance the technology, radiopaque degradable PVA was synthesised, and degradation profiles were determined. Cell growth inhibition of modified PVA and degradable products were also investigated. Results: Redox initiation resulted in non-degradable PVA networks of well-controlled structural properties. Increasing the solid content from 10 to 20wt% prolonged the release time from few hours to ~ 2 days but had no effect on the percent release, with only a maximum release of 65% achieved. Ester attachment to the PVA allowed flexibility in designing networks of variable swelling behaviors and degradation times allowing ease of tailoring for specific clinical requirements. Synthesis of radiopaque degradable PVA hydrogels was successful without affecting the polymer solubility in water or its ability to polymerize by redox. This suggested that this novel hydrogel is a potential liquid embolic with enhanced X-ray visibility. Degradable products had negligible cytotoxicity. Conclusion: Novel non-degradable and radiopaque degradable PVA hydrogels cured by redox initiation were developed in this research. The developed PVA hydrogels showed characteristics in vitro that are desirable for the in vivo application as release systems for anti-angiogenic factors.
21
Piradashvili, Keti [Verfasser]. "Biodegradable protein nanocarriers for drug delivery / Keti Piradashvili." Mainz : Universitätsbibliothek Mainz, 2018. http://d-nb.info/1153025833/34.
Повний текст джерела
22
Pape, Valerie Elizabeth. "Methotrexate-protein conjugates as soluble drug delivery systems." Thesis, University of Bath, 1990. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.277877.
Повний текст джерела
23
Mäe, Maarja. "Rational modifications of cell-penetrating peptides for drug delivery : Applications in tumor targeting and oligonucleotide delivery." Doctoral thesis, Stockholms universitet, Institutionen för neurokemi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-8374.
Повний текст джерелаАнотація:
High molecular weight biomolecules are becoming important in the development of new therapeutics. However, their size and nature creates a major limitation for their application – poor penetration through biological membranes. A new class of peptides, cell-penetrating peptides (CPPs), has shown the capability to transport various macromolecules inside the cells. However, there are at least two limiting factors for successful application of CPPs: the lack of cell-type specificity and restricted bioavailability resulting from endocytic uptake of CPPs and entrapment in endosomal compartments. This thesis aims at designing delivery vehicles for therapeutic substances. In papers I-III, the CPPs have been rationally modified in order to achieve in vivo selectivity towards cancer cells. The first two papers employ tumor homing peptides as targeting moieties coupled to the N-termini of CPPs. In the third paper, a CPP is C-terminally prolonged with a matrix metalloproteinase 2 (MMP-2) specific cleavage site followed by an inactivating amino acid sequence. In tissues overexpressing MMP-2, i. e. in proximity to cancer, the CPP is activated after proteolytic removal of the inactivating sequence, thus the cargo can be transported inside the cells. In paper IV, several CPPs have been N-terminally modified with a stearyl moiety and applied for the delivery of splice-correcting oligonucleotides. We show that stearyl-TP10 is as effective in oligonucleotide delivery as Lipofectamine™ 2000. Moreover, stearyl-TP10 has preserved efficacy in serum and is not toxic to cells. In conclusion, the rational modifications of CPPs greatly potentiate their application in cargo delivery both in vitro and in vivo.
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Lee, Parker Walter. "Melt Processed Polymer/Protein Materials for Sustained Drug Delivery." Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1508886279190443.
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St, Pierre Christine A. "Endocytosis, Phagocytosis, and Innate Immune Responses: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/488.
Повний текст джерелаАнотація:
In this dissertation, the roles of endocytosis and phagocytosis pathways in a variety of clinically relevant scenarios were examined. These scenarios include antibody-mediated internalization of cell surface proteins, titanium wear-particle uptake in failed joint replacements, and polymeric microparticle uptake and immune responses for drug delivery or adjuvant use.
The use of antibodies specific for cell surface proteins has become a popular method to deliver therapeutics to target cells. As such, it is imperative to fully understand the ability of antibodies to mediate internalization and endosomal trafficking of the surface protein that it recognizes, so that drug delivery can be optimized. By comparing the internalization and endosomal localization of two different antibody-bound proteins, the transferrin receptor (TfR) and rabies G, we have found that there is a specific antibody-mediated internalization pathway that occurs when an antibody binds to a cell surface protein. Interestingly, the internalization pathway induced by antibody binding is different than that seen with recycling receptor internalization after ligand binding. This may have broad implications for the future development of antibody-based therapeutics.
Joint replacement failure is a major clinical problem. Studies have indicated that a large amount of metal and polyethylene wear debris is found in the synovial membrane and tissue surrounding failed replacements. Through examination of the immune response following uptake of titanium particles, our results suggest that titanium wear-particle induced inflammation and subsequent joint replacement failure may be due to activation of the NLRP3 inflammasome, leading to increased IL-1ß secretion and IL-1 associated signaling. These findings introduce IL-1 as a target for potential therapeutics for patients exhibiting significant inflammation.
Polymeric microparticles have been widely used in a variety of therapeutic applications, including drug delivery and vaccine adjuvants. It is essential to understand the ability of such particles to either activate or inhibit an immune response following uptake. Through comparison of particles with varying surface morphology, we have determined that particles with regions of high surface curvature (budding) are more immunogenic than particles with low surface curvature (spherical). Budding particles were more rapidly phagocytosed and induced higher levels of the inflammasome-associated cytokine, IL-1ß, when exposed to mouse macrophages. Additionally, budding particles induced a more rapid neutrophil response in vivo, when compared to spherical particles. These findings have broad implications for the development of future targeting vehicles for delivery of vaccines, drugs, proteins, and siRNA therapeutics.
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Barman, Poulami. "The interaction of peptides with functionalized carbon nanotubes /." Online version of thesis, 2009. http://hdl.handle.net/1850/8688.
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Stulz, Anja [Verfasser], and Heiko [Akademischer Betreuer] Heerklotz. "Biophysical interactions of peptides and their analogues with lipid membranes: applications in drug development and drug delivery." Freiburg : Universität, 2019. http://d-nb.info/1211956326/34.
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Estey, Tia Brie. "Protein instability associated with PLGA delivery systems and UV-induced protein oxidation /." Connect to full text via ProQuest. IP filtered, 2006.
Знайти повний текст джерелаАнотація:
Thesis (Ph.D. in Pharmaceutical Sciences) -- University of Colorado, 2006.Typescript. Includes bibliographical references (leaves 144-161). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Fach, Lars Matthias [Verfasser]. "Protein-based nanoparticles for drug delivery applications / Lars Matthias Fach." Mainz : Universitätsbibliothek Mainz, 2018. http://d-nb.info/116056146X/34.
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Beier, Anne Mette. "Chitosan microparticles as a drug delivery system for protein vaccines /." [Cph.] : Pharmexa A/S : Department of Pharmaceutics, The Royal Danish School of Pharmacy, 2002. http://www.dfh.dk/phd/defences/annemettebeier.htm.
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Steiert, Elena [Verfasser]. "Dynamic Protein-based Nanoparticles for Drug Delivery Applications / Elena Steiert." Mainz : Universitätsbibliothek Mainz, 2020. http://d-nb.info/1205821899/34.
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Johansson, Henrik. "Cell-penetrating peptides in protein mimicry and oligonucleotide delivery : Applications and mechanisms." Doctoral thesis, Stockholm : Department of Neurochemistry, Stockholm University, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-7287.
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Chen, Kuangyu. "Intracellular Protein Delivery by Genetically Encoded and Structurally Constrained Cell-Penetrating Peptides." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555628591555136.
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Dogan, Alan B. "LEVERAGING THERMODYNAMIC INTERACTIONS TO ENHANCE DRUG DELIVERY." Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case161901882802915.
Повний текст джерела
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Cooke, Fiona Ghina Mary. "Can exosomes be used as drug delivery vesicles?" Thesis, University of St Andrews, 2018. http://hdl.handle.net/10023/13657.
Повний текст джерелаАнотація:
The inflammatory arthritis Ankylosing Spondylitis (AS) is linked to the human leucocyte antigen HLA-B27. HLA-B27 is thought to drive AS because it misfolds during assembly in the endoplasmic reticulum (ER), inducing ER cell stress. Modulating HLA-B27 folding in the ER is therefore a therapeutic target pathway. The recent discovery of polymorphisms in the ER-resident peptidase ERAP1 that can impact on HLA-B27 and AS, makes ERAP1 one such target. Exosomes are small, typically 50-200 nm sized particles, formed in the endosomal recycling pathway, which can be released into the extracellular environment. Exosomes have a wide range of biological activities depending on the cell type of origin, and on the delivered cargo, which can include bio-active proteins, lipids, mRNA and miRNA. There is interest in the use of exosomes as drug delivery agents. Here, exosomes were studied as a delivery agent to modulate ERAP1, as a potential therapeutic tool for the treatment of AS. Exosomes, isolated from cell lines including CEM and Jurkat (T cell lineage), Jesthom (B cell lineage), U937 (monocyte lineage) and the epithelial HeLa cell line, were characterized by nanoparticle tracking analysis, flow cytometry and immunoblotting using markers including CD9, CD63, CD81 and TSG101. Differential expression of these markers in the immune cell lines indicated the complexity of defining exosomes. EVs were then tested using cell penetrating peptides, electroporation, lipid transfection and sonication for their ability to load FITC-siRNA or FITC-antibody as cargo. Significantly, post-loading RNase A or trypsin incubation demonstrated that many techniques do not lead to efficient cargo loading of exosomes. Sonication proved the most effective technique, with up to 30% efficiency. Loading of exosomes with ERAP1-targetted siRNA did not however lead to notable ERAP1 inhibition. The data indicates that external loading of exosomes with cargo remains a significant challenge in developing exosomes as therapeutic tools.
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Silva, Nigenda Ezequiel. "Synthesis of drug delivery systems based on pantothenic acid and cationic amphiphilic peptides modifications." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8917/.
Повний текст джерелаАнотація:
The constant problems encountered in the fields of medicinal and pharmaceutical chemistry, especially those related to the side effects of drug candidates, have risen the concern of developing methods that can help us achieve the therapeutic effect without undesired properties. This thesis describes the development of two different Drug Delivery Systems based on the modification of natural occurring molecules. The first one is directed to the treatment of parasitic tropical diseases. The alteration of pantothenic acid with the introduction of a double bond has proved to increase the uptake of fluorescent labelled molecules in different model systems with low cytotoxicity. The concept of this Drug Delivery System relies on the necessity of the parasites to consume the host’s pantothenic acid for their own biological processes. Due to their inability to synthesise this vitamin along with the huge supply they need to survive, it was hypothesised that the increased uptake of CJ-15,801 would allow us to attach interesting molecules that could be selectively delivered into parasites. The second example of a Drug Delivery System presented in this work is based on peptides released by cells of the immune system. The so called Cationic Amphiphilic Peptides are released by an organism that is under the attack of potential pathogens. Due to their physicochemical properties, they can stop an infection by direct killing of microorganisms by different mechanisms. Either by the membrane disruption or internalisation and intracellular targeting, the presence of positively charged residues play a major role on the activity of these peptides. By substitution of the natural occurring lysine and arginine residues with a new class of phosphonium based amino acids, a new class of cationic amphiphilic peptides was synthesised. Fluorescent versions of these peptides have allowed us to investigate their properties. They are characterised by their ability to cross cellular membranes with relatively low toxicity compared to the natural occurring versions of the sequences and even though their direct antimicrobial activity is diminished they can be used as potential Cell Penetrating Peptides. Finally, due to the nature of the cation present in these new peptides, it is theorised that they can have certain selectivity to deliver drugs into mitochondria. Although further studies to prove this need to be done, an initial experiment is reported at the end of this work.
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Werner, Vera [Verfasser], and Lorenz [Gutachter] Meinel. "Pharmaceutically relevant protein-protein interactions for controlled drug delivery / Vera Werner. Gutachter: Lorenz Meinel." Würzburg : Universität Würzburg, 2015. http://d-nb.info/1111508895/34.
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Delfino, Davi Barbosa [UNESP]. "Sistemas drug delivery aplicados a novos inibidores de topoisomerases estruturalmente derivados de toxinas bacterianas." Universidade Estadual Paulista (UNESP), 2011. http://hdl.handle.net/11449/87961.
Повний текст джерелаАнотація:
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Este trabalho descreve a síntese de peptídeos em fase sólida (SPFS) derivados de toxinas bacterianas, tais como CcdB e ParE, e a produção de sistemas nanoestruturados como lipossomas e microemulsões. As toxinas intracelulares, produzidas por sistemas de morte pós-segregacional (PSK) em bactérias são exemplos recentes de agentes inibidores de enzimas fundamentais para a reprodução do microrganismo. Resultados promissores foram obtidos em relação a inibição da atividade da DNA girase, por derivados peptídicos destas duas proteínas. In vitro, os valores de concentração inibitória têm sido abaixo de 5 μmol.L-1, porém ensaios in vivo não demonstraram reprodutibilidade, basicamente devido à baixa permeabilidade da membrana bacteriana a estes derivados. Desta forma, foram produzidos lipossomas e microemulsões com o objetivo de promover o acesso de moléculas peptídicas sintéticas, derivadas do CcdB e ParE, ao meio intracelular e, conseqüentemente, aos seus alvos: DNA girase ou topoisomerase IV. Lipossomas do tipo SUV (small unilamellar vesicles) foram preparados por extrusão a partir de fosfatidilcolina de soja e estearilamina e mostraram uma eficiência de encapsulação de 77% e inibiram o crescimento tanto de bactéria Gram positiva quanto Gram negativa em 58 e 75%, respectivamente. Sistemas microemulsionados a base de fosfatidilcolina de soja, Tween 20, etanol e ácido oléico apresentaram uma incorporação do peptídeo acima de 90% e a formulação com 15% de ácido oléico e CcdBET2 a 4 μmol.L-1 apresentou uma inibição do crescimento de bactéria Gram negativa de 75,5%. O diâmetro dos lipossomas foi medido por espalhamento dinâmico de luz e as microemulsões foram caracterizadas por microscopia de luz polarizada e sua viscosidade determinada por reologia. Portanto, lipossomas e microemulsões podem ser utilizados como sistemas de drug delivery para análogos peptídicos derivados do CcdB e do ParE
This work describes the synthesis of peptides derived from bacterial toxins, such as CcdB and ParE, by solid phase peptide synthesis (SPPS) and the production of nanostructured systems such as liposomes and microemulsions. Intracellular toxins produced by systems of killer post-segregational (PSK) in bacteria are recent examples of inhibitors of key enzymes for the reproduction of the microorganism. Promising results were obtained for the inhibition of DNA gyrase activity by peptide derivatives of these proteins. In vitro, the IC100 values have been below 5 μmol.L-1, but not demonstrated in vivo reproducibility, mainly due to the low permeability of the bacterial cell to these derivatives. Thus, the aim with this work was develop of liposomes and microemulsions to promote access of synthetic peptide molecules derived from the CcdB and ParE, to the intracellular medium and consequently to their targets: DNA gyrase and topoisomerase IV. Liposomes SUV type (small unilamellar vesicles) were prepared by extrusion from soybean phosphatidylcholine and estearilamina and showed an encapsulation efficiency of 77% and inhibited the growth of both Gram positive and Gram negative in 58 and 75% respectively. Microemulsion systems based soybean phosphatidylcholine, Tween 20, ethanol and oleic acid showed an incorporation of the peptide above 90% and the specific formulation with 15% oleic acid and the 4 μmol.L-1 CcdBET2 incorporate showed a growth inhibition of Gram negative of 75.5%. The diameter of liposomes was measured by dynamic light scattering and microemulsions were characterized by polarized light microscopy and its viscosity determined by rheology. Therefore, liposomes and microemulsions may be used as drug delivery systems for peptide analogues derived from the CcdB and ParE
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Liang, Wanling, and 梁婉玲. "Formulation of nucleic acid with pH-responsive amphipathic peptides for pulmonary delivery." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/207996.
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Heffernan, Michael John. "Biodegradable polymeric delivery systems for protein subunit vaccines." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/24787.
Повний текст джерелаАнотація:
Thesis (Ph.D.)--Biomedical Engineering, Georgia Institute of Technology, 2008.Committee Chair: Dr. Niren Murthy; Committee Member: Dr. Carson Meredith; Committee Member: Dr. Julia Babensee; Committee Member: Dr. Mark Prausnitz; Committee Member: Dr. Ravi Bellamkonda.
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Marcello, Alessandro. "Escherichia coli heat-labile enterotoxin : a multipurpose delivery system for peptides and epitopes." Thesis, University of Kent, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387151.
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Wikman, Maria. "Rational and combinatorial protein engineering for vaccine delivery and drug targeting." Doctoral thesis, Stockholm : Department of Biotechnology, Royal Insitute of Technology, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-231.
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Badkas, Apurva H. "Modified Antibody for Targeted Drug Delivery and Reduced Immunogenicity." University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1407410100.
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Sharma, Divya. "Drug Delivery Systems for Treatment of Diabetes Mellitus." Diss., North Dakota State University, 2019. https://hdl.handle.net/10365/31745.
Повний текст джерелаАнотація:
Daily injections for basal insulin therapy are far from ideal resulting in hypo/hyperglycemic episodes associated with fatal complications in type-1 diabetes patients. The purpose of this study was to develop a thermosensitive copolymer-based in situ depot forming delivery system to provide controlled release of insulin for extended duration following a single subcutaneous injection, closely mimicking physiological basal insulin requirement. Size and nature of the incorporated therapeutic were observed to affect the release profile of insulin. Modification with zinc and chitosan preserved thermal, conformational, and chemical stability of insulin during the entire duration of storage (up to 9 months at 4 °C) and release (up to 3 months at 37 °C). In vivo, daily administration of long-acting insulin, glargine, resulted in fluctuating blood glucose levels between 91 – 443 mg/dL in type 1 diabetic rats. However, single administration of oleic acid-grafted-chitosan-zinc-insulin complexes incorporated in copolymer formulation demonstrated slow diffusion of insulin complexes maintaining peak-free basal insulin level of 21 mU/L for 91 days. Sustained release of basal insulin also correlated with efficient glycemic control (blood glucose <120 mg/dL), prevention of diabetic ketoacidosis and absence of cataract development, unlike other treatment groups. The suggested controlled basal insulin delivery system has the potential to significantly improve patient compliance by improving glycemic control and eliminating life-threatening diabetes complications.
Furthermore, oleic acid-grafted-chitosan (CO) nanomicelles were investigated as a non-viral vector to deliver plasmid DNA encoding short hairpin RNA (shRNA) against pro-inflammatory cytokines to adipose tissue macrophages and adipocytes for the treatment of insulin resistance. Nanomicelles modified using mannose (COM) and adipose homing peptide (AHP) (COA) showed significantly higher uptake and transfection efficiency in inflamed macrophages- adipocytes co culture owing to glucose transporter-1 and prohibitin receptor mediated internalization, respectively. Ligand modified nanomicelles loaded with shRNA against tumor necrosis factor alpha (COM-TNFα) and monocyte chemoattractant protein-1 (COA-MCP1) demonstrated significant attenuation of pro-inflammatory cytokines and improved insulin sensitivity and glucose tolerance in obese-diabetic mice for six weeks post treatment with single dose of optimized formulation. Overall, chitosan nanomicelles mediated targeted gene therapy can help attenuate inflammation, the chief underlying cause of insulin resistance, thereby helping reverse the progression of diabetes.National Institutes of Health (NIH) grant R15GM114701
ND EPSCoR seed award FAR0030636
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Tantipolphan, Ruedeeporn, and n/a. "Characterisation of protein-phospholipid interactions in implantable delivery systems." University of Otago. School of Pharmacy, 2007. http://adt.otago.ac.nz./public/adt-NZDU20071218.162425.
Повний текст джерелаАнотація:
Purpose: This thesis aimed to gain a better understanding of the effects of salts in modifying in vitro phase behaviour of lecithin and cholesterol solid implants and to obtain further information on in vitro protein release and stability.
Methods: Raman spectroscopy and partial least squares regression (PLSR) were used to investigate lecithin-cholesterol molecular interactions as a function of method of preparation. Lipid-salt interactions were studied by attenuated total reflectance Fourier transform infrared (ATR-FTIR) and Raman spectroscopy using principal component analysis (PCA). In vitro release of bovine serum albumin (BSA), a model protein, from lecithin and lecithin:cholesterol implants comprising 10 and 30% NaCl and CaCl₂ were performed. Size exclusion (SE) HPLC was used for quantitative and qualitative analysis of the released BSA. On hydration, changes in phase behaviour and implant morphology were studied by ATR spectroscopy and light microscopy. SE-HPLC, ATR and fluorescence spectroscopy were used to evaluate the structure of unreleased BSA. Protein adsorption on lipid films was studied by flow through ATR spectroscopy. Increased amide II peak area upon recirculation of BSA in salt solutions over hydrated lecithin and lecithin:cholesterol films cast on ZnSe prisms was used to quantify the deposition of BSA onto the lipid surfaces.
Results: Shifts in the Raman spectra suggested the lecithin headgroup may be involved in lecithin-cholesterol interactions. Greater R� and root mean square error of cross validation in the calibration curves of physical mixing and heating (120�C) methods reflected poor mixing in these preparations. The mean absolute residue and mean Mahalanobis distance values from the physical mixing and granulation methods indicated their spectral similarity and comparable level of lecithin-cholesterol interactions. Calcium exhibited stronger affinity for phospholipids than sodium and it induced headgroup hydration and reorganisation upon binding. PCA of ATR spectra was sensitive to cholesterol addition, calcium binding and method of preparation whilst PCA of Raman spectra only differentiated the presence of cholesterol. In vitro release of BSA from implants produced from wet granulation mixtures of lecithin and lecithin:cholesterol in the absence of salt showed retention of a high monomer content and the release profiles were similar to the literature. Cholesterol increased the swelling, induced phase transformation of lecithin and, subsequently, reduced the BSA release. Salts only slightly modified the BSA release from the lecithin implants. In contrast, for lecithin:cholesterol matrices salts greatly enhanced implant swelling, induced the formation of hydrated lecithin of heterogeneous size and inhibited the in vitro BSA release. Analyses of the protein showed increased aggregation of BSA with a high retention of native structure while retained within the swollen matrices. ATR spectra suggested that salts promoted protein adsorption onto hydrated lecithin surfaces and the effects depend on salt types (NaCl > CaCl₂) and concentration (0.1 M > 1.0 M) but not on lecithin:cholesterol surfaces.
Conclusion: PLSR and PCA can be used to investigate molecular interactions in the solid lipid matrices. In lecithin:cholesterol implants, salts modified the phase behaviour of lecithin which resulted in enhanced swelling, formation of hydrated lecithin of altered morphology and inhibition of in vitro BSA release.
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Delfino, Davi Barbosa. "Sistemas drug delivery aplicados a novos inibidores de topoisomerases estruturalmente derivados de toxinas bacterianas /." Araraquara [s.n.], 2011. http://hdl.handle.net/11449/87961.
Повний текст джерелаАнотація:
Orientador: Reinaldo MarchettoCoorientador: Saulo Santesso Garrido
Banca: Marlus Chorilli
Banca: Pietro Ciancaglini
Resumo: Este trabalho descreve a síntese de peptídeos em fase sólida (SPFS) derivados de toxinas bacterianas, tais como CcdB e ParE, e a produção de sistemas nanoestruturados como lipossomas e microemulsões. As toxinas intracelulares, produzidas por sistemas de morte pós-segregacional (PSK) em bactérias são exemplos recentes de agentes inibidores de enzimas fundamentais para a reprodução do microrganismo. Resultados promissores foram obtidos em relação a inibição da atividade da DNA girase, por derivados peptídicos destas duas proteínas. In vitro, os valores de concentração inibitória têm sido abaixo de 5 μmol.L-1, porém ensaios in vivo não demonstraram reprodutibilidade, basicamente devido à baixa permeabilidade da membrana bacteriana a estes derivados. Desta forma, foram produzidos lipossomas e microemulsões com o objetivo de promover o acesso de moléculas peptídicas sintéticas, derivadas do CcdB e ParE, ao meio intracelular e, conseqüentemente, aos seus alvos: DNA girase ou topoisomerase IV. Lipossomas do tipo SUV (small unilamellar vesicles) foram preparados por extrusão a partir de fosfatidilcolina de soja e estearilamina e mostraram uma eficiência de encapsulação de 77% e inibiram o crescimento tanto de bactéria Gram positiva quanto Gram negativa em 58 e 75%, respectivamente. Sistemas microemulsionados a base de fosfatidilcolina de soja, Tween 20, etanol e ácido oléico apresentaram uma incorporação do peptídeo acima de 90% e a formulação com 15% de ácido oléico e CcdBET2 a 4 μmol.L-1 apresentou uma inibição do crescimento de bactéria Gram negativa de 75,5%. O diâmetro dos lipossomas foi medido por espalhamento dinâmico de luz e as microemulsões foram caracterizadas por microscopia de luz polarizada e sua viscosidade determinada por reologia. Portanto, lipossomas e microemulsões podem ser utilizados como sistemas de drug delivery para análogos peptídicos derivados do CcdB e do ParE
Abstract: This work describes the synthesis of peptides derived from bacterial toxins, such as CcdB and ParE, by solid phase peptide synthesis (SPPS) and the production of nanostructured systems such as liposomes and microemulsions. Intracellular toxins produced by systems of killer post-segregational (PSK) in bacteria are recent examples of inhibitors of key enzymes for the reproduction of the microorganism. Promising results were obtained for the inhibition of DNA gyrase activity by peptide derivatives of these proteins. In vitro, the IC100 values have been below 5 μmol.L-1, but not demonstrated in vivo reproducibility, mainly due to the low permeability of the bacterial cell to these derivatives. Thus, the aim with this work was develop of liposomes and microemulsions to promote access of synthetic peptide molecules derived from the CcdB and ParE, to the intracellular medium and consequently to their targets: DNA gyrase and topoisomerase IV. Liposomes SUV type (small unilamellar vesicles) were prepared by extrusion from soybean phosphatidylcholine and estearilamina and showed an encapsulation efficiency of 77% and inhibited the growth of both Gram positive and Gram negative in 58 and 75% respectively. Microemulsion systems based soybean phosphatidylcholine, Tween 20, ethanol and oleic acid showed an incorporation of the peptide above 90% and the specific formulation with 15% oleic acid and the 4 μmol.L-1 CcdBET2 incorporate showed a growth inhibition of Gram negative of 75.5%. The diameter of liposomes was measured by dynamic light scattering and microemulsions were characterized by polarized light microscopy and its viscosity determined by rheology. Therefore, liposomes and microemulsions may be used as drug delivery systems for peptide analogues derived from the CcdB and ParE
Mestre
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Olof, Sandberg. "Construction and evaluation of plasma protein multilayers used for local drug delivery." Thesis, Linköping University, Department of Physics, Chemistry and Biology, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-56900.
Повний текст джерелаАнотація:
With the studies performed in this theses the local drug delivery technique FibMat developed by the biotech company AddBIO, was shown to be applicable to other plasma proteins and drugs than the fibrinogen-bisphosphonate combination that is today being commercialized. Hence the potential for a broader field of application was demonstrated. The application targeted today is as a surface modification giving improved strength to bone around screws used in bone implants. The effect of changing protein and manufacturing conditions was studied with null ellipsometry. It was demonstrated that with changes in incubation temperature, pH and salinity the fibrinogen could be successfully exchanged for the plasma proteins human serum albumin and immunoglobulin G. With liquid scintillation counting it was shown that the developed protein multilayers were able to absorb and release the bone strengthening drug alendronic acid in levels comparable to that of the fibrinogen based ditto. Disk susceptibility tests with the bacteria S. Aureus showed a potential for antibacterial functionalization with gentamicin. The release was, in the case of the fibrinogen multilayer, detectable up to 48 hours. Similar test revealed an inability of silver nanoparticle incorporated protein multilayers to achieve inhibitory levels.
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Madeira, do Ó. João. "Applications of glycopolymer libraries as protein aggregation modulators and drug delivery systems." Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/38014/.
Повний текст джерелаАнотація:
The biopharmaceutical market has been on the rise for the past two decades and is expected to continue to excel, currently presenting a growing rate of more than double than conventional pharma. Traditionally this growth has been hindered by multiple formulation issues such as poor bioavailability and poor stability. Consequently, the drive to optimise the stability of protein drug candidates via formulation impels the need for development of novel excipients. Novel glycopolymer excipients were reported to confer improved protein stability in selected cases. Nonetheless,their structure-function relationship and wider applicability remain largely unknown. Here we report the synthesis of glycopolymers with different molecular architectures based on mannose, galactose, arabinose, N-acetyl glucosamine, lactose and trehalose, and nvestigate their utility as excipients for the solution formulation of a monoclonal antibody (mAb). In this thesis work the physical stability of selected antibodies was measured as the unfolding transition temperature (Tm) and aggregation onset temperature (Tagg), as a function of glycopolymer properties, such as the nature of sugar repeating unit, macromolecular architecture and concentration. Results show that, in contrast to the stabilising effect of the corresponding mono- and di-saccharide constituents, both linear and 4-arm star glycopolymers generally destabilised the antibody, decreasing both Tm and Tagg. Accelerated stability studies of a concentrated mAb solution followed the same trend, where an increasing glycopolymer:mAb molar ratio generally decreased the percentage monomer(i.e. increased soluble aggregates). Importantly, trehalose-based glycopolymers further generated visible aggregates that could not be predicted from Tm or Tagg data. The data demonstrate a complex interplay of sugar chemistry and solution concentration of synthetic glycopolymers on their modulation of protein conformational stability and aggregation propensity. The mechanisms involved in protein:glycopolymer interaction, both in solution and dry state were further investigated, thus unravelling the behaviour reported in terms of protein stabilisation. Finally, the glycopolymers were studied as drug delivery systems, acting as solubility enhancers for hydrophobic species in aqueous solutions, through the use of extrinsic fluorescent dyes.
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Maddala, Sai P. "Synthesis of phosphonate functionalized silica nanoparticles for protein immobilization, intracellular protein delivery and catalytic applications." Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8961.
Повний текст джерелаАнотація:
Organosilica nanoparticles have attracted a lot of research interest in a variety of areas such as drug delivery and catalysis because of their properties which include high surface area as well as tunable particle and pore size. In particular, nanoparticles with large pore sizes are of great interest because of their potential to host large guest molecules such as proteins and as catalysts. The focus of the work in the thesis was to develop phosphonate functionalized organosilica nanoparticles for biomedical and catalytic applications. Raspberry textured phosphonatesilica nanoparticles denoted, RNPPME(2.5) (where the number in the brackets represents the moles of organophosphonate per gram), with large pore size (11–17 nm), uniform particle size (70 – 90 nm) and high surface area were produced through the use of template directed base catalysed synthesis, using tetraethylorthosilicate (TEOS) and dimethylphosphonatoethyltrimethoxysilane (DMPTMS) as the silica sources. The role of the reaction conditions such as temperature, surfactant concentration, pH, organosilane concentration and type were investigated and a mechanism for the raspberry nanoparticle formation was proposed. The particles were characterized using electron microscopy (SEM and TEM), Dynamic light scattering (DLS), silicon and phosphorus solid state NMR, and solution phase proton NMR of base digested particles, FT–IR, nitrogen adsorption porosimetry and thermal analysis (TGA). The ability of the particles to host protein molecules of the model protein, bovine serum albumin (BSA) was investigated and the particle–protein composite was characterized using circular dichroism (CD). Raspberry textured nanoparticles were found to host large quantities (26 wt%) of protein. Studies on other (small pore (3 nm) phosphonate functionalized nanoparticles NP_PME(0.2) and NP_PME(1.0)) and (3 nm pore) unfunctionalized mesoporous silica nanoparticles (MSN) revealed that phosphonate loading and the pore size influenced the protein uptake In addition to high protein uptake, the RNP_PME(2.5) particles also absorbed protein molecules rapidly (~ 20 minutes to maximum load). CD studies determined that the particle bound protein structure was not affected at physiological pH (7.40). The vast majority of the previously reported studies involving protein immobilization involved the use of bulk silica materials, which cannot be dispersed and hence those materials were unsuitable for in vivo protein delivery applications. The BSA@RNP_PME(2.5) particles showed good protein load and dispersion properties and hence are excellent protein delivery agents. Dispersions of nanoparticle composite BSA#@RNP*_PME(2.5) (where BSA# represents fluorescein isothiocyanate labelled BSA and RNP*_PME(2.5) represents rhodamine B isothiocyanate labelled RNP_PME(2.5)) was used to successfully deliver membrane impermeable protein BSA into HeLa cells. Intracellular protein delivery has attracted great interest due to its potential therapeutic applications and research tool value (e.g. for studying various cellular pathways). The toxicity of the guest free particles RNP*_PME(2.5) and the protein loaded particles BSA#@RNP*_PME(2.5) was studied using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The particles and the protein-particle composite were found to be non-toxic. The mechanism of the particle uptake by the cells was also studied. The unloaded (protein free) particles were found to be taken up by caveolar endocytosis pathway and the protein loaded particles were taken up by folic acid mediated pathway. The results indicated that the particles can successfully deliver membrane impermeable protein across the cell membrane. This result suggested that the particles can potentially be used for intracellular protein delivery applications. Raspberry textured nanoparticles RNP_PME(2.5) were also used to host the enzyme lipase. It was demonstrated that immobilization increased the maximum velocity and Michaelis constant of the enzyme and also that the particles offered protection against the denaturing agent, urea. Finally, in a chemical catalysis application, the RNP_PME(2.5) particles were used to synthesize the platform chemical HMF, through Brönsted acid catalysed dehydration of fructose. High yields of HMF (87 %) were achieved when 10 wt% fructose was used. The particles demonstrated good recyclability and also the ability to convert up to 50 wt% fructose into HMF (80 % yield). The particles therefore acted as protective agents for enzymes and can therefore be used as enzyme immobilizing agents. Additionally, they also acted as excellent Brönsted acid catalysts.
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Fernandez, Christian Antonio. "Development of PEGylated polyacridine peptides for in vivo gene delivery of plasmid DNA." Diss., University of Iowa, 2010. https://ir.uiowa.edu/etd/800.
Повний текст джерелаАнотація:
Gene therapy provides an opportunity to ameliorate several genetic disorders and treat numerous diseases by using nucleic acid-based materials to modulate gene activity. However, the greatest challenge for successful gene therapy applications remains delivery. Two general approaches are currently under investigation to improve gene delivery efficiencies. The first is by encapsulating therapeutic genes into modified viruses that are effective at transfecting cells but that have also caused serious side effects during clinical evaluations in 1999 and 2003. In contrast, non-viral gene therapy provides the safety of conventional pharmaceutical products, but possesses inadequate transfection efficiencies for clinical use. Successful non-viral gene delivery systems require evasion of the reticuloendothelial system (RES) while in circulation, a targeting ligand for efficient cellular uptake, and perhaps several additional components for efficient cellular disposition once the carrier has been internalized.
Engineering sophisticated gene delivery systems requires modular designs that are well characterized and optimized to circumvent each limiting barrier associated with gene delivery. The following thesis is focused on developing stabilized DNA polyplexes for in vivo applications and coupling their administration with current physical methods of non-viral gene delivery. The aim behind this approach is to systematically prepare gene carriers and evaluate their ability to maintain DNA transfection competent in order to determine which bioconjugate is the most successful for ultimately creating gene carriers that do not require physical interventions for gene expression.
The non-viral gene delivery systems presented in the thesis are based on PEGylated polyacridine peptides that bind to DNA predominantly by intercalation rather than by ionic interactions with DNA. The initial experimental chapters deal with the discovery of these novel DNA polyplexes, and the latter chapters focus on the optimization of their design for targeted in vivo gene delivery. The results demonstrate that PEGylated polyacridine DNA polyplexes possess improved compatibility for in vivo administration and that their flexible design is beneficial for preparing multi-component gene delivery systems.