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Development of a Novel Biodegradable Drug Polymer for the Modification of Inflammatory ResponseKhor, Sara 30 July 2008 (has links)
The first objective of this thesis was to assess the feasibility of designing a “smart”
degradable polymer that can release anti-inflammatory drugs in response to inflammatory-related enzymes. The drug polymer was synthesized using diisocyanates, poly(caprolactone)diols, and oxaceprol (OC) biomonomers. Biodegradation studies demonstrated that the trimethylhexamethylene diisocyanate-based drug polymer responded to an inflammatory enzyme to release more OC, while a 1, 12-diisocyanatododecane analog demonstrated minimal drug release. The drug delivery response was believed to be a direct function of the molecular structure and distribution of the hard segment.
The second objective of this thesis was to elucidate the anti-inflammatory mechanisms of OC by investigating its effects on cytokine-induced monocytic-cells adhesion
in human umbilical vein endothelial cells (HUVECs) in vitro. Results showed that OC had
no direct effect on the monocyte-endothelium adhesion, suggesting that OC may mediate
inflammation by mechanisms other than those suggested by the literature.
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Curdlan 1,3-Beta-Glucans: A New Platform for Polymer Drug DeliveryLehtovaara, Benjamin 18 April 2011 (has links)
1,3-β-glucans are a class of natural polysaccharides with unique pharmacological properties and the ability to form triple helical structures and resilient gels. Curdlan and other 1,3-β-glucans have found application pharmacologically in the treatment of cancers and acceleration of wound healing in humans and in the impartation of infection resistance in animal husbandry. Structurally, these polysaccharides have found application in food science as thermal gels, in nanostructure formation as helical scaffolds, and in drug delivery as nanocarriers for drugs and as inclusion complexes with polynucleotides.
A literature review of the important work on Curdlan research reveals two streams of research: investigation of the pharmacological significance of these polymers and their application in increasing host immunocompetency and investigation of the nature of the triple helix and its application in a variety of fields from food gels to drug delivery.
Two significant contributions to the field of Curdlan research have been completed including 1) The development of a Curdlan nanoparticle drug delivery platform and 2) A new multi-component liquid crystalline hydrogel providing a new route to form polynucleotide inclusion complexes with Curdlan for gene delivery. The developed nanoparticle platform exhibited high encapsulation of chemotherapeutic drugs and a 24-hour controlled release with a particle size of 109.9 nm. The liquid crystalline hydrogel exhibited homogeneous inclusion of DNA into amorphous and crystalline phases of Curdlan and delayed and triggered release of polynucleotide content. This work has been a significant demonstration of the potential of Curdlan as a new polymer for multi-functional drug delivery.
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Design of Coated Magnetic Iron-Oxide Nanogels for Drug Delivery SystemsRahmani, Sara January 2011 (has links)
Intelligent and more advanced therapeutic agents, capable of sensing and responding to their environment, are required to treat more complicated and complex diseases. Among all recently developed therapeutic agents, hydrogels are not only intelligent to sense and respond to external stimulus, but also they can be synthesized and designed in the cellular and sub-cellular size scale, which enhance their therapeutic ability. Most body physiological processes are regulated as a consequence of pH gradient in different compartments of the body; besides, changes in pH are also associated with disease or damaged sites within the body. A unique feature of hydrogels is that they can provide a network for loading and release of drugs. Therefore, the drug loaded within pH-responsive nanogels are able to locally release onto the target sites because of their small size, and capability to sense and respond to environmental changes.
The goal of this research is to design and implement novel pH-responsive magnetic nanogels for drug delivery that respond to changes in pH. Semi-continuous emulsion polymerization was conducted to synthesize polyampholyte nanogels comprising of methacrylic acid (MAA) and 2-(diethylamino) ethyl methacrylate (DEAEMA) in the presence and absence of steric stabilizer poly (ethylene glycol) methacrylate (PEGMA). The synthesized nanogels demonstrated swelling behavior at both acidic and basic pHs. Herein, procaine hydro chloride (PrHy) was utilized as cationic drug to investigate the release behavior from synthesized nanogels under different conditions. PrHy was loaded within nanogels through hydrophobic interaction and hydrogen bonding, as confirmed by isothermal titration calorimetry. The release study of PrHy molecules from nanogels was conducted by applying the versatile and easy technique of drug selective electrode, in which the concentration of released drug was measured as a function of time.
In order to facilitate the purification and enhance the detection of nanogels, iron oxide particles (Fe3O4) were co-precipitated within nanogels to form magnetic nanogels. Subsequently, layer-by-layer coating of polyelectrolytes were performed to control and eliminate the initial burst release of PrHy from nanogel by increasing the diffusion barrier and manipulating the permeability of nanogels. For the purpose of this research low molecular weight chitosan (CS) was used as polycation and poly (sodium 4-styrenesulfonate) (PSS) was acted as polyanion to coat magnetic nanogels. The more layers was applied, the more reduction in burst release was observed, which was revealed by using drug selective electrode to measure the concentration of the released drug from coated nanogels. Besides, layer-by-layer coating prolonged the time require to reach the steady state drug release. Therefore, this synthesized polyampholyte coated iron-oxide nanogels demonstrate great potential for use in controlled drug delivery systems.
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Modeling and Control of a Magnetic Drug Delivery SystemAfshar, Sepideh January 2012 (has links)
Therapeutic operation risk has been reduced by the use of micro-robots, allowing highly invasive surgery to be replaced by low invasive surgery (LIS), which provides an effective tool even in previously inaccessible parts of the human body. LIS techniques help delivering drugs effectively via micro-carriers. The micro-carriers are divided into two groups: tethered devices, which are supported by internally supplied propulsion mechanism, and untethered devices. Remote actuation is the critical issue in micro-device navigation, especially through blood vessels. To achieve remote control within the cardiovascular system, magnetic propulsion offers an advantage over other proposed actuation methods.
In the literature, most research has focused on micro-device structural design, while there is a lack of research into design and analysis of combined structure and control. As the main part, integrating the principle of electromagnetic induced force by feedback control design will lead to the desired automatic movement. An actuator configuration should thus first be designed to initiate the desired force. The design is basically defining the type and placement of a set of coils to achieve an operational goal.
In this project, the magnetic actuation is initiated by a combination of four electromagnets and two sets of uniform coils. Preliminary studies on 2D navigation of a ferromagnetic particle are used to show the effect of actuator structure on controller performance. Accordingly, the performance of the four electromagnets combination is compared to the proposed augmented structure with uniform coils. The simulation results show the improved efficiency of the augmented structure. In more general cases, the arrangement and number of electromagnets are unknown and should be defined. An optimization method is suggested to find these variables when the working space is maximized.
Finally, the problem of robust output regulation of the electromagnetic system driven by a linear exosystem, is also addressed in this project. The exosystem is assumed to be neutrally stable with unknown frequencies. The parallel connection of two controllers, a robust stabilizer and an internal model-based controller, is presented to eliminate the output error. In the latter one, an adaptation is used to tune the internal model frequencies such that a steady-state control is produced to maintain the output-zeroing condition. The robust regulation with a local domain of convergence is achieved for a special class of decomposable MIMO nonlinear minimum-phase system. The simulation results show the effectiveness and robustness of this method for the electromagnetic system when two different paths are considered.
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Development of stat-3 targeting siRNA nano-carriers for cancer therapyAlshamsan, Aws 11 1900 (has links)
In many tumors, persistently-active signal transducer and activator of transcription 3 (STAT3) imparts several oncogenic features such as survival, proliferation, angiogenesis, and immune escape. Therefore, STAT3 targeting in cancer and cancer-exposed dendritic cells (DCs) is important for cancer therapy. Our objective is developing delivery modalities of STAT3-targeting small interfering RNA (siRNA) using lipid-modified polyethylenimine (PEI) polyplexes and poly(D,L lactic-co-glycolic) acid (PLGA) nanoparticles (NPs), and evaluating the therapeutic outcomes in vitro and in vivo. Significant increase in siRNA condensation, protection, and cellular uptake by B16.F10 melanoma was seen by stearic-acid-modified PEI (PEI-StA) compared to unmodified PEI. Moreover, PEI-StA increased the STAT3 silencing potency of siRNA compared to PEI. STAT3 knockdown was accompanied with significant induction of interleukin-6 (IL-6) secretion and reduction of vascular endothelial growth factor (VEGF) production and cytotoxicity evidenced by increased Caspase 3 activity in vitro and in vivo, and significant inhibition in tumor growth. Analysis of tumor microenvironment showed CD3+ cells infiltration corresponding to STAT3 knockdown. The levels of CD4+ helper cells, CD8+ cytotoxic cells, and NKT cells significantly increased. DC infiltration and activation significantly increased in tumor mass following STAT3 knockdown as evidenced by high expression of CD86 and CD40. Moreover, IFN-, IL-12, and TNF- significantly increased following STAT3 knockdown by PEI-StA compared to PEI, suggesting Th1-type immunity. Allogenic capacity of DCs isolated from siRNA-treated mice was evidenced by the high T cell proliferation and IL-2 production in mixed lymphocytes reaction (MLR). Then, we explored STAT3 knockdown in DCs exposed to tumor derived factors (TDFs). We investigated encapsulation of siRNA complexes (PEI or PEI-StA) into PLGA NPs (PLGA-P and PLGA-PS). PLGA-P and PLGA-PS had an average diameter of ~ 370 nm and zeta potential of ~ -16 mV. Uptake and endosomal localization was confirmed. After TDFs exposure, DCs showed high STAT3 and low CD86 expression. STAT3 silencing by PLGA-P and PLGA-PS restored DC functionality as evidenced by upregulation of CD86, IL-12, and TNF- and MLR activity. PLGA significantly reduced PEI-associated toxicity. Therefore, STAT3 targeting in B16 cells by siRNA polyplexes of PEI and PEI-StA, or in DCs by PLGA-P and PLGA-PS provide potential strategies for cancer therapy. / Pharmaceutical Sciences
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Preparation and evaluation of novel drug alginate granule systems using paracetamol as model drugMukhopadhyay, Debashis, n/a January 2006 (has links)
Purpose: The aim of this thesis was to investigate a novel method of preparing crosslinked alginate matrices. Current methods use large quantities of water and hence are not suitable for large scale manufacturing of drug alginate particulate systems. Moreover, the current processes offer little scope for control of the crosslinking process. The aim was to overcome these problems through studies of paracetamol alginate granular matrices prepared by the novel method and to explore if these granules could be used to improve the taste of paracetamol.
Methods: The novel method involves preparation of dried drug alginate granules (moisture content: <5-6 %) using conventional granulation followed by crosslinking treatment of the dried granules with calcium chloride or a combination of calcium and magnesium ion solution in a crosslinking bath. The effect of the process (shear rate, binder quantity) to prepare untreated granules, composition of the raw materials (drug particle size and type of alginate) and subsequently the crosslinking treatment process variables (Ca�⁺ ion concentration, agitation rate, time and temperature of Ca�⁺ solution) on the physicochemical properties of granule systems were studied using factorial designs together with supporting studies.
The granules were characterized using sodium and calcium content analysis, drug release studies (mainly sub-60s release) matrix swelling rate and equilibrium swelling studies, tensile strength studies, ion permeation studies, SEM and X Ray analysis and gravimetric studies. Sensory studies correlating sub-60 s drug release (determined using a specially designed apparatus) and human taste scores (measured using an analogue scale) were then undertaken. Selected formulations were evaluated for taste improvement and to determine if mucoadhesion led to an increased unpalatability of paracetamol.
Results: Of the crosslinking treatment factors, the calcium concentration had the greatest effect on crosslinked granules. Although other treatment factors also affected the granule properties, alteration of the salt concentration allowed considerable control over the crosslinking process (not possible in the conventional method) in addition to providing a mechanistic understanding of the crosslinking process in the dried state. The use of low calcium concentrations (< 20 mg/ml, CaCl₂. 2H₂O) during treatment led to granule erosion (hence drug loss) due to overall incomplete crosslinking but led to a reduction in the short-term drug release compared to the granules treated with intermediate (100- 250 mg/ml) or high calcium concentrations (>400 mg/ml) due to reduction in the granule porosity after crosslinking. Although intermediate calcium concentrations led to complete crosslinking and longer release times (T 85 %: 25 min) high calcium crosslinking restricted the crosslinking to the surface of the granules leading to faster drug release (T 85 %: 8 min) with low calcium granules showing intermediate crosslinking and drug release rates (T 85 %: 18 min). High calcium treatment limited drug loss during crosslinking (95 % recovered compared to 83 % recovery at intermediate calcium concentration) without affecting the short-term drug release much. Low calcium granules showed the lowest drug recovery (< 70 %) and slowest sub-60s drug release followed closely by intermediate and high calcium treated granules.
The granule preparation factors (shear rate, binder quantity) and type of alginate used, considerably affected the sub-60s drug release by affecting surface porosity especially when a low shear rate was used. However, these factors only slightly reduced the drug loss during crosslinking treatment phase (about 4 % increase in drug recovery). Smaller drug particle size had a slightly larger incremental effect on drug recovery (about 8 % increase in the drug recovery) during crosslinking treatment due to better embedding of the drug particles inside the untreated granule matrix. This was true as long as the particle size of the drug was > 98 [mu]m. Below this size drug recovery remained unaffected by changes in drug particle size. Although granule surface porosity considerably affected the sub-60s drug release, its effect on drug release (long-term) was much less.
A linear correlation was observed between the sub-60s drug release and sensory scores despite high individual variability. Both granule formulations evaluated showed taste improvement and mucoadhesion did not lead to an increase in the bitter taste of the uncrosslinked paracetamol alginate granules.
Conclusions: Unlike the traditional method, the new technique of preparation of crosslinked drug alginate particulate systems uses very little water and allows greater control over the the crosslinking process compared to the swollen state crosslinking. The novel process of preparation is versatile, and should be scalable. It offers the formulator a platform to prepare a matrix, reservoir or a combination of these two systems using alginates and other drugs and polymers as well. Adequate short-term control over paracetamol release, very little loss of paracetamol during treatment (< 5 % loss), reduction in mucoadhesion of the granules and lastly improvement of the taste of paracetamol is possible using alginate based systems especially if high calcium is used during the crosslinking treatment. Hence, it is likely that these taste-improved granules could be used to prepare tablets without the need for a protective film coating to improve taste. Finally, this research established the utility of short-term drug release in taste improvement research and characterization of solid controlled release dosage forms.
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Liposomes in drug delivery :Er, Yan. Unknown Date (has links)
Liposomes are used as biocompatible carriers of drugs, peptides, proteins, plasmic DNA, antisense oligonucleotides or ribozymes, for pharmaceutical, cosmetic, and biochemical purposes. They are considered as effective drug delivery systems due to their colloidal size, easily controllable surface and membrane properties, large carrying capacity of drugs and biocompatibility. / This study was concerned with the stability of liposomes, their interaction at solid-liquid interfaces and their release of hydrophilic drug compounds. Either conventional liposomes containing lecithin and cholesterol, and Stealth® liposomes containing polyethylene glycol (PEG) 5000-lipids or PEG2000-lipids were investigated. Steric hindrance introduced by PEG chains proved to be influential in controlling liposome stability, interaction and drug release processes. Electrostatic forces were shown to be essential to the mechanisms and kinetics of liposome adsorption and colloidal stability, but not influential for the release of guanosine, used as a model hydrophilic drug. / Findings from this research improve the understanding of liposome interaction during drug delivery, give insight into the actions of liposomes in the body and may form the basis for improved liposome formulation. In addition, this research has developed a more comprehensive understanding of the role of PEG in controlling the colloidal stability, interfacial interactions of liposomes and drug transport kinetics across the lipid bilayers of liposomes. / Thesis (PhDAppliedScience)--University of South Australia, 2005.
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Development of acid-cleavable polymeric nano/microparticles for delivery of therapeuticsChan, Yannie Ka Yan, Chemical Sciences & Engineering, Faculty of Engineering, UNSW January 2007 (has links)
For controlled drug delivery applications, an ideal carrier system should release its drug payload only at the site where the therapeutic activity is required. One elegant strategy for site-selective release of drugs is to utilize the acidic sites in the body, for example, tumor sites and intracellular endocytic compartments. The objective of this thesis is to develop a series of new acid-cleavable polymeric nanoparticles for pH-triggered delivery oftherapeutics. Four new acid-cleavable benzaldehyde acetal crosslinkers have been designed and synthesized. They were then used in the generation of acid-labile polymeric nanoparticle drug carrier systems via various synthetic strategies and drug loading approaches for the delivery of therapeutics with different nature: (l) the coreshell poly(butyl acrylate)-g-poly(polyethylene glycol acrylate) nanoparticles, synthesized via the reversible addition-fragmentation chain transfer (RAFT)-mediated dispersion polymerization, were used for the delivery of hydrophobic drugs; (2) the core-crosslinked poly(hydroxyethyl acrylate)-b-poly(butyl acrylate) copolymer micelles, synthesized via the RAFT-mediated chain-extension polymerization, were used for the delivery of an antitumor drug, doxorubicin; (3) the poly(hydroxyethyl methacrylate) microgel particles, synthesized via the inverse-emulsion polymerization, were used for the delivery of biomacromolecular drugs. The designed physiochemical features such as the size, surface chemistry, cytotoxicity and the pH-triggered drug release properties of the developed carrier systems have been assessed. The synthesized systems offered release of the drug payload at slightly acidic conditions. The structural integrity of the polymeric carriers remained intact in the physiological, neutral pH conditions. The results support the potential value of the developed systems to be used for acidic-site delivery of therapeutics e.g. tumor sites and intracellular compartments. The content of this thesis has been published as three peer-reviewed international journal articles.
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Tryptamine terminated 1st generation polyamide dendrimer synthesis and drug release /Komurcu, Ramazan. January 2007 (has links)
Thesis (M.S.)--University of Akron, Dept. of Chemical Engineering, 2007. / "December, 2007." Title from electronic thesis title page (viewed 02/25/2008) Advisor, Stephanie T. Lopina; Faculty readers, Bi-min Newby, Helen Qammar; Department Chair, Lu-Kwang Ju; Dean of the College, George K. Haritos; Dean of the Graduate School, George R. Newkome. Includes bibliographical references.
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Synthesis, characterization, and application of polyethylene glycol modified insulin for oral delivery using complexation hydrogels /Tuesca, Anthony D. Lowman, Anthony M. January 2008 (has links)
Thesis (Ph.D.)--Drexel University, 2008. / Includes abstract and vita. Includes bibliographical references (leaves 251).
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