Дисертації з теми "DRUG DESIGNING"

Unspecific interactions, at the interface between a synthetic material and an aqueous biological environment, leading to irreversible protein adsorption can cause to undesired consequences. These include fouling of a boat hull or a triggered immune response. Thus, stealthy materials are a topic that has generated a great deal of interest in the scientific community. This work deals with the design of networks, nanoparticles, and surfaces containing poly(ethylene glycol) (PEG), known for its resistance to protein adsorption and non-toxic nature. Initially, PEG-based networks, hydrogels, were synthesized using photoinduced thiol-ene chemistry in order to afford coatings targeted for marine antifouling applications. By varying the length of the PEG chain, curing chemistry, cross-linker as well as hydrolytical stability, a library of hydrogel coatings was produced. The coatings were subsequently characterized with respect to curing efficiency, thermal and mechanical properties, and aqueous stability. Furthermore, the antifouling properties of coatings were evaluated using in vitro tests with proteins, marine bacteria, and diatoms. As a final test the coatings were evaluated in a four month field test. It was found that coatings comprising longer PEG chains displayed enhanced antifouling performance, compared to shorter PEGs. In addition, the choice of cross-linker, curing chemistry, and hydrolytical stability also affected the properties to a great extent. This thesis further deals with the design of amphiphilic linear dendritic hybrids, with PEG as the hydrophilic block. Using non-toxic 2,2-bis(methylol) propionic acid (bis-MPA) based dendrons, bearing click functional cores (alkyne or allyl) and peripheral hydroxyl groups, as macrointitiators for ring-opening polymerization of ε-caprolactone, a library of star branched materials was afforded. As a final step, click functional (azide or thiol) PEGs were attached using copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) or thiol-ene click chemistry. The size of the dendrons was varied from generation 0-4, along with variation of both poly(ε-caprolactone) (PCL) length and PEG length. The materials were designed in order to allow a study of the impact of the dendron generation. Finally, the hybrid materials were used for the preparation of micelles, as well as for the formation of honeycomb membranes. The micelles critical micelle concentration, size and drug loading capacity were shown to be highly dependent on the generation of the dendron. The generation of the dendron also had a profound effect on the ability of the hybrid materials to form ordered honeycomb membranes, and hybrid materials of the 3rd generation yielded the most highly ordered membranes.
Ickespecifika interaktioner vid gränsytan, mellan ett syntetiskt material och en vattenbaserad biologisk miljö, kan leda till irreversibel adsorption av proteiner. Detta kan i sin tur leda till oönskade följdeffekter, såsom beväxning på båtskrov eller trigga en immunologisk reaktion. För att motverka dessa effekter har forskare utvecklat så kallade smygmaterial. Denna avhandling behandlar design av nätverk, nanopartiklar och ytor innehållande poly(etylenglykol) (PEG), som är känt för sina smygegenskaper och för att vara icke-toxiskt. Initialt behandlar avhandlingen PEG-baserade nätverk, hydrogeler, syntetiserade med fotoinitierad tiol-enekemi, för användning som beväxningsavvisande beläggningar för marina applikationer. Genom att variera olika parametrar, såsom längden på PEG-kedjan, härdningskemin, tvärbindaren samt den hydrolytiska stabiliteten, byggdes ett bibliotek av hydrogelbeläggningar upp. Hydrogelbeläggningarna karaktäriserades sedan med avseende på härdningseffektivitet, termiska och mekaniska egenskaper, samt hydrolytisk stabilitet. Vidare studerades beläggningarnas avvisande förmåga mot proteiner, bakterier samt kiselalger. Slutligen studerades ytbeläggningarna i ett fyra månader långt fälttest. Av testerna framgick att längre PEG-kedjor gav beläggningar med bättre avvisande förmåga. Dessutom framgick att valet av tvärbindare, härdningskemi samt hydrolytisk stabilitet var av betydelse för beläggningarnas effektivitet. Denna avhandling behandlar vidare design av amfifila linjära dendritiska hybridmaterial, med PEG som den hydrofila delen. Genom att använda icke-toxiska 2,2-bis(metylol)propionsyrabaserade dendroner, med en klickfunktionalitet i kärnan (alkyne eller allyl) och perifera hydroxylgrupper, som makroinitiatorer för ringöppningspolymerisation av ε-kaprolakton byggdes ett bibliotek av material upp. För att göra materialen amfifila, kopplades klickfunktionella PEG-kedjor (azid eller tiol) till kärnan med koppar(I)-katalyserad azid-alkyn cykloadditionskemi alternativt tiol-enekemi. Storleken på dendronerna varierades från generation 0-4, dessutom varierades längden på både poly(ε-kaprolakton)- och PEG-kedjorna. Materialen designades så att inverkan av dendrongenerationen kunde studeras. Slutligen användes dessa hybridmaterial för att framställa miceller samt isoporösa filmer. Micellernas kritiska micellbildningskoncentration, storlek samt förmåga att laddas med läkemedel visade sig vara mycket beroende av dendrongenerationen. Dendrongenerationen visade sig vidare även ha stor inverkan i hybridmaterialens förmåga att självorganisera sig till en isoporös struktur och material av tredje generationen gav de mest välordnade filmerna.
QC 20101125

This thesis describes syntheses and characterization of star-like amphiphilic block copolymers consisting of poly(ethylene glycol) (PEG) as the hydrophilic block,polycarbonate as the hydrophobic block and an amine-containing dendrimer as the core molecule. The macromolecules were synthesized by either a convergent or adivergent approach that includes tandem click reactions and ring opening polymerizations (ROP) of methyl trimethyl carbonates (MTC) with differentfunctionalities. The ROP of MTC monomers was performed using organocatalysts that allow mild reaction condition and reasonable molecular weight distribution(PDI~1.3). These synthetic approaches provide the resultant polymers with three different conformations, which are; mikto-arm type, comb-block with short PEGbrushes, and linear block with long PEG chain. The star-like polymers that were synthesized were all water soluble and most of them formed nano aggregates inwater. Different morphologies were observed in AFM study depending on the polymer conformation. Interestingly, some of them had indications pointing towards alower critical solution temperature.

Parmi les récentes découvertes dans le monde des matériaux, les silices mésoporeuses ordonnées (SMO) ont suscité un intérêt considérable, notamment grâce à leurs perspectives d’application dans de nombreux domaines tels que le biomédical ou les technologies de séparation. Un tel engouement s’explique par la nature unique de leurs propriétés. En effet, les SMO possèdent en général de grandes surfaces spécifiques, de grands volumes poreux, des tailles de pores ajustables, des surfaces aisément modifiables, ainsi que des tailles et morphologies de particules adaptables. L’objectif principal de ce doctorat est donc d’utiliser au mieux ces propriétés pour synthétiser et caractériser de nouveaux systèmes ayant un potentiel d’application en imagerie par résonnance magnétique (IRM) et en relargage contrôlé de médicaments par voie orale. Les premières et secondes parties de ce travail (chapitres 4 et 5) portent sur l’étude des paramètres de synthèse des SMO de type SBA-15 et KIT-6 ainsi que sur leurs effets sur les propriétés poreuses obtenues après calcination. Les résultats présentés montrent toute l’importance de bien contrôler cette porosité afin de caractériser correctement les différentes structures et topologies poreuses accessibles. La troisième et la quatrième partie de cette thèse (chapitres 6 et 7) visent à concevoir et évaluer le potentiel de nouveaux agents de contraste (AC) positifs pour l’IRM basés sur des nanoparticules (Nps) de MCM-41 et MCM-48 fonctionnalisées avec des ions paramagnétiques tels que le gadolinium (Gd) ou le manganèse (Mn). Les résultats de ces études démontrent la supériorité des réseaux poreux 3-D comme supports pour l’insertion d’atomes paramagnétiques, utilisés pour bonifier le signal en IRM. Les Nps de MCM-48 dopées avec du Gd ou du Mn améliorent significativement la relaxivité des protons d’hydrogène dans l’eau tout en conservant un rapport r2/r1 proche de l’unité (1.5 – 2), confirmant leur performance en tant qu’AC positifs. Par ailleurs, l’utilisation de nombreuses techniques de caractérisation et de tests in vitro ont permis de délimiter clairement le potentiel effectif ainsi que les limitations de ces Nps pour des études de traçage cellulaire. La dernière partie de ce travail (chapitre 8) se concentre sur le greffage d’une protéine succinylée, la β-lactoglobuline, sur des Nps de MCM-48 fonctionnalisées afin de développer une nouvelle plateforme de relargage contrôlé de médicaments par voie orale. Les résultats obtenus avec ce système nano-conjugué et nutraceutique montrent un bon contrôle du relargage en fonction du pH ainsi qu’une bonne biocompatibilité et une excellente stabilité colloïdale dans un milieu physiologique. L’utilisation de cette protéine bon marché représente une alternative potentielle à l’utilisation des bio-polymères classiques.
Among recent discoveries in material science, ordered mesoporous silica (OMS) have been in the limelight and attracted considerable attention because of their prospects of application, especially in the biomedical field and separation technologies. Such growing interest is explained by their unique physico-chemical properties. Indeed, OMS usually exhibit high specific surface areas, high pore volumes, adjustable pore sizes, ease of surface functionalization and customizable particle size and shape. The main objective of this Ph.D. thesis is to use these properties in order to design and characterize novel systems with potential applications in magnetic resonance imaging (MRI) and/or oral drug delivery. The first and second parts of this project (chapters 4 and 5) deal with SBA-15 and KIT-6 materials and the effects of the different synthesis parameters on the porosity features of the structures, obtained after calcination. The results showed that it is of prime interest to thoroughly and accurately characterize the porosity of these silicas in order to correctly assess their porous topologies. Such knowledge could be of substantial importance for high-tech applications of OMS. The third and fourth part of this thesis (chapters 6 and 7) are aimed to design, characterize and evaluate the potential of novel positive contrast agents (CA) for MRI based on MCM-41 and MCM-48 nanoparticles (Nps) functionalized with paramagnetic ions such as gadolinium (Gd) or manganese (Mn). The results reported in these studies demonstrate the superiority of 3-D pore networks as a host for the insertion of paramagnetic atoms used to enhance the signal in MRI. Also Gd and Mn loaded MCM-48 Nps provide a significant increase in 1H proton longitudinal relaxivity while maintaining low r2/r1 ratio (1.5 – 2) in water. Furthermore, various modern techniques and in vitro tests were used to clearly delineate the true potential and limitations of these inorganic contrast agents for cellular and in vivo tracking studies. The last part of this work (chapter 8) is focused on the binding of a succinylated protein, the β-lactoglobulin, onto functionalized MCM-48 Nps for the development of a new oral drug delivery platform. This nutraceutical nano-conjugate system reveals promising features such as high biocompatibility, efficient pH-responsive properties for both hydrophilic and hydrophobic drugs/dyes and excellent colloidal stability. The use of this low-cost protein could represent an alternative over classical biopolymers.

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Nanoparticle-based drug delivery has been explored to circumvent the often-toxic chemotherapy treatments used today by providing a more efficient and specific delivery to diseased tissues. Recently we have developed polymeric pH-responsive expansile nanoparticles (eNPs) for intracellular delivery of paclitaxel (Pax) as an improvement upon the traditional methods of delivery of Pax with using Cremophor/ethanol. As eNPs are internalized by the cell, the hydrophobic protecting groups found on side chains along the polymer backbone are hydrolyzed, leaving behind hydrophilic moieties that cause the eNPs to slowly swell with water. In this manner, the encapsulation and controlled release of a hydrophobic drug can be achieved. By altering the surface characteristics of the eNPs, one can change the behavior of the delivery vehicle as well as the biological response. To explore this approach, two surfactant strategies were employed. Specifically, the original sodium dodecyl sulfate (SDS) surfactant has been substituted with PEGylated surfactants (either lipids or poloxamer) to improve circulation and in vivo stability. In addition, these surfactants were functionalized to target the folate receptor (FR), which is overexpressed in several cancers, in order to increase cancer cell-specific localization and uptake. The resulting eNPs retained their swelling characteristics while demonstrating improved cellular uptake in folate receptor-expressing KB and MDA-MB-231 carcinoma cells with no change in uptake in A549 cells, which do not express the folate receptor.
2031-01-01

The purpose of this novel research was to understand the flow behaviour and improve the efficiency of the Volumatic™ spacer, using a combination of engineering tools such as CFD, Laser Doppler Anemometry (LDA) and Row visualization techniques. The lack of information on the Volumatic /A/ spacer meant that, initial understanding had to be gained into the flow behaviour within the spacer. This was initially performed by injecting air carrying a tracer concentration to represent t li<^drug portion of the medicine. The efficiency (volume of drug collected at the mouth piece) was found to be about 6.5% which was in the same order as the figure quoted in the literature Chuffart A series of parametric studies were carried out to discover the effects of various parameters on The overall efficiency of the spacer. In the initial part a series of jet profiles were studied at the inlet, these were in the shape of straight, cone shape and spray jet profiles. It was concluded that the jet with a cone angle of 5° increased the efficiency of the spacer from G.5% to 9.4%. The next stage of parametric study involved reducing the length of the spacer from 0.24 m to 0.12 m and varying the inlet velocity from 40 m/s down to 10 m/s. The findings concluded that t in1 efficiency of the spacer could be increased to 23%, using a velocity of 40 m/s at inlet. The length was reduced from 0.12 m to 0.06 m and a similar study as described above was carried out. This time it was concluded that reducing the velocity to 30 m/s increased the efficiency to 30%. The other interesting feature to come out of this study was that the whole of tIk1 spacer volume was used, hence the drug was mixing better than in the original Volumatic /A/ spacer, where about one third of the spacer volume remained completely empty of the drug. The studies carried out so far had shown that the additional increase in drug delivery efficiency in the case of the Volumatic 7 A/ spacer, was not substantial enough to justify the considerable manufacturing costs which have to be met, if the Volumatic 7 A/ spacer was to be remanufactured in its improved design. The way forward seemed to be in the development of a new design. The new design had to be small enough, so that it could be carried around easily by patients, who do not use1 the current spacer due to its size. The new design had to be economical in terms of manufacture, simple to use and easy to clean. The reasons mentioned above and the current trend towards the tube type spacer designs, implied the logical approach would be to base the design on a similar geometry. A tube type spacer was modelled with two holes drilled directly opposite each other, a distance of 10 mm away from the pMDI's nozzle. The holes introduced a pressure difference, hence directing the drug towards the patient's airway system. The new spacer had a length of 0.1 m. The computational results showed that the efficiency had increased to 71% for this particular design. The CFD results obtained from the initial study on the Volumatic 7 M spacer were validated using LDA measurements. The velocities along four different locations were measured. At each location the velocities were measured at increments of 5 mm for a distance of 50 mm inside the spacer. The LDA results showed very good agreements with those obtained from CFD. The volume of data sampled experimentally at each point was 25,000 data points. This large volume of data eliminated any random sources of error, and as the CF D simulations were carried out some six months prior to LDA results, it was safe to assume that the drug had been modelled accurately. The same experimental set up was used to measure velocity values for the tube spacer, but in this instance, velocity measurements were made only along two planes, due to limited time and availability of the drug source. Finally laser light sheeting was used to illuminate the Volumatic T spacer and a high speed KODAK camera capable of capturing 4500 frames per second was used. The visualization study proved that there was a portion of the Volumatie /A/ spacer which at times was free of any drug. The originality of the work has been described in the following paragraph: Prior to this research there was no comprehensive study available combining engineering tools such as Computational Fluid Dynamics (CFD), Laser Doppler Anemoinetry (LDA) and High Speed Photography to study the (low pattern within the current Volumatic /A/ spacer design and hence analysing its efficiency. The studies carried out were of the impaction type. The results of this study have confirmed that there are several parameters contributing to the efficiency of the Volumatic' A/ spacer. This knowledge was not available in the open literature previously. The initial part of this study has provided a scientific approach to analysing the flow patterns, hence obtaining an accurate value for the efficiency of the current device. This part of the study alone is a valuable tool for industry, because it has given industry data which has not been previously available. The results from this study have indicated that, the Aero Chamber Spacer type design has an efficiency of 71% compared to the current 10% efficiency of the Volumatic 7 A/ spacer. The efficiencies discussed are measured in terms of the percentage of the drug delivered to the mouth piece. The benefit to industry would be saving at a conservative estimate in terms of millions of Pounds annually. This can be calculated from industry's own figures that, 1 out of every 5 new born baby suffers from asthma in various degrees. The drug is the most expensive component of the device, hence a more efficient device would use a lesser quantity of the drug. Finally the combination of techniques used, and the number of data samples taken for example in the case of LDA measurements some 25000 data samples were taken and averaged at each point, has ensured a high degree of accuracy and confidence in the results presented.

Aminoglycosides are valuable broad-spectrum antibiotics effective in both Gram-positive and Gram-negative bacteria. Antibiotic resistance has however been a scourge since the advent of modern antibiotics. One of the main mechanisms of resistance to aminoglycosides is antibiotic modification by the clinically widespread enzyme aminoglycoside N-6'-acetyltransferase (AAC(6')). Inhibiting resistance-causing enzymes is an important strategy among the multiple approaches to counter antibiotic resistance. The Auclair lab has previously developed a series of aminoglycoside-coenzyme A bisubstrates that was found to be potent inhibitors of AAC(6')-Ii, but lacked activity in cell-based assays. In order to combat aminoglycoside resistance, this thesis aims at developing a new class of AAC(6') inhibitors using fragment-based drug design with NMR-based assays for the initial screening. This approach has the advantage of potentially identifying new structural scaffolds that are fundamentally different from those that have been previously developed in the group. Following the introductory chapter 1, chapter 2 describes the NMR-based screening of a library of fragments against AAC(6')-Ii as well as the characterization of these hits in complex with the protein by NMR methods. Two hits with significant affinity for the enzyme were discovered, and their binding was further defined by HSQC methods. Chapter 3 describes the synthesis of derivatives of these initial hits, including hybrids, as well as the evaluation of their binding to AAC(6')-Ii using differential scanning fluorimetry and kinetic measurements. From the library of modified hits, only one was found to be an improvement over the initial hits. One of the hybrid molecules was found to have slightly improved affinity over the initial hits, but its activity was still too weak to be useful in further studies.
Les aminoglycosides sont une classe importante d'antibiotiques à large spectre, efficaces contre les bactéries Gram-positives et Gram-négatives. La résistance des bactéries envers les antibiotiques demeure un problème depuis leur découverte. Un des mécanismes principaux de résistance aux aminoglycosides est leur modification par l'enzyme aminoglycoside N-6'-aminotransférase (AAC(6')). Inhiber la résistance antibiotique est une stratégie qui a fait ses preuves pour contrer ce problème. Le groupe Auclair a précédemment développé une série de bisubstrats aminoglycoside-coenzyme A qui sont de puissants inhibiteurs in vitro mais sont inefficaces dans des essais cellulaires. Pour combattre la résistance aux aminoglycosides, cette thèse vise le développement d'une nouvelle classe d'inhibiteurs d'AAC(6') en utilisant une approche par fragments avec des essais à base de RMN pour le criblage initial. Cette approche a l'avantage de potentiellement trouver de nouveaux patrons structurels, fondamentalement différents de ceux qui ont été précédemment découverts. Suivant l'introduction dans le chapitre 1. Le chapitre 2 décrit le criblage par RMN d'une librairie de composés avec l'enzyme AAC(6')-Ii. Les molécules actives ont ensuite été caractérisées en complexe avec la protéine par RMN dont la HSQC. Le chapitre 3 décrit la synthèse de composés modifiés basés sur les résultats du criblage initial aussi bien que la caractérisation de leur complexation avec l'enzyme par DSF et par mesures d'essais cinétiques. Seul un ligand a été trouvé un meilleur ligand que les ligands initiaux. Un des composés hybrides montrait une légère amélioration dans son affinité pour AAC(6')-Ii, mais son activité est trop faible pour que cet inhibiteur mérite de plus amples études.

A novel Dynamic Colon Model (DCM) that represents the anatomy and physiology of the human proximal colon was developed. Analysis of the hydrodynamics was performed using Positron Emission Particle Tracking (PEPT) system and Positron Emission Tomography (PET). The pressures generated by the wall motion of the DCM tube compared with the available published in vivo data. The hydrodynamics in USP 2 dissolution apparatus were also assessed using Particle Image Velocimetry (PIV) and Planar Induced Fluorescence (PLIF). Areal distribution and individual striation methods showed high mixedness level close to tip. PEPT experiments were performed using particles of different buoyancy. Use of different particles gave different results in terms of velocities and residence times within the DCM tube. PET images showed that antegrade propagating waves of amplitude lower than the minimum threshold used in vivo studies were associated with flow episodes. In addition, flow episodes can occur which are not related to the wall motion. Dissolution profiles of theophylline, a high water soluble drug, released from a hydrophilic matrix obtained at viscous shear thinning media, mimicking the dewatering process in the human colon. The novel DCM provides a realistic colonic environment, enabling biorelevant in vitro assessment of the in vivo performance of dosage forms.

Digital music software can limit the forms of music we create by using interfaces that directly copy those of the analogue instruments that came before. In this study we report on a new multi-touch interface that affords a completely new form of drum sequencing. Based on ideas from Avant-guard music and embodied interaction, a technology probe was created and then evaluated by a wide range of users. We found that for users with no musical training, and for users with a large amount of musical training, the software did allow them to be more creative. However, users with limited training on existing sequencing software found the new interface challenging.

Heart failure resulting from different forms of cardiomyopathy is defined as the inability of the heart to pump sufficient blood to meet the body's metabolic demands. It is a major disease burden worldwide and the statistics show that 50% of the people who have the heart failure will eventually die from sudden cardiac death (SCD) associated with an arrhythmia. The central cause of disability and SCD is because of ventricular arrhythmias. Genetic mutations and acquired modifications to RyR2, the calcium release channel from sarcoplasmic reticulum, can increase the pathologic SR Ca2+ leak during diastole, which leads to defects in SR calcium handling and causes ventricular arrhythmias. The mechanism of RyR2 dysfunction includes abnormal phosphorylation, disrupted interaction with regulatory proteins and ions, or altered RyR2 domain interactions. Many pharmacological strategies have shown promising prospects to modulate the RyR2 as a therapy for treating cardiac arrhythmias. Here, we are trying to establish a novel approach to designing new drugs to treat heart failure and cardiac arrhythmias. Previously, we demonstrated that all pharmacological inhibitors of RyR channels are electron donors while all activators of RyR channels are electron acceptors. This was the first demonstration that an exchange of electrons was a common molecular mechanism involved in modifying the function of the RyR. Moreover, we found that there is a strong correlation between the strength of the electron donor/acceptor, and its potency as a channel inhibitor/activator, which could serve as a basis and direction for developing new drugs targeting the RyR. In this study, two new potent RyR inhibitors, 4-methoxy-3-methyl phenol (4-MmC) and the 1,3 dioxole derivative of K201, were synthesized which are derivatives of the known RyR modulators, 4-chloro-3-methyl phenol (4-CmC) and K201. The ability of K201, 1,3 dioxole derivative of K201 and 4-MmC to inhibit the cardiac calcium channel is examined and compared at the single channel level. All of these compounds inhibited the channel activity at low micromolar concentrations or sub-micromolar concentrations.

I designed the set for Fool For Love by Sam Shepard in the McLeod Theater, Fall Semester 2013 for my thesis production. Fool For Love Is a short and intense hyper-realistic play about two lovers with a dark past. The entire play takes place in one extended scene in a motel room on the edge of the desert. Eddie tries to win May back, while she tries to free herself from her need to go back to him. The Old Man is a figure outside of reality that intrudes on the play, the father they share and the source of the shame in their relationship. A suitor, Martin, appears to set this combustible mixture off. I designed a cramped and derelict space which pushed the auditory surrealism of the play and made the experience as intimate and intense as I could for the audience. Chapter 1 contains me research and initial response to both the script and the thesis process. Chapter 2 walks through the process of designing and building the show. Chapter 3 reflects on my performance overall. Chapter 4 is a deeper look into design communication, a weakness this process revealed in my work.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2019
"DOCTOR OF PHILOSOPHY IN BIOLOGICAL ENGINEERING With a focus in Polymers and Soft Matter (PPSM)." Cataloged from PDF version of thesis.
Includes bibliographical references (pages 106-112).
Osteoarthritis is a debilitating joint disease that affects over 30 million people and has no disease-modifying therapies. The current standard of care for the disease is merely palliative until joint replacement is necessary. Disease-modifying osteoarthritis drugs have been tested in the clinic, but all have been unsuccessful in clinical trials. A key point of failure for several of these drugs has been inefficient and inadequate delivery to target cartilage cells. Cartilage is avascular and thus cannot be targeted efficiently through the systemic circulation. Due to the localized nature of osteoarthritis, direct injection of therapeutics into affected joints is an attractive solution to this problem. However, delivery via this approach remains impeded by rapid turnover of the synovial fluid within joints and the dense, highly charged nature of cartilage tissue.
To overcome this biological barrier, we took advantage of a recently demonstrated phenomenon in which positively charged nanomaterials electrostatically interact with anionic cartilage, both avoiding joint clearance and facilitating diffusion through the tissue in the process. This work describes two strategies using such polycationic materials to deliver insulin-like growth factor 1 (IGF-1), a promising anabolic growth factor for osteoarthritis that has known delivery challenges. The first approach used an electrostatic assembly of IGF-1, poly(L-glutamic acid), and poly(L-arginine) into a nanoscale complex coacervate, or nanoplex, for delivery of unmodified, bioactive IGF-1. The second approach involved a densely charged polyamidoamine (PAMAM) dendrimer, end-grafted with poly(ethylene glycol) (PEG) of various molecular weights at various % end group functionalization.
From this panel of nearly 50 PEGylated dendrimers, an optimally charged dendrimer was selected based on criteria of cartilage uptake and nontoxicity. The selected dendrimer was covalently modified with IGF-1. Both systems were tested to ensure that they could deliver bioactive IGF-1, penetrate human thickness cartilage tissue, extend joint residence time in vivo, and mitigate the progression of early traumatic osteoarthritis in rats. Both the nanoplex and optimally PEGylated dendrimer-IGF-1 achieved these goals, suggesting that polycationic nanocarriers could potentially improve pharmacokinetics and efficacy of disease-modifying osteoarthritis drugs in the clinic.
by Brett Charles Geiger.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Biological Engineering

The current study describes the development of wireless controlled iontophoretic drug delivery system. The control system was made using ZigBee communication protocol. The circuit performance analysis of the current injecting circuit was performed to ascertain minimal error combined with high efficiency. Finally, the developed controlled system was used to manipulate the functioning of the two independent iontophoretic drug delivery systems. In gist, a wireless controlled drug delivery system based on ZigBee communication protocol was developed and tested successfully.

All pharmaceutical products are required by law to display an expiry date on the packaging. The period between the date of manufacture and expiry date is known as the label shelf-life. The label shelf-life indicates the period of time during which the consumer can expect the product to be safe and effective. Methods for determining the label shelf-life from stability data are discussed in the guidelines on the evaluation of stability data issued by the International Conference for Harmonization. These methods are limited to data that can be analysed using linear model methods. Furthermore, in the situation where a number of batches are used to determine a label shelf-life, the current regulatory method (unintentionally) penalizes good statistical design. In addition, the label shelf-life obtained this way may not be a reliable guide to the properties of future batches produced under similar conditions. In this thesis it is shown that the current definition of the label shelf-life may not provide the consumer with the desired level of confidence that the product is safe and effective. This is especially the case when the manufacturer has performed a well designed stability study with many assays. Consequently, a new definition for the label shelf-life is proposed, such that the consumer can be confident that a certain percentage of the product will meet the specification by the expiry date. Several methods for obtaining such a label shelf-life under linear model and generalized linear model assumptions are proposed and evaluated using simulation studies. The new definition of label shelf-life is extended to allow a label shelf-life to be obtained from stability studies that make use of many batches, such that a proportion of product over all batches can be assured to meet specifications by the expiry date. Several methods for estimating the label shelf-life in the multi-batch case are proposed and evaluated with the help of simulation studies.
Thesis (Ph.D.)--School of Agriculture and Wine, 2003.

Self-assembled supramolecular gels obtained from low molecular weight gelators (LMWGs)have received significant attention over past few decades because of their wide range of applications that includes cosmetics, sensors,bio-mineralization, wound healing, liquid crystalline materials etc. the main objective of the thesis was to develop various drugs and/or bioactive agent based supramolecular gels fro their plausible biomedical applications such as wound healing, drug delivery etc. various new LMWGs were designed and synthesized from well known non-steroidal anti-inflammatory drugs .
Research was carried out under the supervision of Prof. P Dastidar of the Organic Chemistry division under SCS [School of Chemical Sciences]
Research was conducted under DST & DBT grant and CSIR fellowship

Despite advancements in therapies, such as surgery, irradiation (IR) and chemotherapy, outcome for patients suffering from glioblastoma (GBM) remains fatal; the median survival time is only about 15 months. Even with novel therapeutic targets, networks and signaling pathways being discovered, monotherapy with such agents targeting such pathways has been disappointing in clinical trials. Poor prognosis for GBM can be attributed to several factors, including failure of drugs to cross the blood-brain-barrier (BBB), tumor heterogeneity, invasiveness, and angiogenesis. Development of tumor resistance, particularly to temozolomide (TMZ) and IR, creates a substantial clinical challenge.

The primary focus of the work described herein was to develop a modeling and simulation approach that could be applied to rationally develop novel combination therapies and dose regimens that mitigate resistance development. Specifically, TMZ was combined with small molecule inhibitors that are either currently in clinical trials or are approved drugs for other cancer types, and which target the disease at various resistance signaling pathways that are induced in response to TMZ monotherapy. To accomplish this objective, an integrated PKPD modeling approach was used. A PK model for each drug was first defined. PK models were subsequently linked to a PD model description of tumor growth dynamics in the presence of a single drug or combinations of drugs. A key outcome of these combined PKPD models was tumor static concentration (TSC) curves of TMZ in combination with small molecule inhibitors that identify combination drug exposures predicted to arrest tumor growth. This approach was applied to TMZ in combination with abemaciclib (a dual CDK4/6 small molecule inhibitor) based on data from a published study evaluating abemaciclib (ACB) efficacy in combination with TMZ in a U87 GBM xenograft model. TSC was also constructed for TMZ in combination with RG7388 (MDM2 inhibitor) based on the data from an in-vivo study that evaluated effects on tumor growth suppression of these small molecule inhibitors in combination with TMZ in GBM 10 patient derived xenografts.

In GBM 43 mouse xenografts, emergence of resistance to TMZ treatment was identified. Thus, a resistance integrated PKPD model was developed to predict tumor growth kinetics after treatment with TMZ in GBM 43 tumors. Population PK models in immune deficient NOD.Cg-Prkdc^scid Il2rg^tm1Wjl/SzJ (NSG) mice for TMZ and small molecule inhibitors (GDC0068/RG7112) were developed based on a combination of data obtained from an in-vivo study and published sources. Subsequently, PK models were linked to tumor volume data obtained from GBM 43 subcutaneous xenografts. Model parameters quantifying tumor volume dynamics were precisely estimated (coefficient of variation < 40%) compared to a base tumor growth inhibition model in GBM 43 that did not incorporate resistance development. Graphical diagnostics of the resistance incorporated PKPD tumor growth inhibition model demonstrated a superior fit compared to the base model, and accurately captured the emergence of resistance to the TMZ monotherapy treatment observed in the GBM 43 patient derived xenograft model.

博士
國立臺北科技大學
設計學院設計博士班
106
Motivation: Many urban water environments have been established as waterfront spaces; however, some problems exist, with the most serious and urgent ones being water quality control. Purpose: In this study, concentration of drug-resistant microorganisms was used as an indication to understand the degree of contamination in urban waterfront, so as to design healthy urban waterfronts that are suitable for sustainable management. Methods: Twenty five open and closed urban water bodies in Taiwan were investigated, from which 270 water samples were collected. For each sample, pH value was measured, while total bacterial counts and drug-resistance patterns were assayed by plating on Luria-Bertani agar (LA) and MacConkey agar (MAC) with or without ampicillin (Ap), kanamycin (Km), and tetracycline (Tc). In addition, several alloys were tested for their antibacterial effects and adhesion ability to bacteria. Results: In the open water bodies, the amounts of bacteria reached 79,200 CFU/ml, drug-resistant (resistant to Ap, Km, or Tc) bacteria were mostly above 4,000 CFU/ml, and 8 different antibiotic-resistance patterns were identified, suggesting that these waterbodies received great amounts of pollutants released by the upstream animal farms or untreated waste water. In most of the closed waterbodies, amounts of antibiotic-resistant bacteria were below 2,000 CFU/ml; it is possible that the water received less pollutants and/or because control measures had periodically been taken. Species identification results showed that bacteria resistant to one, two, or all of Apr, Kmr, and Tcr in the waterbodies included human pathogens such as Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae. These results suggest that caution has to be taken to avoid frequent contact with the water from these waterbodies, because serious infections can be caused once the multidrug-resistant bacteria enter human body through the mouth, nose or wounds. Some of the alloys tested did show antibacterial effects. Conclusion: Based on the results, design strategies and treatment methods are recommended for urban waterfront with different levels of water pollution, which include establishment of monitoring mechanisms and improved designing, using non-biological materials or biological agents (such as bacteriophages) to reduce the bacterial population, improvement of water purification technology, application of biomedical materials in water environment, etc., so as to reduce the concentrations of drug-resistant microorganisms.

The Downtown Eastside of Vancouver is one of the city’s oldest neighbourhoods and one of Canada’s poorest. Once home to city hall and a bustling entertainment district, this neighbourhood has slowly been overtaken by an open drug market. With many individuals in this area without permanent residence, temporary shelters have become a refuge for the homeless. As a response to the need for permanent housing in this area, this thesis explores the role of architecture in housing the homeless, specifically those who suffer from drug addiction. Building on precedents of mixed use affordable housing programs in Canada and the U.S., this project focuses on ways of facilitating services and activities that seek to improve the quality of life for the disenfranchised.

碩士
國立屏東科技大學
工業管理系
92
As the economy continues to flourish and develop, the trend of production has taken on a design that aims at the product variety, but not its quantity. The trend of pharmaceutical development is like it. However, the strict government regulations of controlled drugs significantly increase the complexity and the difficulty of pharmaceutical utilization and circulation for medical professionals. Although the rapid development of information technologies and worldwide web, which applies information systems onto the routing management of operation, constitutes one of the effective solutions to the problems mentioned above, the application of completed software set of information systems often lacks a logical process design and the related routing structure analysis, undermining the expected performance of the information systems. Thus, this study seeks to establish a set of information systems for controlled drugs based on a routing management, using an example of a local hospital that employs the pharmaceutical information systems. The goal of the study is to systematically make the operation routing logical, transforming it into information systems with a routing basis, to solve the management problems of controlled drug regulations.

碩士
大葉大學
設計研究所
96
Designing the form of super-mileage car concerns the fuel economy and styling image. How to design a beautiful form with low drag forces requires both design and engineering considerations. This research aims to investigate the possibility of designing forms of super-mileage car with different images while not changing much of the drag coefficients. A form of fish type was first designed to envelop the car structure and driver, followed by a study on effect of tail length on drag coefficient. Two forms of different images, denoted as edge body and smooth body were then derived from the form of fish type. Computer program based on computational fluid dynamics was used to analyze the aerodynamic characteristics of three different forms. The results show that drag coefficients of fish type, edge body and smooth body differ from each other less than 3.5%.