RÉSUMÉ en françaisLes systèmes de délivrance de médicaments sont fortement investigués dans le but d’obtenir la meilleure efficacité thérapeutique et la plus faible toxicité possible. De nombreux systèmes existent à l’heure actuelle qu’ils soient mécaniques ou chimiques. Dans ce travail, nous nous sommes tout d’abord intéressés à une nouvelle approche basée sur la macropinocytose pour augmenter l’internalisation d’agents thérapeutiques aussi bien dans des cellules cibles de médicaments que dans des cellules souches mésenchymateuses d’origine musculaire (mdMSCs) actuellement de plus en plus étudiées comme nouveaux systèmes de délivrance. La macropinocytose est en effet une voie d’endocytose clathrine-indépendante permettant l’internalisation non sélective de fluide extracellulaire. Ce processus semble contribuer à l’agressivité des cancers en favorisant leur apport en nutriments, le recyclage de la membrane plasmatique et de ses récepteurs ainsi que l’internalisation d’exosomes. La macropinocytose est déclenchée notamment par l’activation des récepteurs epidermal growth factor receptor (EGFR) et platelet-derived growth factor receptor (PDGFR) qui sont des marqueurs connus d’agressivité des gliomes. Au cours de ce travail, nous nous sommes demandé si la macropinocytose ne pourrait pas être utilisée pour améliorer l’internalisation d’agents chimiothérapeutiques dans les cellules de glioblastomes. Nous avons tout d’abord montré que l’expression des acteurs clés de la macropinocytose au niveau de leur ARNm est fortement altérée en fonction du grade de la tumeur en utilisant des bases de données publiques d’échantillons de tumeurs gliales humaines. Une « signature » basée sur l’expression de 38 gènes liés à la macropinocytose permet la discrimination des échantillons de glioblastomes, c’est-à-dire des tumeurs les plus agressives. Nous avons ensuite comparé les effets induits par le MOMIPP et le Vacquinol-1, deux inducteurs connus de macropinocytose, à ceux de l’Honokiol qui induit également une vacuolisation sévère au sein de cellules de gliomes. Malgré de fortes similarités morphologiques, l’Honokiol se distingue par l’induction de vacuoles provenant à la fois d’endocytose mais aussi du réticulum endoplasmique. Chacun des trois composés induit néanmoins une nette augmentation de l’internalisation de dextrans de 10 kDa. Le marquage à l’acridine orange suggère pourtant des différences dans le devenir des vacuoles induites par ces trois molécules. Il a récemment été démontré que le MOMIPP agit en empêchant la maturation des macropinosomes ce qui concorde avec notre observation d’une fusion avec les lysosomes qui serait très limitée. Si les trois molécules permettent bien d’augmenter également la concentration de témozolomide (traitement de référence) au sein des cellules de gliomes, leur impact sur l’internalisation de la doxorubicine est plus faible. L’augmentation de l’internalisation des médicaments par l’induction de macropinocytose ne semble donc pas toujours efficace et pourrait dépendre de leurs propriétés physico-chimiques ainsi que de leur voie d’internalisation basale. Étant donné que l’induction soutenue de macropinocytose peut également déclencher la mort cellulaire tant de cellules de glioblastome chimio-sensibles que chimio-résistantes, nous proposons d’envisager la macropinocytose dans des approches combinées pour bénéficier d’une augmentation de l’internalisation de médicaments et d’effets additifs/ synergiques. Comme les cellules souches mésenchymateuses sont intensément étudiées pour leur utilisation en tant que transporteur de médicaments en plus de leur potentiel intrinsèque pour la médecine régénérative, les effets de ces inducteurs de vacuolisation ont également été étudiés sur des mdMSCs. Ces dernières sont caractérisées par un niveau basal de macropinocytose plus élevé que les modèles de gliomes utilisés et elles semblent mieux répondre au Vacquinol-1 qui permet d’ailleurs d’augmenter plus efficacement la concentration intracellulaire en doxorubicine que le MOMIPP, avec une internalisation environ 2 fois plus importante qu’en absence de stimulation. Ces cellules pouvant être utilisées comme véhicule pour le transport de molécules ayant une faible biodisponibilité afin d’améliorer leur usage en clinique, nous avons ensuite évalué l’impact du chargement de mdMSCs avec de la curcumine, un polyphénol naturel bien connu pour ses propriétés antioxydantes et anti-inflammatoires dont le potentiel clinique reste limité notamment par sa faible solubilité. Pour cette raison, l’utilisation du NDS27, un complexe de lysinate de curcumine et d’hydroxy-propyl-bêta-cyclodextrine qui présente une bien meilleure solubilité dans l’eau, a été préférée. Nous avons observé que l’internalisation de la curcumine, provenant du NDS27, dans les mdMSCs est concentration-dépendante et non temps-dépendante. De plus, elle ne peut pas être augmentée par l’utilisation d’inducteurs de macropinocytose. De plus amples investigations des effets de l’internalisation de la curcumine à partir du NDS27 en fonction de la concentration sur leur viabilité, prolifération, propriétés mésenchymateuses et leur fonction mitochondriale nous ont permis de montrer qu’un chargement de 2 h avec 7 µM de NDS27 était acceptable en vue de préserver la possibilité de bénéficier des mdMSCs en tant qu’agent de thérapie cellulaire régénérative en sus de leur aspect de délivrance. L’investigation du potentiel thérapeutique de telles mdMSCs chargées en curcumine pour traiter l’arthrose chez le cheval est toujours en cours. / SUMMARYDrug delivery systems are highly investigated with the aim to promote the best therapeutic efficacy and the lowest possible toxicity. Nowadays, several systems either mechanical or chemical exist. In this work, we were first interested in studying a new approach based on macropinocytosis to increase the internalisation of therapeutic agents in both target cells of drugs and skeletal muscle-derived mesenchymal stem cells (mdMSCs) currently more and more studied as new deliverance systems. Macropinocytosis is indeed a clathrin-independent endocytosis pathway allowing the nonselective internalisation of extracellular fluid. This process seems to contribute to cancer aggressiveness by favouriting nutrient supply, recycling of plasma membrane and its receptors, and exosome internalisation. Macropinocytosis may notably be triggered by epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR), two well-known markers of glioma aggressiveness. During this work, we wondered whether macropinocytosis could be used to improve the internalisation of chemotherapeutic agents into glioblastoma cells. We first showed that the mRNA expression levels of key actors of macropinocytosis are strongly altered according to the grade of the tumour using public datasets of human glioma tumour samples. A “signature” based on the expression of 38 macropinocytosis-related gene allows the discrimination of the glioblastoma samples, i.e. the most aggressive tumours. We next compared the effects induced by MOMIPP and Vacquinol-1, two well-known macropinocytosis inducers to those of Honokiol which also induces a severe vacuolisation within glioma cells. Despite high phase-contrast morphological similarities, Honokiol appeared different from the others by the induction of vacuoles from both endocytosis and endoplasmic reticulum origins. Each of the three compounds nevertheless induces a marked increase in 10 kDa dextran internalisation. Acridine orange staining however suggested differences in the fate of vacuoles induced by those three molecules. MOMIPP has recently been shown to prevent the macropinosomes maturation which is consistent with our observation ofthe lack of acridine orange staining of the vacuoles that may be attributed to a limited fusion with lysosomes. Although each of the three compounds allows nevertheless a marked increase of temozolomide (i.e. first-line treatment) concentration into glioma cells, their impact on the internalisation of doxorubicin is poor. The increased internalisation of drugs by inducing macropinocytosis does not seem to be always efficient and could depend on their physicochemical properties and their basal way of internalisation. Considering that sustained macropinocytosis induction may also trigger cell death of both chemo-sensitive and chemo-resistant glioblastoma cells, we proposefor future perspectives to consider macropinocytosis in combination approaches to benefit from an increased drug uptake and additive/synergistic effects. As mesenchymal stromal / stem cells are increasingly studied for their use as drug-carrier in addition to their intrinsic potential for regenerative medicine, the effects of these vacuolisation inducers were also studied on mdMSCs. These lasts are characterised by a higher basal level of macropinocytosis than the glioma models used in this work. They seem to better respond to Vacquinol-1 which allows to increase more efficiently the intracellular concentration of doxorubicin than MOMIPP, with an uptake approximatively 2-fold higher than without stimulation. Given that these cells can be used as vehicle to transport molecules with a poor bioavailability in order to improve their clinical usage, we evaluated the impact of the loading of mdMSCs with curcumin, a natural polyphenol well-known for its antioxidant and anti-inflammatory properties whose clinical potential remains limited notably by reason of its poor solubility. Therefore, the use of NDS27, a complex of curcumin lysinate and hydroxypropyl-beta-cyclodextrin displaying an increased solubility in aqueous solution, was preferred. We observed that the uptake of curcumin from NDS27 into mdMSCs is concentration-dependent and not time-dependent. Moreover, it cannot be improve using macropinocytosis inducers. Further investigations of the effects of curcumin internalisation from NDS27 depending on the concentration used on their viability, proliferation, mesenchymal properties and their mitochondrial function allowed us to show that a loading of 2 h with NDS27 at 7 µM seems acceptable to preserve the possibility to benefit from mdMSCs as a cellular therapy agent in addition to the delivery aspect. The investigation of the double potential therapeutic benefits of such curcumin-loaded mdMSCs to treat osteoarthritis in horses is still ongoing. / Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie) / info:eu-repo/semantics/nonPublished

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Background: E-cigarettes, also known as electronic nicotine delivery systems (ENDS), are the second most used tobacco product in the US. Cigarette smoking, alcohol, and tobacco use, which contribute to a large portion of disease burden caused by substance use disorders (SUDs), have all been shown to be associated with ENDS use. The co-occurrence of mental disorders and SUDs is well established despite unclear causality. Understanding the associations between e-cigarette use, substance use, and mental health disorders is imperative to understanding the full impact of ENDS use. The aim of our study is to examine these associations in Tennessee, where the prevalence of cigarette smokers and drug overdose deaths is higher than the national average. Methods: We used cross-sectional data from the 2021 Behavioral Risk Factor Surveillance System a nationally representative U.S. telephone-based survey of adults aged 18 years, and extracted data for Tennessee (n=4,788). Logistic regression analysis was conducted to test the association between cigarette use, substance use, depression, and ENDS use. We controlled for income, race, educational status, health insurance status, race/ethnic minority status, and age. Results: Overall, 6.7% (n=320) of participants in our sample reported ENDS use. Results of our logistic regression model revealed that cigarette use (OR=2.58, 95% CI, 1.99,3.44), depression (OR=2.33, 95% CI, 1.82, 2.98), alcohol use (OR =2.50, 95% CI, 1.96, 3.20), male gender (OR =1.30, 95% CI, 1.02, 1.60), and no health insurance (OR =1.48, 95% CI, 1.02, 2.15) were associated with ENDS use, while race/ethnic minority status, low income, and non-completion of high school were not associated with ENDS use. Conclusion: Our results showed that cigarette use, alcohol use, and depression were associated with ENDS use in Tennessee after controlling for common confounders. Our results corroborate other studies that show a strong association between ENDS use, co-occurring substance use disorders, and mental disorders. This cross-sectional study from a sample in Tennessee can serve as the basis for future longitudinal research in this population.

Filled hydrogel particles consisting of emulsified oil droplets encapsulated within a hydrogel matrix were fabricated based on the phase separation of proteins and polysaccharides through aggregative and segregative mechanisms. A 3% (wt/wt) pectin and 3% (wt/wt) caseinate mixture at pH 7 separated into an upper pectin-rich phase and a lower casein-rich phase. Casein-coated lipid droplets added to this mixture partitioned into the lower casein-rich phase. When shear was applied, an oil-in-water-in-water (O/W1/W2) emulsion consisting of oil droplets (O) contained within a casein-rich dispersed phase (W1) suspended in a pectin-rich continuous phase (W2) was formed. Acidification from pH 7 to 5 promoted adsorption of pectin onto casein-rich W1 droplets, forming filled hydrogel particles. Particles were then cross-linked using transglutaminase. Particles were assessed for stability to changes in pH, increasing levels of salts (sodium chloride and calcium chloride), and susceptibility to lipid oxidation. Both cross-linked and not cross-linked particles were stable at low pH (pH 2-5). At high pH, cross-linked particles maintained their integrity while not cross-linked particles disintegrated. Particles were stable to sodium chloride (0-500 mM). Calcium chloride levels above 4 mM resulted in system gelation. The rate of lipid oxidation for 1% (vol/vol) fish oil encapsulated within filled hydrogel particles was compared to that of oil-in-water emulsions stabilized by either Tween 20 or casein. Emulsions stabilized by Tween 20 oxidized faster than either filled hydrogel particles or casein stabilized emulsions, while filled hydrogel particles and casein stabilized emulsions showed similar oxidation rates. Using an in-vitro digestion model, the digestion of lipid encapsulated within filled hydrogel particles was compared to that of a casein stabilized oil-in-water emulsion. Results showed similar rates of digestion for both hydrogel and emulsion samples. Attempts to fabricate particles using free oil (rather than emulsified oil) were unsuccessful and resulted in the formation of large non-encapsulated oil droplets (d ~10 μm). By controlling particle concentrations of biopolymer, water, and oil, it was possible to fabricate particles that were highly resistant to gravitational separation which was attributed to the equivalent density of the continuous and particle phases. Results highlight the potential applications and versatility of this delivery system.

This study seeks to develop smart hydrogel formulations for injectable controlled drug delivery from Pluronics to enhance patients compliance, decrease side effects, reduce dose and frequency. A biocompatible copolymer, Pluronic F127 was probed as the main ingredient for the injectable systems owing its low gelation concentration and ease of modification the system properties through excipients addition. The matrix properties were studied through a series of thermal, rheological and structural (SAXS/SANS) experiments as a function of concentration and shear rate, covering both static and dynamic environments. It has shown that gelled viscosity (and structure) can be critically controlled by shear rate and the structures recorded do not match those predicted for sheared colloids. Two further Pluronics F68 and F108, were studied showing similar but shifted gelation properties to F127. Effects of additives were studied by introducing different Mw PEGs and a model hydrophobic drug ‘ibuprofen’ to a F127 20% formulation. PEGs addition effects on the system properties and gelation transition were largely dependent on the Mw used in the blend, which became more prominent with increasing chain length. Ibuprofen’s addition has resulted in reduced gelation temperature and smaller hard spheres without having a great effect on the system rheological properties compared to neat gels. Blends containing both additives PEG and ibuprofen exhibited a synergistic effect, where comparisons show that Ibuprofen had the largest effect on the blends lowering gelation boundaries and slightly increasing the size of the hard spheres indicating the necessity of full characterisation of the formulation with any API.

This thesis presents the design and optimization of a dendrimer-based cationic nanoparticle system tailored for versatile applications, ranging from anti-inflammatory scavenging to targeted pain relief through endosomal delivery. By harnessing the unique attributes of this platform, various strategies were devised to overcome hurdles in drug delivery, offering promising avenues for nanomedicine in anti-inflammatory and nociceptive treatments. In our scavenging screening project, we rigorously screened various materials to find the best universal anti-inflammatory carrier. We started by exploring the potential of dendrimer-based materials as scavengers of inflammatory signals and studied how they could be used to develop therapeutic carriers. With intrinsic therapeutic properties and the ability to create tunable nanocarriers, dendrimer-based delivery systems are powerful multimodal delivery systems. The dendrimer base of our delivery system, cationic PAMAM Generation 3 dendrimer (PAMAM-G3), was selected due to its efficient scavenging ability and low biotoxicity. Conjugation with cholesterol facilitated the formation of polymeric micelles, exhibiting a cationic and hydrophilic exterior coupled with a hydrophobic interior, resulting in a high drug-loading capacity. Among the developed scavengers, PAMAM-Cholesterol (PAMAM-Chol) nanoparticles demonstrated a potent reduction in toll-like receptor activation with minimal toxicity and extended endosomal retention. We then exploited the endosomal retention of PAMAM-Chol nanoparticles to target the activated PAR2 receptor within endosomes of relevant cancer cells, aiming to alleviate oral cancer-induced nociception. Extensive characterization confirmed the platform's stability, physical attributes, and ability to encapsulate PAR2 inhibitor, AZ3451. The platform exhibited high drug loading capacity and sustained release profiles across various pHs. Cellular uptake studies demonstrated efficient endosomal targeting, with subsequent modulation of PAR2 signaling pathways. Preclinical studies in oral cancer pain models revealed a significant and prolonged reduction in nociception for over 24 hours, surpassing the efficacy of free drugs. Further diversification of the PAMAM-Chol platform explored its potential as a "Push" chemotherapy carrier and a "Pull" cfDNA scavenger against chemotherapy-induced neurological and neuropathic side effects. Evaluation in wild-type mice demonstrated the platform's effectiveness in mitigating chemobrain and chemotherapy-induced peripheral neuropathy, highlighting its translational potential for multimodal cancer therapy. We found that NPs loaded with chemotherapy significantly reduced the painful effects of chemotherapy-induced peripheral neuropathy and decreased recovery times. Collectively, this body of work underscores the potential of PAMAM-Chol as a versatile tool in drug delivery and endosome-localized pain therapeutics. It contributes to the evolving landscape of precision medicine through tailored therapeutic approaches for minimizing side effects and enhancing patient well-being. The innate therapeutic properties coupled with efficient and sustained drug delivery mechanisms position the PAMAM-Chol platform as a foundational element for the development and delivery of next-generation therapeutics.

Yes / TOBI® is a recently marketed preservative and sulphate free tobramycin formulation approved by FDA for maintenance therapy for patient with cystic fibrosis. The performance of selected recent nebuliser delivery systems has been assessed using the developed method to determine the optimum combinations to deliver approved tobramycin inhaled solution (TOBI)®. A simple, sensitive and specific high performance liquid chromatographic method has been developed and used to quantitative determination of the aminoglycoside tobramycin following pre-column derivatisation with phenylisocyanate (PIC). The reaction time was 10 min at 80º C and the resulting derivative was stable for five days at room temperature. The quantitative performance of the assay was further improved by using another aminoglycoside (neomycin) as internal standard. The stable resulting PIC-tobramycin derivative was separated using a HPLC 5μm Columbus C18 column (150x4.60 mm i.d, Phenomenex). The mobile phase was consisted of acetonitrile-glacial acetic acid-water (450:5:545, v/v/v) and ultraviolet detection at (240 nm). The proposed method showed good validation data. The standard curve was linear (n=5) at seven different concentrations, ranging from 20 to 140μg/ml and the correlation coefficient (R2) of the regression line was 0.9995. The limit of detection (LOD) and limit of quantitation (LOQ) were 0.86μg/ml and 2.62μg/ml, respectively. The relative standard deviation (RSD %) was less than 0.6% for intra-day assay (n=5) and 2.5% for inter-day assay (n=5). A number of nebuliser performance comparison studies have been demonstrated for aerosolise TOBI® to choice the optimum combination produces high repirable inhaled mass of tobramycin. The objective of this study was to evaluate the performance of recent nebuliser delivery systems to nebulise approved tobramycin inhaled solution (TOBI)®.

Yes / Three-dimensional printing (3DP) has the potential to cause a paradigm shift in the manufacture of pharmaceuticals, enabling personalised medicines to be produced on-demand. To facilitate integration into healthcare, non-destructive characterisation techniques are required to ensure final product quality. Here, the use of process analytical technologies (PAT), including near infrared spectroscopy (NIR) and Raman confocal microscopy, were evaluated on paracetamol-loaded 3D printed cylindrical tablets composed of an acrylic polymer (Eudragit L100-55). Using a portable NIR spectrometer, a calibration model was developed, which predicted successfully drug concentration across the range of 4–40% w/w. The model demonstrated excellent linearity (R2 = 0.996) and accuracy (RMSEP = 0.63%) and results were confirmed with conventional HPLC analysis. The model maintained high accuracy for tablets of a different geometry (torus shapes), a different formulation type (oral films) and when the polymer was changed from acrylic to cellulosic (hypromellose, HPMC). Raman confocal microscopy showed a homogenous drug distribution, with paracetamol predominantly present in the amorphous form as a solid dispersion. Overall, this article is the first to report the use of a rapid ‘point-and-shoot’ approach as a non-destructive quality control method, supporting the integration of 3DP for medicine production into clinical practice. / Open Access funded by Engineering and Physical Sciences Research Council United Kingdom (EPSRC), UK for their financial support (EP/L01646X).

Thesis (PhD)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: The primary aim of this study was to investigate the feasibility of the amphiphilic block copolymer poly((vinylpyrrolidone)-b-poly(vinyl acetate)) (PVP-b-PVAc) as a vehicle for hydrophobic anti-cancer drugs. PVP-b-PVAc block copolymers of constant hydrophilic PVP block length and varying hydrophobic PVAc block lengths were synthesized via xanthate-mediated controlled radical polymerization (CRP). The methodology consisted of growing the PVAc chain from a xanthate end-functional PVP. In an aqueous environment the amphiphilic block copolymers selfassembled into spherical vesicle-like structures consisting of a hydrophobic PVAc bilayer membrane, a hydrophilic PVP corona and an aqueous core. The self-assembly behaviour and the physicochemical properties of the self-assembled structures were investigated by 1H NMR spectroscopy, fluorescence spectroscopy, transmission electron microscopy (TEM) and dynamic and static light scattering. Drug loading studies were performed using a model hydrophobic drug, clofazimine, and a common anti-cancer drug paclitaxel (PTX) to evaluate the potential of the PVP-b-PVAc block copolymers for drug delivery,. Clofazimine and PTX were physically entrapped into the hydrophobic domain of the self-assembled PVP-b-PVAc block copolymers via the dialysis method. The drug-loaded PVP-b-PVAc block copolymers were characterized regarding particle size, morphology, stability and drug loading capacity in order to assess their feasibility as a drug vehicle. The polymer vesicles had a relatively high drug loading capacity of 20 wt %. The effect of the hydrophobic PVAc block length on the drug loading capacity and encapsulation efficiency were also studied. Drug loading increased with increasing the hydrophobic PVAc block length. The effect of the drug feed ratio of clofazimine and PTX on the drug loading capacity and encapsulation efficiency were also investigated. The optimal formulation for the drug-loaded PVP-b-PVAc was determined and further investigated in vitro. The size stability of the drugloaded PVP-b-PVAc block copolymers was also assessed under physiological conditions (PBS, pH 7.4, 37 °C) and were stable in the absence and presence of serum. PVP-b-PVAc block copolymers were tested in vitro on MDA-MB-231 multi-drug-resistant human breast epithelial cancer cells and normal MCF12A breast epithelial cells to provide evidence of their antitumor efficacy. In vitro cell culture studies revealed that the PVP-b-PVAc drug carrier exhibited no cytotoxicity towards MDA-MB-231 and MCF12A cells, confirming the biocompatibility of the PVP-b-PVAc carrier. In vitro cytotoxicity assays using clofazimine-PVPb- PVAc formulations showed that when MDA-MB-231 cells were exposed to the formulations, an enhanced therapeutic effect was observed compared to the free drug. Cellular internalization of the PVP-b-PVAc drug carrier was demonstrated by fluorescent labeling of the PVP-b-PVAc carrier. Fluorescence microscopy results showed that the carrier was internalized by the MDAMB- 231 cells after 3 hours and localized in the cytoplasm and the perinuclear region. Overall, it was demonstrated that PVP-b-PVAc block copolymers appear to be promising candidates for the delivery of hydrophobic anti-cancer drugs. / AFRIKAANSE OPSOMMING: Die studie is gebaseer op die gebruik van amfifieliese blokkopolimere van poli((Nvinielpirolidoon)- b-poli(vinielasetaat)) (PVP-b-PVAc) as potensiële geneesmiddeldraers. PVP-b-PVAc blokkopolimere van konstante hydrofiliese bloklengte en verskillende hydrofobiese bloklengte is voorberei via die RAFT/MADIX-proses. Blokkopolimere met vinielasetaat is vanaf poli(N-vinielpirolidoon) met ‘n xantaatendfunksie voorberei. In ‘n wateromgewing vorm die PVP-b-PVAc blokkopolimere vesikel strukture met ‘n hydrofobiese membraan en ‘n hydrofiliese mantel. Die fisies-chemiese eienskappe van die PVP-b-PVAc blokkopolimere is gekarakteriseerd met gebruik van KMR spektroskopie, fluoresent spektroskopie, transmissie elektronmikroskopie (TEM) en dinamiese en statiese lig verstrooiing. Die potensiaal van PVP-b-PVAc as ‘n geneesmiddeldraer is ondersoek deur gebruik te maak van die hydrofobiese geneesmiddel, clofazimine, en ‘n anti-kanker geneesmiddel, paclitaxel. Clofazimine en paclitaxel is ge-inkapsuleer in die hydrofobiese gedeelte van die blokkopolimere via die dialise-metode. Clofazimine-PVP-b-PVAc en paclitaxel-PVPb- PVAc blokkopolimere is gekarakteriseerd met betrekking tot die partikel grootte, morfologie, stabiliteit en laai kapasitiet om die PVP-b-PVAc blokkopolimere as geneesmiddeldraers te evalueer. Die PVP-b-PVAc geneesmiddeldraer het ‘n relatiewe hoë laai kapsiteit van 20 gew % aangetoon. Die invloed van die bloklengte op die laai kapasitiet is ook ondersoek en beskryf. ‘n Toename in die laai kapasitiet is gesien met ‘n toename in die hydrofobiese bloklengte. Die invloed van die hoeveelheid geneesmiddel op die laai kapasitiet en die inkapsuleer doeltreffendheid is ook ondersoek. Die optimale formulasie is gevind en verder gebruik vir in vitro studies. Die stabiliteit van die geneesmiddeldraer in fisiologiese omstandighede (pH 7.4, 37 °C) is ook beskryf. Resultate toon aan dat die sisteem stabiel is onder hierdie omstandighede in die afwesigheid en aanwesigheid van serum. In vitro eksperimente is op MCF12A epiteel-borsselle en MDA-MB-231 epiteelborskankerselle getoets om die anti-tumoraktiwiteit te ondersoek. Resultate toon aan dat die PVP-b-PVAc geen sitotoxiese effek op die selle het nie, wat aandui dat die polimere bioverenigbaar is. Verder is dit bewys dat die PVP-b-PVAc geneesmiddel formualsie ’n hoër sitotoxisiteit besit as die vry-geneesmiddel. Fluoresent studies het aangetoon dat die geneesmiddeldraer na 3 uur opgeneen word deur MDA-MB231 selle en gelokaliseerd is in die sitoplasma en in die omgewing van die kern van die selle. In die algemeen is dit aangetoon dat PVP-b-PVAc blokkopolimere potensiële kandidate vir die lewering van hydrofobiese geneesmiddels is.

Traffic congestion can cause late deliveries, decreased profits from vehicle fuel idling in traffic, and delayed distribution in tight delivery windows. The focus of this study was on developing strategies that business leaders could use to increase on-time deliveries. The conceptual frameworks for this case study were systems theory, traffic equilibrium theory, bathtub theory, and kinematic wave theory. Data were collected from semistructured interviews with 6 delivery service leaders from 3 delivery businesses in Southcentral Alaska. In addition, secondary data were collected from government information. Interview responses were coded to identify trends including delivery time, business activity, and amount of roadway congestion. Two major themes emerged from the interviews: time of day affecting when traffic congestion occurred, and limited alternate transportation routes causing congestion in Southcentral Alaska. The findings indicated that the best strategy to help reduce traffic congestion involved instituting toll optimization and high occupant vehicles lanes. The implications for effecting social change include how business leaders can help reduce traffic congestion using toll optimization, and how high occupant vehicle lanes could encourage Southcentral Alaskans to carpool.