L’auto-assemblage de macromolécules amphiphiles dans des solutions aqueuses est un mécanisme important sous-jacent à de nombreux processus présents dans les organismes vivants. La formation spontanée de structures auto-organisées de phospholipides et de biomacromolécules se produit en raison d'un équilibre délicat entre les forces d'attraction et de répulsion. Ces forces comprennent l'attraction hydrophobe, la liaison hydrogène, les forces de coordination des métaux et la répulsion stérique ou électrostatique. En outre, l'auto-assemblage de molécules amphiphiles synthétiques est largement utilisé dans divers domaines technologiques. Un exemple frappant est celui des surfactants de faible poids moléculaire qui peuvent modifier de manière significative les propriétés des systèmes. Les autres domaines importants dans lesquels les tensioactifs et les macromolécules amphiphiles sont activement utilisés sont la cosmétologie et l'hygiène. Cependant, l'utilisation de structures auto-organisatrices de macromolécules amphiphiles nécessite une étude approfondie et soulève quelques questions pour les chercheurs concernant leur structure, leur comportement sous l'influence de facteurs externes et leur stabilité. L'objectif principal de la thèse était de développer une théorie de champ analytique auto-cohérente de l'auto-organisation dans des solutions de copolymères de déblocage non ioniques linéaires dendritiques et dendritiques doubles dans des solvants sélectifs. Cette théorie nous permet de prédire comment la dendronisation d'un ou des deux blocs affecte les propriétés structurelles et thermodynamiques d'assemblages auto-organisés formés par des copolymères. Il a été démontré que la dendronisation des corona bloc permet d’obtenir les micelles stables de taille relativement petite, mais avec de nombreux groupes terminaux. Cette dernière caractéristique est particulièrement intéressante dans le contexte de la liberation contrôlée, puisque les groupes terminaux exposés à l'environnement peuvent être facilement fonctionnalisés par des groupes de ligands pouvant être ciblés. Ces deux caractéristiques peuvent être obtenues simultanément car la dendronisation des corona bloc réduit le nombre d'agrégation à l'équilibre et les dimensions globales des micelles par rapport aux micelles formées par des molécules de copolymères diblocs linéaires homologues tout en conservant un grand nombre de groupes terminaux par micelle. La dendronisation du bloc insoluble peut être utilisée pour augmenter le nombre d'unités monomères terminales dans le core. Nous avons également démontré que la dendronisation des blocs solubles favorise la formation de micelles sphériques, alors que les gammes de stabilité thermodynamique des micelles cylindriques et des dendrimersomes sont déplacées vers un degré plus élevé de polymérisation des séquences insolubles. Au contraire, la dendronisation du bloc insoluble a l'effet inverse et conduit à un élargissement des gammes de stabilité des polymeres et des micelles cylindriques.Nous avons étudié les effets de l'extensibilité finie dans les brosses polyélectrolytes à chaîne linéaire et à dendron contenant des groupes ioniques. Nous avons développé la théorie analytique des brosses polyélectrolytiques dans l'approximation de Poisson-Boltzmann qui explique explicitement l'extensibilité finie des chaînes de polyélectrolytes formant des brosses. Il a été montré que pour la même série de paramètres de la brosse, la théorie basée sur l’élasticité non linéaire des polyions prédit une épaisseur de la brosse plus faible et une plus grande amplitude du saut de la densité du polymère au bord du pinceau. Les connaissances obtenues fourniront une base rationnelle pour la conception moléculaire de nouveaux copolymères à blocs complexes sur le plan architectural, y compris ceux destinés à des applications médicales. / An important mechanism underlying many processes occurring in living organisms is self-assembly of amphiphilic (macro)molecules in aqueous solutions. Spontaneous formation of self-organized structures of phospholipids and biomacromolecules occurs because of a delicate balance between attraction and repulsion forces. Such forces include hydrophobic attraction, hydrogen bonding, metal coordination forces and steric or electrostatic repulsion.In addition, self-assembly of synthetic amphiphilic molecules is widely used in various technical fields. A striking example are low molecular weight surfactants (small amphiphilic molecules) that can significantly change the properties of systems. Other important areas in which surfactants and amphiphilic macromolecules are actively used are cosmetology and hygiene. However, the use of self-organizing structures of amphiphilic macromolecules requires detailed study and raises a few questions for researchers regarding their structure, behavior under the influence of external factors and their stability.The main goal of the present work was development of the theory of self-assembly of diblock copolymers where one or both of blocks (soluble or/and insoluble) exhibit dendritic branching and established relations between degree of branching of the block(s) and structural properties (size, shape, aggregation number) of the self-assembled aggregates.The major focus of the thesis was on developing an analytical self-consistent field theory of self-organization in solutions of non-ionic linear-dendritic and double-dendritic deblock copolymers in selective solvents. This theory enables us to predict how dendronization of one or both blocks affects structural and thermodynamic properties of self-organized assemblies formed by copolymers. It was demonstrated that dendronisation of the corona blocks allows obtaining the stable micelles of relatively small size, but with many terminal groups.The latter feature is most attractive in the context of controlled delivery, since the exposed to the environment terminal groups can be readily functionalized by targetable ligand groups. Both these features can simultaneously be achieved because dendronization of the corona blocks reduces the equilibrium aggregation number and overall dimensions of micelles compared to micelles formed by homologous linear-linear diblock copolymer molecules while keeping large number of terminal groups per micelle. Dendronization of the insoluble block may be used for increasing of the number of terminal monomer units in the core. Such terminal groups can be further functionalized to be able to interact with active drugs, thereby increasing the loading capacity of the micelle.We have also demonstrated that dendronization of the soluble blocks favors formation of spherical micelles, whereas the ranges of thermodynamic stability of cylindrical wormlike micelles and dendrimersomes are shifted to larger degree of polymerisation of the insoluble blocks. On the contrary, dendronization of the insoluble block has the opposite effect and leads to widening of the stability ranges of polymersomes and cylindrical micelles.We investigated effects of finite extensibility (non-linear elasticity) in linear chain and dendron polyelectrolyte brushes containing ionic groups. We developed the analytical theory of polyelectrolyte brushes within the Poisson-Boltzmann approximation which explicitly accounts for finite extensibility of the brush-forming polyelectrolyte chains. It was shown that for the same set of the brush parameters the theory based on non-linear elasticity of the polyions predicts smaller thickness of the brush and larger magnitude of the jump in polymer density at the edge of the brush.The obtained knowledge will provide a rational background for molecular design of novel architecturally complex block copolymers, including those for medical applications.

Les copolymères à blocs amphiphiles s’auto-assemblent en solution aqueuse grâce à l’association de leurs segments hydrophobes. Les nanoparticules formées à partir de copolymères biocompatibles et biodégradables tels que les poly(hydroxyalkanoates) (PHAs) sont particulièrement attractives pour la conception de systèmes à libération prolongée de principes actifs. La relation entre la composition/structure chimique du copolymère, ses propriétés d’auto-assemblage et ses effets sur les cellules in-vitro doit être étudiée. Des copolymères à blocs poly(acide malique)-b-poly(3-hydroxybutyrate) (PMLA-b-PHB), PMLA-b-PHB-b-PMLA et poly(triméthylène carbonate)-b-poly(acide-malique) (PTMC-b-PMLA) ont été synthétisés par polymérisation par ouverture cycle (ROP) des monomères correspondants, suivie d’une hydrogénolyse. Une gamme de copolymères bien définis, caractérisés par spectroscopie RMN 1H, 13C{1H}, HSQC, HMBC, et DOSY, par analyses SEC, DSC, TGA, et mesure des angles de contact, présentant des balances hydrophile/hydrophobe modulables, a été obtenue grâce au control précis de la fraction hydrophile f (11-82%). Des auto-assemblages modulables ont été formés par nanoprécipitation des copolymères en l’absence d’agent tensio-actif. De larges agrégats ainsi que des micelles cœur-couronne (Rh = 16-335 nm) ont été obtenus en fonction du copolymère utilisé (dibloc vs. tribloc). Des micelles stables pendant 10 jours à 37 °C en solution aqueuse ont été obtenues pour les copolymères avec f allant jusqu’à 50%. Les copolymères PMLA-b-PHB et PTMC-b-PMLA n’ont pas révélé de toxicité aigüe in-vitro. De plus, l’utilisation du PHB a avantageusement permis de diminuer la captation des nano-objets par les macrophages et d’augmenter la captation par les cellules hépatiques. / Amphiphilic block copolymers are able to form self-assembled systems in aqueous solution by association of their hydrophobic segments. Nanoparticles formed from biodegradable and biocompatible polymers such as poly(hydroxyalkanoate) copolymers are particularly attractive for drug delivery applications. The relationship between the chemical structure/composition of the macromolecule, its self-assembly properties and its effect on cells in-vitro has to be studied.The synthesis of poly(-malic acid)-b-poly(3-hydroxybutyrate) (PMLA-b-PHB), PMLA-b-PHB-b-PMLA, and poly(trimethylene carbonate)-b-poly(-malic acid) (PTMC-b-PMLA) was established through the ring-opening polymerization (ROP) of the corresponding monomers followed by hydrogenolysis. A range of well-defined copolymers characterized by 1H, 13C{1H}, HSQC, HMBC, DOSY NMR spectroscopy, SEC, DSC, TGA, contact angle analyses, with tunable hydrophilic/hydrophobic balance were thus obtained through the precise control of the hydrophilic weight fraction f (11-82%). Tunable self-assembled systems were obtained by nanoprecipitation of the amphiphilic PHA-based copolymers without the use of a surfactant. Large aggregates and core-shell micelles (Rh = 16-335nm) were obtained depending on the polymer topology. PHB-based copolymers with f up to 50% formed highly stable micelles at 37 °C over a period of 10 days in aqueous solution. PMLA-b-PHB as well as PTMC-b-PMLA copolymers revealed no acute in-vitro cytotoxicity. The use of PHB as hydrophobic segment enabled to minimize the non-specific scavenging by macrophages cells while the cellular uptake by hepatocytes was favored.

Une famille de copolyélectrolytes amphiphiles en peigne (polysavon) composés de styrène (unité hydrophobe) et de chlorométhylstyrène quaternisé par une amine tertiaire portant une chaine alkyle longue (unité tensioactive) a été étudiée. Dans l’eau, les chaines polymères forment des auto-assemblages dont la morphologie dépend de la fraction en unité tensioactive. Pour une composition de 80 %mole de ces dernières, les micelles ont une forme cylindrique ce qui au niveau macroscopique se traduit par des propriétés rhéologiques intéressantes. L’objectif principal de cette thèse a consisté à caractériser les propriétés rhéologiques et structurales des auto-assemblages cylindriques, puis de les corréler à la structure chimique du polysavon.L’étude structurale, par diffusion de rayonnement (Lumière et Neutrons) et microscopie (Cryo-TEM), a montré que la longueur des cylindres croit avec la concentration. La présence de défauts hydrophobes à la surface des micelles induit des branchements entre les cylindres, et conduit à la formation d’un réseau. L’écrantage des charges par l’ajout de sel, augmente le nombre de jonctions et favorise la percolation, jusqu'à une séparation de phase.L’étude rhéologique de ces réseaux montre des propriétés viscoélastiques, caractérisées par une distribution relativement étroite des temps de relaxation. Le processus de relaxation d’une contrainte macroscopique est attribué à un mécanisme de cassure/recombinaison des micelles et des jonctions. La variation de la longueur de la chaine alkyle greffée ou l’ajout d’un tensioactif neutre permet de modifier le temps de relaxation des réseaux sur plusieurs ordres de grandeur. / Comb-like amphiphilic copolyelectrolytes (polysoap) based on styrene (hydrophobic unit) and N,N dimethylalkyl(vinylbenzyl)ammonium chloride (surfactant-like unit) have been studied. In aqueous solution, the comonomer ratio influences the morphology of the self-assemblies displayed by these polymers. For a composition of 80 %mol of the surfactant-like unit, the micelles have a cylindrical shape; such topology displays interesting rheological properties at the macroscopic scale. The main goal of this thesis has consisted in characterizing the rheological and structural properties of these self-assembly, in order to correlate them with the chemical structure of the polysoaps.The structural study, with scattering techniques (Light and Neutron) and Cryo-microscopy, have shown that the cylindrical micelles grow in length with increasing polymer concentration and display some hydrophobic defects at their interface which induce their connection leading to the formation of a network. Addition of salt screens cationic charges, increases the density of junction, and leads to a phase separation.Branched cylindrical micelles networks display viscoelastic behaviors, with a narrow distribution of relaxation times. Break-up of the micelles and of the junctions accounts for the origin of the relaxation. Increasing the length of the alkyl side chain affects as well as adding a neutral surfactant affects deeply the relaxation time of the gels.

Computational methodologies were employed to study a supramolecular micellar structure and its application, nanoreactor. This task was done through rigorous scale-up procedure using both atomistic and mesoscopic simulations. Primarily, density functional theory (DFT) calculation was used to characterize the smallest unit of complex molecules in the multicomponent mixture system. The following step involved transferring the information achieved by DFT calculation to larger scale simulation, such as molecular dynamics (MD) simulation. Lastly, based on the atomistic simulation results, we performed a series of dissipative particle dynamics (DPD) simulations to study a full body of polymeric multicompartment micelle. In the course of research, we built a systematic procedure to minimize the complexity of computation and efficiently characterize macromolecular structures and its application.

Eicosanoids are potent mediators of inflammatory response whose role has been well established in inflammatory disorders. Release of arachidonic acid by group IVA cytosolic phospholipase A2 α (cPLA2α) is the initial rate limiting step for the production of eicosonoids in response to inflammatory mediators. Previous findings from our laboratory have demonstrated that cPLA2α is directly activated by the emerging bioactive sphingolipid, ceramide-1-phosphate (C1P). In this study, we have developed a modified Triton X-100/phosphatidylcholine (PC) mixed micelle assay which was utilized to determine the kinetics and specificity of this lipid-enzyme interaction. Using this assay, the activity of the enzyme increased in a dose dependent manner with increasing amount of C1P in the mixed micelle and the stoichiometry of this interaction was found to be 2 molecules of C1P to achieve full activation. This activation was found to be lipid specific as other phospholipids such as PE, PS, PA, DAG, and S1P had insignificant effect on cPLA2α activity. Furthermore, based on previous studies we hypothesized that the specific interaction site for C1P was localized to the cationic β-groove (R57, K58, R59) of the C2 domain of cPLA2α. In this regard, mutants of this region of cPLA2α were generated ((R57A/K58A/R59A), (R57A/R59A), (K58A/R59A), (R57A/K58A), (R57A), (K58A), and (R59A)) and examined for C1P affinity by surface plasmon resonance (SPR). The triple, the double mutants, and the single mutant (R59A) demonstrated significantly reduced affinity for C1P containing vesicles compared to wild-type cPLA2α. Examining these five mutants for enzymatic activity demonstrated significant reduction in the ability of C1P to increase the Vmax of the reaction and significantly decreased the dissociation constant (KSA) of the reaction as compared to the wild-type enzyme. The mutational effect was specific for C1P as all of the cationic mutants of cPLA2α demonstrated normal basal activity as well as normal affinities for PC and PtdIns(4,5)P2 compared to wild-type cPLA2α. Finally, we demonstrated these amino acids were critical for translocation of cPLA2α in A549 lung adenocarcinoma cells in response to inflammatory agonists like A23187 and IL-1β. Lastly, we also demonstrated the mechanistic difference between activation of cPLA2α by the two anionic lipids, C1P and PI(4,5)P2.

The development of materials for advanced applications requires innovative macromolecules with well-defined structures and the inherent ability to be tailored in a straightforward manner. Dendrimers, being a subgroup of the dendritic polymer family, possess properties which fulfill such demands. They have a highly branched architecture with a high number of functional groups and are one of the most well-defined types of macromolecules ever synthesized. However, despite their well-defined nature and high functional density, traditional dendrimers commonly lack diverse chemical functionalities. Therefore, this thesis focuses on the synthesis of more complex dendritic materials to extend their tailoring capacity by introduction of dualfunctionalities for multipurpose actions. It covers the synthesis of dualfunctional dendrimers, dendritic modification of linear poly(ethylene glycol) polymers and cellulose surfaces, and the synthesis of linear dendritic hybrids. The building blocks enabling this synthesis, AB2C monomers, were also developed during this work. The orthogonal nature between click groups (azide, alkyne and alkene) and hydroxyl groups have efficiently been utilized for postfunctionalization by robust click chemistry and traditional esterification reactions. Furthermore, linear dendritic hybrids were synthesized, merging the properties of linear and dendritic macromolecules. The dendritic frameworks were tailored towards the production of bone fracture adhesives, novel biofunctional dendritic hydrogels, biosensors and micellar drug delivery vehicles. / Utveckling av material för avancerade applikationer kräver innovativa makromolekyler med väldefinierade strukturer och som kan skräddarsys på ett enkelt sätt. Dendrimerer är en undergrupp av dendritiska polymerer vars egenskaper uppfyller dessa krav. De har en mycket förgrenad arkitektur med många funktionella grupper och är en av de mest väldefinierade befintliga syntetiska makromolekylerna. Trots dess väldefinierade karaktär och höga funktionalitet saknar ofta traditionella dendrimerer multipla kemiska funktionaliteter. Denna avhandling fokuserar därför på syntesen av mer komplexa dendritiska material för att förbättra deras kapacitet att skräddarsys, detta görs genom att introducera fler funktionaliteter som kan utnyttjas för multipla ändamål . Avhandlingen redogör för syntesen av difunktionella dendrimerer, dendritiska modifikationer av polyetylenglykol och cellulosaytor samt syntes av traditionella dendritiska hybrider. Byggstenarna som möjliggör syntesen, AB2C monomerer, framställdes också under detta arbete. Den ortogonala karaktären mellan klick grupper (azid, alkyn och alkene) och hydroxylgrupper har utnyttjats effektivt för funktionaliseringar genom användande av robust ”Click”-kemi och traditionella esterifikationsreaktioner. Vidare tillverkades de linjära dendritiska hybrider för att kombinera egenskaperna hos både linjära och traditionella dendritiska polymerer i en och samma makromolekyl. Samtliga dendritiska strukturer skräddarsyddes för applikationer så som benlimmer, biofunktionella dendritiska hydrogeler, biosensorer och läkemedels-bärande miceller. / <p>QC 20130830</p>

Graft copolymers with a dendritic (arborescent) architecture and unimolecular micelle properties have been synthesized and examined for their solution properties as well as their ability to serve as templates for the preparation of metallic nanoparticles. The research focused on two types of arborescent copolymers, namely core-shell (CS) and core-shell-corona (CSC) architectures. Copolymer amphipolarity was provided by a hydrophobic polystyrene (PS) component and a polar poly(2-vinylpyridine), P2VP, phase. The CS copolymers were obtained by grafting P2VP onto linear or branched PS substrates to yield PS-g-P2VP unimolecular micelles. These copolymers exhibited solubility with limited aggregation in aqueous environments after protonation with HCl. Coordination of the coronal P2VP phase with HAuCl4 was achieved, and the resulting polymer-stabilized metallic nanoparticles had a spherical morphology. The tri-layered copolymers were synthesized in similar fashion, by grafting PS-b-P2VP block copolymers onto linear or branched PS substrates to afford a CSC morphology with a PS core, a P2VP inner shell, and a PS corona. While the grafting reaction proceeded with lower than expected grafting yields as compared to grafting reactions of homopolymer side-chains, significant P2VP content and molecular weight increases were achieved. It was determined that aggregation of the block copolymer side-chains hindered the coupling reaction of the reactive centers with the substrate. After purification of the PS-g-(P2VP-b-PS) arborescent copolymers, in part by developing a cloud-point centrifugation purification technique, the spherical copolymers were successfully loaded with various metallic compounds. The uptake of compounds such as HAuCl4 by the P2VP phase of the copolymers induced intramolecular phase segregation for copolymers of generations (G) 2 and above. Phase segregation produced some unique and intricate morphologies different from the ones observed previously for other unimolecular metal scaffolds. Intramolecular toroidal, nodular, and cylindrical morphologies were observed for the G2, G3, and G4 arborescent copolymers, respectively. Templates of generations 0 and 1 displayed a spherical morphology similar to their PS-b-P2VP intermolecular micelle analogues when loaded with metals. Phase segregation is believed to be mediated mainly by the characteristics of the PS core, the length of the P2VP segments having less influence on the morphologies obtained. Reduction of the metallic salts was performed using various agents and protocols. Stronger reducing agents yielded smaller and more narrowly distributed gold nanoparticles, while other reduction methods also removing the polymer scaffold resulted in larger nanoparticles.

Self-assembly of polymeric building blocks is a powerful tool for the design of novel materials and structures that combine different properties and may respond to external stimuli. In the past decades, most studies were focused on the self-assembly of amphiphilic diblock copolymers in solution. The dissolution of these block copolymers in a solvent selective for one block results mostly in the formation of micelles. The micellar structure of diblock copolymers is inherently limited to a homogeneous core surrounded by a corona, which keeps the micelle in solution. Thus, for drug-delivery applications, such structures only offer a single domain (the hydrophobic inner core) for drug entrapment. Whereas multicompartment micelles composed of a water-soluble shell and a segregated hydrophobic core are novel, interesting morphologies for applications in a variety of fields including medicine, pharmacy and biotechnology. The separated incompatible compartments of the hydrophobic core could enable the selective entrapment and release of various hydrophobic drugs while the hydrophilic shell would permit the stabilization of these nanostructures in physiological media. However, so far, the preparation and control of stable multicompartment micellar systems are in the first stages and the number of morphological studies concerning such micelles is rather low. Thus considerably little is known about their exact inner structures. In the present study, we concentrate on four different approaches for the preparation of multicompartment micelles by self-assembly in aqueous media. A similarity of all approaches was that hydrocarbon and fluorocarbon blocks were selected for all employed copolymers since such segments tend to be strongly incompatible, and thus favor the segregation into distinct domains. Our studies have shown that the self-assembly of the utilized copolymers in aqueous solution leads in three cases to the formation of multicompartment micelles. As expected the shape and size of the micelles depend on the molecular architecture and to some extent also on the way of preparation. These novel structured colloids may serve as models as well as mimics for biological structures such as globular proteins, and may open interesting opportunities for nanotechnology applications. / Die Selbstorganisation von synthetischen amphiphilen Blockcopolymeren ist ein vielseitiger Prozeß, der die Entwicklung von neuartigen Materialien, die verschiedene Eigenschaften miteinander verbinden und auch auf äußere Reize reagieren können, ermöglicht. In den letzten Jahrzehnten haben sich viele Untersuchungen mit der Selbstorganisation von Diblockcopolymeren in Lösung beschäftigt. So bilden zum Beispiel amphiphile Diblock-Copolymere in Wasser meist Mizellen die einen hydrophoben Kern und eine hydrophile Hülle besitzen. Ihre potentielle Anwendung als Wirkstoffträger ist jedoch begrenzt, da für die Einlagerung nur ein hydrophober Bereich zur Verfügung steht. Multikompartment-Mizellen, bestehend aus einer wasserlöslichen Hülle und einem unterteilten hydrophoben Kern, sind dagegen neuartige und sehr interessante Strukturen für die Nanotechnologie und im speziellen für die Nanobiotechnologie, da sie sich zum Beispiel als Träger für Arznei- und Wirkstoffe eignen. So könnten in die separaten und untereinander nicht mischbaren Kompartimente im Kern der Mizelle verschiedene hydrophobe Wirkstoffe selektiv eingelagert und auch freigesetzt werden, wobei die hydrophile Hülle die Nanostrukturen im physiologischen Medium stabilisiert. Aus diesem Grund wurden in den letzten Jahren verschiedene Strategien für die Herstellung von Multikompartiment-Mizellen vorgeschlagen. Bis jetzt gibt es jedoch nur eine begrenzte Anzahl an Untersuchungen, die sich mit der Morphologie solcher Mizellen befassen und somit ist auch wenig über ihre innere Struktur bekannt. In der vorliegenden Arbeit konzentrieren wir uns auf vier verschiedene Ansätze zur Herstellung von Multikompartiment-Mizellen durch Selbstorganisation in wässriger Lösung. Eine Gemeinsamkeit bei allen Ansätzen ist, das die untersuchten Copolymere einen hydrophoben Kohlenwasserstoff-Block sowie einen Fluorkohlenstoff-Block besitzen. Die Kombination von Kohlenwasserstoff- und Fluorkohlenstoff-Blöcken wurden gewählt, weil solche Segmente in der Regel nicht miteinander kompatibel sind und somit die Aufteilung in separate Domänen begünstigen. Unsere Untersuchungen haben gezeigt, dass die Selbstorganisation der verwendeten Copolymere in wässriger Lösung in drei Fällen zu Multikompartiment-Mizellen führt. Die Form und Größe der Mizellen ist erwartungsgemäß von der Molekülarchitektur und zum Teil auch vom Präparationsweg abhängig. Diese neuartigen, nanostrukturierten Kolloide könnten als Modell und Mimetika für biologische Strukturen wie die von globulären Proteinen fungieren. Sie eröffnen weiterhin interessante Möglichkeiten für Anwendungen in der Nanotechnologie.

Recent advancements in pharmaceutical technology based on principles of nanotechnology, polymer chemistry, and biomedical engineering have resulted in the creation of novel drug delivery systems with the potential to revolutionize current strategies in cancer chemotherapy. In oncology, realization of significant improvements in therapeutic efficacy requires minimization of drug exposure to healthy tissues and concentration of the drug within the tumor. As such, encapsulation of chemotherapeutic agents inside nanoparticles capable of enhancing tumor-targeted drug delivery is a particularly promising innovation. Yet, initial investigations into the intratumoral fate of nanomedicines have suggested that they may be heterogeneously distributed and achieve limited access to cancer cells located distant from the tumor vasculature. As such, uncovering the determinants of nanoparticle transport at the intratumoral level is critical to the development of optimized delivery vehicles capable of fully exploiting the therapeutic potential of nanomedicines. In this work, the chemotherapeutic agent, docetaxel (DTX), was incorporated into nano-sized, biocompatible PEG-b-PCL block copolymer micelles (BCMs). Encapsulation of DTX in micelles via chemical conjugation or physical entrapment resulted in a dramatic increase in drug solubility and customizable drug release rate. The use of multicellular tumor spheroids (MCTS) was established as a viable platform for assessing the efficacy and tumor tissue penetration of nanomedicines in vitro. A series of complementary assays was validated for analysis of DTX-loaded micelle (BCM+DTX) toxicity in monolayer and spheroid cultures relative to Taxotere®. Cells cultured as spheroids were less responsive to treatment relative to monolayer cultures due to mechanisms of drug resistance associated with structural and microenvironmental properties of the 3-D tissue. Computational, image-based methodologies were used to assess the spatial and temporal penetration of BCMs in spheroids and corresponding human tumor xenografts. Using this approach, the tumor penetration of micelles was found to be nanoparticle-size-, tumor tissue type- and time- dependent. Furthermore, spheroids were found to be a valuable platform for the prediction of trends in nanoparticle transport in vivo. Overall, the results reported herein serve to demonstrate important determinants of nanoparticle intratumoral transport and to establish computational in vitro and in vivo methodologies for the rational design and optimization of nanomedicines.

Recent advancements in pharmaceutical technology based on principles of nanotechnology, polymer chemistry, and biomedical engineering have resulted in the creation of novel drug delivery systems with the potential to revolutionize current strategies in cancer chemotherapy. In oncology, realization of significant improvements in therapeutic efficacy requires minimization of drug exposure to healthy tissues and concentration of the drug within the tumor. As such, encapsulation of chemotherapeutic agents inside nanoparticles capable of enhancing tumor-targeted drug delivery is a particularly promising innovation. Yet, initial investigations into the intratumoral fate of nanomedicines have suggested that they may be heterogeneously distributed and achieve limited access to cancer cells located distant from the tumor vasculature. As such, uncovering the determinants of nanoparticle transport at the intratumoral level is critical to the development of optimized delivery vehicles capable of fully exploiting the therapeutic potential of nanomedicines. In this work, the chemotherapeutic agent, docetaxel (DTX), was incorporated into nano-sized, biocompatible PEG-b-PCL block copolymer micelles (BCMs). Encapsulation of DTX in micelles via chemical conjugation or physical entrapment resulted in a dramatic increase in drug solubility and customizable drug release rate. The use of multicellular tumor spheroids (MCTS) was established as a viable platform for assessing the efficacy and tumor tissue penetration of nanomedicines in vitro. A series of complementary assays was validated for analysis of DTX-loaded micelle (BCM+DTX) toxicity in monolayer and spheroid cultures relative to Taxotere®. Cells cultured as spheroids were less responsive to treatment relative to monolayer cultures due to mechanisms of drug resistance associated with structural and microenvironmental properties of the 3-D tissue. Computational, image-based methodologies were used to assess the spatial and temporal penetration of BCMs in spheroids and corresponding human tumor xenografts. Using this approach, the tumor penetration of micelles was found to be nanoparticle-size-, tumor tissue type- and time- dependent. Furthermore, spheroids were found to be a valuable platform for the prediction of trends in nanoparticle transport in vivo. Overall, the results reported herein serve to demonstrate important determinants of nanoparticle intratumoral transport and to establish computational in vitro and in vivo methodologies for the rational design and optimization of nanomedicines.