No description available.

Marine biofouling has troubled mankind, both environmentally and economically, since they set sail, resulting in many undesired consequences such as increased drag, reduced maneuverability, increased fuel consumption and greenhouse gas emissions, and heightened maintenance costs. This problem is highly complex as it involves more than 4000 marine organisms with varying modes of adhesion and surface preferences as well as many aquatic environments. The common state-of-the-art approaches to contend with marine biofouling on the submerged surfaces of ships in seawater has antifouling (AF) and fouling-release (FR) surfaces. As AF coating systems utilize biocides which are often toxic to the environment to prevent settlement of biofoulants, the endeavors have been shifted towards non-toxic FR marine system. Many FR systems take advantage of low surface energy and modulus polydimethylsiloxane (PDMS) on their surface, while the recent attempts explored the simultaneous effect of PDMS and hydrophilic moieties (i.e. polyethylene glycol (PEG) or zwitterionic polymers) on an FR surface, known as amphiphilic surfaces. Thus, the work in this dissertation focused on attaining amphiphilic surfaces with desirable FR performance. The studies in this dissertation were investigated to deliver two goals: 1) Enhancing the (FR) fouling-release performance of previously developed coating systems; 2) Introducing novel fouling-release marine coatings with set criteria. To address the former, a series of amphiphilic additives containing PDMS and hydrophilic polymers (zwitterionic-based or PEG) were prepared in chapters two-five. These additives were incorporated in several previously developed FR coating systems in order to modify their surfaces and enhance their FR performance. To address the latter, two amphiphilic marine coating systems were explored for accessing durable, non-toxic, and effective FR surfaces using epoxy-amine crosslinking chemistry. Overall, the studies in this dissertation not only demonstrated viable FR surfaces with desirable performance against several representative marine organisms such as N. incerta, U. linza, C. lytica, barnacles, and mussels but also contributed a deeper understanding about the effect of amphiphilicity concentration/balance on surface and FR properties.

Doctor of Philosophy / Department of Biochemistry / John M. Tomich / Peptide-based delivery systems show great potential as safer drug delivery vehicles. They overcome problems associated with lipid-based or viral delivery systems, vis-a-vis stability, specificity, inflammation, antigenicity, and tune-ability. We have designed and synthesized a set of 15 and 23-residue branched, amphiphilic peptides that mimic phosphoglycerides in molecular architecture. They undergo supramolecular self-assembly and form solvent-filled, bilayer delineated spheres with 50-150 nm diameters (confirmed by TEM and DLS). Whereas weak hydrophobic forces drive and sustain lipid bilayer assemblies, these structures are further stabilized by β-sheet hydrogen bonding and are stable at very low concentrations and even in the presence of SDS, urea and trypsin as confirmed by circular dichroism spectroscopy. Given sufficient time, they fuse together to form larger assemblies and trap compounds of different sizes within the enclosed space. They are prepared using a protocol that is similar to preparing lipid vesicles. We have shown that different concentrations of the fluorescent dye, 5(6)-Carboxyfluorescein can be encapsulated in these assemblies and delivered into human lens epithelial cells and MCF-7 cells grown on coverslips. Besides fluorescent dyes, we have delivered the plasmid (EGFP-N3, 4.7kb) into N/N 1003A lens epithelial cells and observed expression of EGFP (in the presence and absence of a selection media). In the case of large molecules like DNA, these assemblies act as nanoparticles and offer some protection to DNA against certain nucleases. Linear peptides that lacked a branching point and other branched peptides with their sequences randomized did not show any of the lipid-like properties exhibited by the branched peptides. The peptides can be chemically decorated with target specific sequences for use as DDS for targeted delivery.

Visando o crescente interesse em pesquisa de novos materiais que utilizam polímeros biodegradáveis, este presente trabalho teve como objetivo a síntese de novos copolímeros através da reação de transesterificação no estado fundido entre poli(3-hidroxibutirato) (PHB), um polímero biodegradável, com poli(etileno glicol) (PEG). Sabe-se que um dos grandes problemas no uso do PHB é a sua elevada cristalinidade e instabilidade térmica, pois possui temperatura de fusão entre 170 e 180°C e apresenta degradação térmica a 190°C. A reação de transesterificação é uma alternativa para fazer a modificação química deste polímero, o que também viabiliza a formação de copolímeros anfifílicos triblocos. O objetivo final foi utilizar este novo material para o preparo de nanopartículas poliméricas a partir do método de difusão do solvente. Tais partículas são utilizadas para microencapsulamento de fármacos. Os copolímeros foram sintetizados e caracterizados por ensaio de solubilidade, espectrometria de ressonância magnética nuclear de hidrogênio (RMN), calorimetria diferencial exploratória (DSC), espectroscopia no infravermelho com transformada de Fourier (FTIR), cromatografia de permeação em gel (GPC), análise por difração de Raios-X (WAXS), microscopia ótica de luz polarizada (MOLP) e microscopia eletrônica de varredura (MEV). A indicação de formação de copolímero anfifílico pode ser observada nos ensaios de solubilidade, pois o copolímero mostrou-se parcialmente solúvel em uma série de solventes em que o PHB original é insolúvel. A modificação química pode ser observada com as técnicas de RMN e FTIR, cujos espectros apresentaram absorções referentes ao grupo carbonila da ligação éster. As técnicas de DSC, WAXS e MOLP mostraram uma ligeira redução na cristalinidade do material, além da temperatura de fusão reduzir-se de 171ºC para 154°C. Com o GPC observou-se uma redução da massa molar, o que facilita a formação das nanopartículas poliméricas. As nanopartículas apresentaram tamanhos com diâmetros ao redor de 250nm, quando observadas por MEV. / Aimed at the growing interest in research on new materials using biodegradable polymers, the present work was aimed at the synthesis of new copolymers through transesterification reaction in the molten state of poly (3-hydroxybutyrate) (PHB), a biodegradable polymer, poly (ethylene glycol) (PEG). It is well known that a major problem in the use of PHB is its high crystallinity and thermal instability, as it has melting temperature between 170 and 180° C and shows thermal degradation at 190°C. The transesterification reaction is an alternative to the chemical modification of this polymer, which also enables the formation of amphiphilic triblock copolymers. The mainly goal of this studies was to use this new material for the preparation of polymeric nanoparticles from the solvent diffusion method. Such particles are used for microencapsulation of drugs. The copolymers were synthesized and characterized by solubility test, Nuclear Magnetic Resonance Spectroscopy of Hydrogen (NMR), Differential Scanning Calorimetry (DSC), Infrared Spectroscopy with Fourier transform (FTIR), Gel permeation chromatography (GPC) analysis by X-ray diffraction (WAXS), polarized light optical microscopy (MOLP) and scanning electron microscopy (SEM). The signs of the formation of amphiphilic copolymer can be observed in the trials of solubility, since the copolymer was found to be partially soluble in a variety of solvents in the original PHB is insoluble. The chemical modification can be observed with the techniques of NMR and FTIR spectra which showed absorptions for the carbonyl group of the ester linkage. The techniques of DSC, WAXS and MOLP showed a decrease in crystallinity of the material in 15%, and reduce the melting temperature is 171ºC to 154°C. With the GPC showed a reduction in molar mass, which facilitates the formation of polymeric nanoparticles. The nanoparticles showed sizes with diameters around 250nm observed by SEM.

Amphiphilic polymers are a subset of macromolecules that exhibit both hydrophobic and hydrophilic moieties within their covalently bonded structures. Because of the differing solubilities of the contrasting regions of the amphiphilic polymers, they exhibit an inherent ability to self-assemble in the solution phase where one block exhibits poor compatibility with the solvent. And by tuning the composition, size and shape of the polymers, a variety of morphologies of the assembly in solution were observed, like spherical micelle, vesicle, rod-like and lamellar. The propensity to self-assemble to complex structures makes them promising candidates in wide varieties of applications, for example, drug delivery, gene transfection, catalyst, and sensing. Nowadays, most of the researches of amphiphilic polymers have been focused on simple linear di-block copolymers. Amphiphilic non-linear architectures, like dendrimers, star polymers, hyperbranched polymers, brush polymers and cyclic polymers, have been proved to exhibit unique properties compare to their linear analogs, such as lower critical micelle concentrations and better-assembled strengths because the structures are covalently tethered together. These unique properties make them a particularly attractive vehicle in drug/gene delivery. However, investigations of the amphiphilic homopolymers are limited and the majority of work have been done is focused on charged polymers, anionic or cationic. The amphiphilic ionic homopolymers largely relied on the pH of the solution to assemble into complex morphologies, perturbation of pH could result in deformation of assemblies and pro-release of encapsulate. Also, extremely severe pH environment prohibit the usages of the amphiphilic polymers in biological systems. Well defined non-ionic amphiphilic linear homopolymers bearing hydrophobic decyl groups and hydrophilic tri(ethylene glycol) monomethyl ether groups was synthesized by atom transfer radical polymerization technique and the structures were confirmed by NMR and GPC. The low polyedispersity polymers, were found to readily self-assembled to form micelles in non-polar organic phase and reverse micelles in polar aqueous phase. The assemblies were studied with UV-vis spectroscopy, fluorescence spectroscopy, dynamic light scattering, and transmission electron microscopy to determine the critical micelle concentrations and assembly size in both conditions. The synthesis towards more complex architectures of the homopolymers was also investigated. / acase@tulane.edu

WHO has reported that antibiotic resistance is the third major cause of human death all over the globe. Recent study, has focused on the development of new antibacterial resistance drugs. Herein, we tried to synthesis a series of polymers that can mimic the HDPs. HDPs can target the bacterial cell membrane and they have less chances to develop bacterial resistance. We synthesized the amphiphilic polycarbonates that are highly selective to Gram-positive bacteria, including multidrug resistant pathogens. The membrane disruption activity of these polymers was proved by fluorescence and TEM studies and the drug resistance study showed that the polymers don’t develop bacterial resistance. In order to further design the molecules that can target a broad spectrum of bacteria, we have designed a series of lipidated dendrimers that can target the Gram-positive and Gram-negative bacteria. These dendrimers mimic the HDPs and target the bacterial cell membrane. Dendrimers are reported to inhibit the formation of bacterial biofilm which makes them promising for their future development of antibiotic agents. Apart from the synthesis of polymers and dendrimers as antibacterial agents, we have designed a series of small molecular antibacterial agents that are based on the acylated reduced amide scaffold and small dimeric cyclic guanidine derivatives. These molecules display good potency against a panel of multidrug-resistant Gram-positive and Gram-negative bacterial strains. Meanwhile, they also effectively inhibit the biofilm formation. Mechanistic studies suggest that these compounds kill bacteria by compromising bacterial membranes, a mechanism analogous to that of host-defense peptides (HDPs). Lastly, we also demonstrate that these molecules have excellent in vivo activity against MRSA in a rat model. This class of compounds could lead to an appealing class of antibiotic agents combating drug-resistant bacterial strains.

The emergence of antibiotic resistant bacteria has prompted the research into novel kinds of antibacterial small molecules and polymers. Nature has solved this issue with the use of cationic antimicrobial peptides, which act as nonspecific antibiotics against invading species. Herein, we have tried to mimic this general mechanism in a biocompatible and biodegradable polymer micelle based on the polymerization of naturally occurring amino acids lysine and phenylalanine linked to a PEG tether. This amphiphilic structure allows for the spontaneous collapse into stable nanoparticles in solution, which contains a hydrophilic outer layer and a hydrophobic core. Our polymers have shown activity against clinically relevant strains including Methicillin Resistant S. epidermidis, B. subtilis, K. pneumoniae, and P. aeruginosa. To further the application of our biopolymers, we have used them as drug delivery vehicles as well. First, we have used an anionic analogue based on glutamic acid to encapsulate a super hydrophobic drug Tanshinone IIA, and use it against a hepatoma bearing mouse model. Second, we have used a cationic analogue to form a complex with miRNA-139 and use it against a hepatoma bearing mouse model as well. In both cases, our PEG poly(amino acids)s have shown promising efficacy in drastically reducing the tumor size compared to the control only. Taken together, our results show that our nanoparticles have the potential to be versatile biomaterials as antibacterials as well as drug delivery vehicles in vivo.

A series of amphiphilic copolymers is prepared by copolymerization of choline methacrylate with 1,1,2,2-tetrahydroperfluorooctyl methacrylate in varying amounts. The copolymers bearing fluorocarbon chains are studied concerning their effects on viscosity, solubilization and surface activity in aqueous solution, exhibiting a general behavior characteristic for polysoaps. The results are compared with the ones obtained for an analogous series of amphiphilic copolymers bearing hydrocarbon chains.

Living anionic polymerization techniques were applied to the synthesis of arborescent (dendritic) well-defined graft polymers having core-shell morphologies, with a hydrophobic core and a hydrophilic shell. Cycles of polystyrene substrate acetylation and anionic grafting yielded successive generations of arborescent polystyrenes. The anionic polymerization of styrene with sec-butyllithium provided polystyryllithium serving as side chains. These were coupled with a linear acetylated polystyrene substrate to obtain a generation zero (G0) arborescent polymer. An analogous G0 hydroxyl-functionalized polystyrene substrate with hydroxyl end groups was also obtained by a variation of the same technique, using a bifunctional organolithium initiator containing a hydroxyl functionality protected by a silyl ether group to generate the polystyrene side chains. These were coupled with the linear acetylated polystyrene substrate and subjected to a deprotection reaction to give the G0 polymer functionalized with hydroxyl groups at the chain ends. A similar procedure was used to generate a hydroxyl-functionalized arborescent G1 polymer from the corresponding G0 acetylated polystyrene substrate. The growth of polyglycidol chain segments was attempted from the hydroxyl-functionalized cores, to form a hydrophilic shell around the hydrophobic cores, but led to extensive degradation. A click reaction was also developed to synthesize the amphiphilic copolymers and was much more successful. In this case alkyne-functionalized arborescent polystyrene substrates, obtained by a modification of the hydroxyl-functionalized arborescent polystyrenes, were coupled with azide-functionalized polyglycidol side chains.

En aquest treball es descriu la síntesi de tres noves fosfines ambifíliques hidrosolubles (CH3)3C-CH2-C(CH3)2-Ph-(OCH2CH2)n-P(Ph)CH2CH2SO3Na (amb n= 1 (1), 5 (2)), Ph2PCH2CH2CH2P(Ph)CH2CH2-SO3Na (3), les quals varen ser caracteritzades per tècniques de ressonància magnètica nuclear de 1H, 13C i 31P, i per espectrometria de masses electrosprai.S'ha estudiat la reacció d'hidroformilació d'olefines superiors amb catalitzadors de rodi en sistemes bifàsics amb onze lligands ambifílics. Tot i que amb un dels lligands es va obtenir un elevat percentatge de conversió, la presència de metall en la fase orgànica impossibilita l'ús d'aquests lligands en processos industrials. Un estudi sintètic paral·lel en condicions d'hidroformilació va permetre caracteritzar la formació del complex [RhH(CO)L3] (L=fosfina ambifílica) a partir del precursor [Rh(acac)(CO)2].Estudis de complexació de les fosfines ambifíliques amb pal·ladi(II) han portat a la caracterització de complexos d'estequiometria [PdCl2L2]. A partir d'aquests estudis s'han obtingut per primera vegada dades experimentals que indiquen la coordinació del grup sulfonat de les fosfines al pal·ladi.Es varen efectuar estudis d'agregació de les fosfines ambifíliques i dels seus respectius complexos de pal·ladi. Mitjançant mesures de tensió superficial es va confirmar el caràcter tensioactiu de (1) i (2) i del complex [PdCl2(2)2]. Es va obtenir en cada cas el valor de la concentració micel·lar crítica. Per tal de visualitzar els agregats formats es varen estudiar solucions aquoses d'alguns dels lligands ambifílics i els seus complexos de pal·ladi per microscòpia electrònica usant la tècnica de la criofractura. L'estructura dels agregats no va poder ser caracteritzada completament mitjançant aquest mètode, probablement a causa de que es formarien principalment micel·les, les quals són massa petites per ser observades a través del microscopi electrònic.Finalment s'han realitzat estudis de radiocompostos de 99m-Tecneci per tal de ser aplicats en medicina nuclear com a radiofàrmacs. Es va estudiar la formació de radiocompostos amb les fosfines ambifíliques mitjançant diferents mètodes cromatogràfics. Es va estudiar la biodistribució del radiocompost format amb la difosfina (3) en una rata de laboratori, mostrant una acumulació preferencial en el ronyó i el fetge. Paral·lelament es va realitzar un estudi sintètic de complexos homòlegs de reni no radioactius. En aquest cas es va poder caracteritzar, mitjançant 31P-RMN, la formació del complex octaèdric [ReO2(3)2] on el lligand difosfina actua com a quelat. Es va poder comprovar la dificultat per obtenir complexos octaèdrics d'estructura semblant amb lligands monofosfina. / The synthesis of the following three new water soluble amphiphilic phosphines is described (CH3)3C-CH2-C(CH3)2-Ph-(OCH2CH2)n-P(Ph)CH2CH2SO3Na (n = 1 (1), 5 (2)), Ph2PCH2CH2CH2P(Ph)CH2CH2-SO3Na (3). These phosphines were characterized by 1H, 13C and 31P nuclear magnetic resonance, and electrospray mass spectrometry.The hydroformylation reaction of higher olefines with rhodium catalysts in two-phase systems with eleven amphiphilic ligands was studied. Although a high conversion was observed with one ligand, the use of these ligands in industrial processes was disabled because the catalyst was partially soluble in the organic phase. A synthetic study under hydroformylation conditions allowed to characterize the complex [RhH(CO)L3] (L= amphiphilic phosphine) starting from the precursor [Rh(acac)(CO)2].Complexation studies of the amphiphilic phosphines with palladium(II) allowed to the characterization of [PdCl2L2] complexes. As far as we know, these studies supplied the first experimental data points to the coordination of the sulphonate group to the metal in phosphine ligands with the ethylsulphonate fragment.Aggregation studies of the amphiphilic phosphines and their respective palladium complexes were carried out. Superficial tension measures confirmed the tensioactive character of (1), (2) and the complex [PdCl2(2)2]. The critical micellar concentrations were determined.Aqueous solutions of some amphiphilic ligands and their palladium complexes were studied by transmission electron microscopy (TEM) using the freeze-fracture technique in order to visualize the formed aggregates. The structure of the aggregates could not be fully characterized by this method, probably because micelles were mainly formed and they are too small to be characterized by this technique.Finally, synthetic studies of 99m-Technecium radiocompounds for nuclear medicine applications as radiopharmaceuticals were carried out . The formation of radiocompounds with the amphiphilic phosphines was studied by means of TLC methods. The bio-distribution of the radiocompound formed with the diphosphine (3) was studied in a rat, showing a preferential accumulation in kidney and liver. A synthetic study with the homologous non radioactive rhenium complex was carried out. The octahedral complex [ReO2(3)2]- was characterised by 31P NMR data and the results are consistent with the chelation of the diphosphine ligand acts to the metal. The synthesis of similar octahedral complexes with monophosphine ligands was unsuccessful.