This thesis describes the synthesis of yttrium oxide nanoparticles in an AOT/isooctane reverse micelle solution. Two synthetic methods are compared. First is the precipitation reaction between yttrium nitrate and ammonia, second is the hydrolysis of yttrium isopropoxide. The effects of annealing of the resulting the yttrium oxide nanoparticles are also described. The nitrate method produced network-like aggregates of yttrium oxide nanoparticles ranging from 10 nm to 40 nm in diameter. Reaction conditions, including the water/AOT ratio (1 to 15), the nitrate concentration (0.02 M to 1.0 M), the ammonia concentration (2 M to 14.8 M), the AOT concentration (0.1 M and 0.5 M), the aging time (1 h to 5 d), and the washing method, were varied to investigate their influence on nanoparticle formation. The optimized synthetic conditions were: a water/AOT ratio of 7.5, [NO₃⁻] = 0.5 M, [NH₃] = 2 M, and [AOT] = 0.1 M. The as-prepared yttrium oxide nanoparticles had highly distorted structures related to the cubic Y2O3 phase. Annealing improved the crystallinity of the as-prepared nanoparticle products and led to larger particles. As annealing temperatures increased, the yttrium oxide nanoparticles gradually evolved into the cubic Y₂O₃ phase. However, an unknown intermediate phase was also observed during the annealing process, which disappeared when the annealing temperature was sufficiently high and the annealing time was long enough (>1000 °C and 4 h). As-prepared products from the isopropoxide hydrolysis also contained network-like nanoparticle aggregates. Particle sizes ranged from 10 nm to 20 nm. Some experimental conditions were varied; they were the water/AOT ratio (10 to 40), the isopropoxide concentration (0.0001 M to 0.003 M), the aqueous phase pH (7.0 and 12.0), the aging temperature (room temperature, approximately 25 °C, and refluxing temperature, approximately, 100 °C), and the aging time (1 h to 5 d). Transmission Electronic Micrographs showed that products of desirable morphology could be produced in a much wider range of experimental conditions by this method compared to those produced by nitrate hydrolysis. / Master of Science

Yes / The structure and dynamics of a single molecule of the nonionic surfactant polysorbate 80 (POE (20) sorbitan monooleate; Tween 80 ) as well as a micelle of polysorbate 80 in water have been investigated by molecular dynamics simulation. In its free state in water the polysorbate 80 molecule samples almost its entire conformational space. The micelle structure is compact and exhibits a prolate ellipsoid shape, with the surface being dominated by the polar terminal groups of the POE chains. The radius of gyration of the micelle was 26.2 A. The physical radius, determined from both the radius of gyration and atomic density, was about 35 A. The estimated diffusion constants for the free molecule (1.8 10 6 cm2 s 1) and the micelle (1.8 10 7 cm2 s 1) were found to be remarkably close to the respective experimental values. The lateral diffusion of the molecules on the micelle surface was estimated to be 1.7 10 7 cm2 s 1, which confirms the highly dynamic nature of the micelle structure. / Tehran University of Medical Sciences & Health Services

Quaternary ammonium lipids containing long hydrocarbon-chains can cause deleterious effects when administered to many types of microorganisms. Some compounds have potent activity against spermatozoa and the HIV virus. Consequently, quaternary ammonium lipids are key components in spermicidal and antiseptic formulations. Surface-active quaternary ammonium lipids, containing a hydrophobic and hydrophilic moiety, will aggregate into micelles when dissolved in water above a narrow concentration range, termed the critical micelle concentration (CMC). This project investigates how the CMC relates to spermicidal and microbicidal properties. The CMC’s of the AD-nX and AT-nX compounds [see documents for figures] were determined by conductivity measurements. Relationships among the CMC and factors such as alkyl-chain length, head-group size, counteranion, and biological activity are discussed. [See document for figures of ADn and ATn] / Master of Science

In this project, we synthesized a new homologous series of five long-chain, two-headed amphiphiles [2CAm13, 2CAm15, 2CAm17, 2CAm19, 2CAm21; CH3(CH2)n-1CONHC(CH3)(CH2CH2COOH)2, n = 13, 15, 17, 19, 21]. The synthesis of the 2CAmn series was accomplished in four steps. The first step involves a reaction of nitroethane and two equivalents of tert-butyl acrylate to create the nitrodiester synthon [O2NC(CH3)(CH2CH2COOtBu)2] by successive Michael additions. The second step in the synthesis consists of a reduction of nitrodiester with H2 and Raney nickel to give the diesteramine [H2NC(CH3)(CH2CH2COOtBu)2]. The third step is the condensation of an acid chloride with diesteramine to give an alkanamido diester [2EAmn; CH3(CH2)n-1CONHC(CH3)(CH2CH2COOtBu)2, n = 13, 15, 17, 19, 21]. The final step is the removal of the tert-butyl protecting groups to give 2CAmn. Critical micelle concentration measurements were collected by the pendant drop method for measuring surface tension for a series of triethanolamine/2CAmn solutions to establish the concentration required for detergency. The CMCs for the 2CAmn series were found to decrease in value from 3.0 Ã 10â 2 M (2CAm13) to 1.7 Ã 10â 4 M (2CAm21) in a linear fashion [log CMC = (â 0.28 ± 0.01)n + (2.2 ± 0.1)]. The CMCs for the 2CAmn series falls in between the CMCs for three series of homologues three-headed amphiphiles (3CAmn, 3CCbn, 3CUrn) and the CMCs for fatty acids, with fatty acids having the lowest CMCs. Antibacterial activity (minimal inhibitory concentrations, MICs) for a series of homologous dendritic two-headed amphiphiles and three series of homologous, three-headed amphiphiles against Staphylococcus aureus and methicillin-resistent S. aureus (MRSA) were measured by broth microdilution to compare the effect of chain length and, hence, hydrophobicity. Inoculum density affected antibacterial activity of the 2CAmn series against both S. aureus and MRSA. MIC measurements at different cell densities showed that activity decreased with higher cell densities. For all four series, the MICs were relatively flat at low inoculum densities. This flat region defines the intrinsic activity, MIC0. The MIC0 results revealed that inoculum density, chain-length, and hydrophobicity all influenced antibacterial activity and that activity correlates strongly with clogp, an established measure of hydrophobicity. The most hydrophobic members from each homologous series exhibited antibacterial activity. The most active homologue of the 2CAmn series was 2CAm21 with MIC0 of 2.0 ± 1.0 and 3.2 ± 1.0 μM against S. aureus and MRSA, respectively. The CMCs and MIC0s of the two- and three-headed amphiphiles were compared for both S. aureus and MRSA to gauge the effect that micelles may have on activity. Amphiphile 2CAm19 has the largest ratio between CMC and MIC0 (CMC/MIC0 = 205) against S. aureus and 3CUr20 has the largest ratio (CMC/MIC0 = 339) against MRSA. These ratios suggest that micelle formation is not a mechanism of action for anti-Staphylococcal activity. / Master of Science

This project is about the synthesis of homologous series of two-headed, long-chain amphiphiles (the 2CCbn series, where n = 16, 18, 20, 22, 30, 5α-cholestan-3Ã -ol). The 2CCbn series was synthesized in five steps. The first step involves a reaction of nitroethane and two equivalents of tert-butyl acrylate to form nitrodiester by successive Michael addition reaction. The second step is the reduction of nitrodiester with Raney nickel to form aminodiester. The third step involves a reaction of aminodiester with di-tert-butyl dicarbonate [(Boc)2O] to form isocyanatediester. The fourth step is addition of iscocyanatediester with aliphatic alcohol to give alkyl carbamate diester (2ECbn) series. The fifth step is the removal of the tert-butyl protecting group to give the 2CCbn series. The critical micelle concentrations (CMC) were measured by the pyrene-based fluorescent probe method. The pyrene excited at 345 nm and fluoresces with maxima at 374 nm (I1) and 385 nm (I3). The stock solution and the dilution series for each amphiphiles were made in 0.9% triethanolamine solution. The CMCs were measured at two pH ~9.2 and 7.4. The CMCs were determined by plotting I1/I3 vs. concentrations. The CMCs were decreasing with increasing chain length. The CMCs for the 2CCbn series are lower than the 3CCbn series but higher than the fatty acids. The minimal inhibitory concentrations were measured against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus. These strains were grown on BHIB+S with 5% triethanolamine. The MICs of the 2CCbn series amphiphiles were measured by using microtiter plate reader and by looking turbidity. The cutoff effect was found for the 2CCbn series. The MIC decreased up to C20 chain length and started rising for C22. The 2CCb18 (MICâ 2.2 µg/mL) of the 2CCbn series was the most effective amphiphile against S. aureus and MRSA. The CMC/MIC ratio was used to determine the safety of an amphiphile as a drug use. The amphiphile 2CCb18 has given the largest safety ratio (CMC/MIC = 273) against S. aureus and MRSA. It suggests that micelle formation is not a mechanism of action for anti-Staphylococcal activity. / Master of Science

Les oligonucléotides (ONs) antisens présentent un fort potentiel en tant qu’agents thérapeutiques. Toutefois, leurs propriétés physicochimiques limitent leur utilisation en thérapie génique. Pour pallier aux divers obstacles, des systèmes de vectorisation, tels que les micelles polyioniques (PICMs), ont été développés. Grâce à leur structure unique, les micelles protégent l’ON contre une dégradation prématurée et le couplage d’un ligand à leur surface augmente leur spécificité et leur internalisation. Dans d’autres systèmes, un polymère adjuvant aux propriétés pH-sensibles peut être ajouté pour faciliter la sortie de l’endosome et augmenter l’efficacité de l’ON. L’objectif général de ce mémoire était de mettre au point des PICMs ternaires ciblées pour l’administration d’ONs. Ces micelles assureraient à la fois l’internalisation cellulaire de leur cargaison en interagissant avec des récepteurs cellulaires et sa fuite de l’endosome grâce à un mécanisme de déstabilisation de la membrane endosomale. Pour cela, des PICMs composées d’un copolymère cationique de type poly(éthylène glycol)-bloc-poly(méthacrylate d’(alkylamino)éthyle) et d’un copolymère d’acide méthacrylique ont été préparées. Les propriétés physicochimiques de ces vecteurs ont démontré qu’ils permettaient une condensation efficace de l’acide nucléique et ce, indépendamment de la nature du polymère cationique et de l’acide nucléique. Finalement, une approche de couplage par pont disulfure a été développée afin de greffer au copolymère un fragment d’anticorps dirigé contre les récepteurs de la transferrine. En conclusion, ces travaux démontrent la versatilité et le potentiel des PICMs ternaires en tant que vecteurs d’acide nucléique, et proposent une méthodologie de couplage d’un ligand afin de formuler des PICMs ciblées. / Antisens oligonucleotides (ONs) present great potential as therapeutic agents. However, their physicochemical properties hinder their use in gene therapy. Targeting systems, such as polyion complex micelles (PICMs), have been proposed to circumvent the main hurdles related to ON delivery. Their unique core/shell structure can protect the ON against premature degradation and the coupling of a ligand on their surface can increase their specificity and internalization. In other systems, a polymer with pH-sensitive properties can be added to facilitate the release of the ON from the endosome and increase its efficiency. The present work was aimed at optimizing ternary PICMs targeted for the delivery of antisens ON. Such systems would provide both cellular internalization of cargo by interaction with receptors on the surface of cell membranes and escape from the endosome through a mechanism of destabilization of the endosomal membrane. PICMs composed of cationic copolymers of poly(ethylene glycol)-bloc-poly((alkylamino)ethyl methacrylate) with a methacrylic acid copolymer adjuvant were prepared. Their physicochemical properties suggest that efficient complexation of nucleic acids was obtained, regardless of the nature of the cationic polymer and the nature of the nucleic acid. Finally, a synthetic approach was developed for the conjugation of an antibody fragment directed against the transferrin receptor via a labile disulfide bond at the end of the cationic copolymer. In conclusion, the work presented herein displays the versatility and potential of ternary PICMs as vehicles for the delivery of ONs and also provides a method for the conjugation of a ligand to generate targeted ternary PICMs.

Cette thèse a pour objectif l’élaboration de nanoparticules hybrides à base de silice par microémulsion inverse. Les nanoparticules de silice constituent une matrice de base permettant de confiner et de protéger des molécules organiques et/ou des nanoparticules métalliques. L’incorporation combinée de différentes entités dans la silice ouvre ainsi de larges perspectives de par l'introduction de nouvelles propriétés liées à la structure hybride. Afin d’élaborer de tels objets, nous avons utilisé des micelles inverses à base d'eau, de Triton X-100, d'hexanol et de cyclohexane comme milieu réactionnel. L’influence des conditions opératoires sur le contrôle de la taille des micelles inverses a d'abord été étudiée. Ces micelles inverses ont ensuite été mises à profit comme nanoréacteurs pour la synthèse de nanoparticules de silice par procédé sol-gel en utilisant les précurseurs alkoxysilanes adéquats. Nous avons regardé dans quelle mesure il était possible de contrôler la taille des nanoparticules de silice en fonction du pourcentage d’eau par rapport au tensioactif. Il a ainsi été possible d’accéder de façon reproductible à des nanoparticules avec de tailles variables, de 30 nm à 200 nm. Nous avons ensuite regardé qu'il était possible d'encapsuler au sein de cette matrice nanométrique des fluorophores et des nanoparticules d’or et d’argent de façon contrôlée. En vue d’assurer une bonne stabilisation colloïdale en solution, ces nanoparticules hybrides ont été fonctionnalisées d'une part par ajout d'un silane fonctionnel et d'autre part par click chemistry. Nous avons ainsi pu montrer qu’il est possible d’effectuer dans un même milieu micellaire l’ensemble des processus de fabrication de la nanoparticule hybride, de la matrice de silice à sa fonctionnalisation en passant par l’incorporation d’entités fonctionnelles. Cette méthode de synthèse séquentielle nous a ainsi permis de supprimer les étapes de purification et de redispersion qui peuvent s’avérer problématiques dans les procédés classiques. L’ensemble de ce travail a été mis à profit pour la conception d’un agent antibactérien à base de nanoparticules argent/silice capables d’empêcher la prolifération bactérienne grâce au relargage progressif des ions argent. Les tests effectués en solution comme sur le coton et le polyéthylène téréphtalate imprégnés montrent effectivement un caractère antibactérien certain de ces systèmes. / This thesis aims at developing hybrid nanoparticles based on silica by reverse microemulsion. The silica nanoparticles are the basic matrix containing and protecting organic molecules and/or metallic nanoparticles. The combined incorporation of different entities within the silica opens wide prospects for the introduction of new properties related to the hybrid structure. To develop such objects, we used reverse micelles based on water, Triton X-100, hexanol and cyclohexan as reaction medium. The influence of operating conditions on the control of the size of reverse micelles was first studied. These micelles were then set to be used as nanoreactors for the synthesis of silica nanoparticles by sol-gel using suitable alkoxysilanes precursors. We monitored how it was possible to control the size of silica nanoparticles based on the water to surfactant ratio. It was thus possible to prepare in a reproducible way nanoparticles with sizes varying from 30 nm to 200 nm. We then investigated the possibility to encapsulate, in this nanoscaled matrix, fluorophores and nanoparticles of gold and silver in a controlled manner. To ensure a good colloidal stability in solution, these hybrid nanoparticles were, on the one hand, modified by adding a functional silane and, on the other hand, by click chemistry. We have thus shown that it is possible to perform, in a same micellar media, all of manufacturing process of the hybrid nanoparticle, from the silica matrix to its functionalization passing by the incorporation of functional entities. This method of sequential synthesis allowed us to bypass the purification and redispersion steps that can be problematic in the conventional methods. All this work has been extended to the design of an antibacterial agent based of silver/silica nanoparticles, capable of preventing bacterial growth through the gradual release of silver ions. Tests conducted in solution on the impregnated cotton and polyethylene terephtalate indeed show an interesting antibacterial character of these systems.

L'objectif de ce travail était d'étudier l'influence qu'exerce la microstructure des caséines sur la diffusion moléculaire de petites sondes ayant des tailles et des déformabilités différentes. La mobilité de sondes moléculaires flexibles (''PEGs'') et rigides (dendrimères) de taille variée a été étudiée dans des suspensions et des gels de PPCN et de CaNa à différentes concentrations en protéines. Les mesures ont été réalisées par RMN qui permet de sonder des mobilités translationnelles sur une distance de 1,5 µm, mais également des mobilités locales à l'échelle moléculaire (quelques nanomètres) à travers les temps de relaxation T2. Un modèle cohérent a été utilisé et un mécanisme unique a été proposé pour décrire la diffusion de petites sondes dans les deux systèmes de caséine. C'est la combinaison de différents facteurs qui doivent être pris en considération : le rapport de la taille de la sonde à la distance entre les particules obstruantes ou les points d'enchevêtrement ainsi que la flexibilité de la sonde. La mobilité locale des sondes était beaucoup moins réduite que la mobilité translationnelle dans les deux systèmes de caséine. Différents comportements de relaxation ont été obtenus entre les deux systèmes de caséine et une diminution des T2 a été mesurée dans les gels. Ces résultats ont été liés à la mobilité intrinsèque de la matrice. L'ensemble des résultats obtenus ont permis d'avoir une meilleure compréhension de la mobilité des sondes dans les systèmes caséiques et de proposer un nouveau modèle qui contredit celui déjà proposé par Le Feunteun et al. pour expliquer la diffusion des sondes dans ces systèmes. / The aim of this study was to investigate the impact of the casein microstructure on the molecular diffusion of probes with different sizes and deformabilities. The mobility of molecular flexible (‘PEG’) and rigid (dendrimer) probes of various sizes was studied in suspensions and gels of NPC and SC at various protein concentrations. Measurements were carried out by NMR, which makes it possible to probe translational mobilities over a distance of 1.5 microns, as well as local mobilities at the molecular scale (several nanometers) through the relaxation times, T2. A coherent model was used and the same mechanism was proposed to describe the diffusion of small probes in both casein dispersions. It is the combination of different factors that should be considered: the ratio of the probe size to the distance between the obstructing particles or the entanglement points, as well as the flexibility of the probe. The rotational diffusion of PEG and dendrimer probes was less hindered than translational diffusion in both casein systems. Different relaxation behaviors were observed between the two casein systems and retardation in T2 relaxation times was highlighted in rennet and acid casein gels. These results are probably related to the local mobility of the matrix. The overall results of this project led to a better understanding of probe mobility in casein systems and made it possible to propose a new model that challenges the previous one proposed by Le Feunteun et al. to describe the diffusion of probes in casein systems.

The thesis, which contains nine chapters, reports extensive large scale atomistic molecular dynamics (MD) simulation studies of water structure and dynamics at the surface of an anionic micelle, hydration layer of two proteins, and in the grooves of a 38-base pairs long DNA. Understanding the structure and dynamics of water molecules at the surfaces of self-organized assemblies and complex biological macromolecules has become a subject of intense research in recent times. Chapter 1 contains a brief overview of the biomolecular hydration dynamics. Relevant experimental, computational, and theoretical studies of biomolecular hydration and the time scales associated with the water dynamics are discussed. In Chapters 2 and 3, the structure, environment, energetics, and dynamics of constrained water molecules in the aqueous anionic micelle of cesium perfluorooctanoate (CsPFO) have been studied using large scale atomistic molecular dynamics simulations. Based on the number of hydrogen bond (HB) that interfacial water molecule makes with the polar head group (PHG) oxygen of the micelle, we find the existence of three kinds of water at the interface. We introduce a nomenclature to identify the species as IBW2 (form two HBs with two different PHG), IBW1 (form one HB with PHG), and IFW (no HB with PHG). Despite of possessing two strong w-PHG bonds, the concentration of the IBW2 species is rather low due to entropic effect. The ion solvation dynamics study at the interface shows the presence of a slow component, with a relaxation time 1-2 order of magnitude slower than that in the corresponding bulk solvent in agreement with the experimental results. Both the translational and orientational dynamics of the water molecules near the micellar surface is found to be much slower than those in the bulk. The HB between the PHG of the micelle and the water molecule has almost 13 times longer life time than that in the bulk between two tagged water molecules. In Chapter 4, we present results of extensive atomistic MD simulation studies of the structure and dynamics of aqueous protein solution of the toxic domain of Enterotoxin (1ETN) and the chicken villin headpiece sub-domain containing 36 amino acid residues (HP-36). Reduced water structure and the faster water dynamics around the active site of these proteins have been observed which may have biological significance. Chapter 5 presents an extensive atomistic molecular dynamics simulations study of water dynamics in the hydration layer of a 38 base long hydrated DNA duplex. The computed rotational time correlation function (TCF) of the minor groove water dipoles is found to be markedly non-exponential with a slow component at long time. The constrained water molecule is also found to exhibit anisotropic diffusion in both the major and minor grooves. At short-to-intermediate times, translational motion of water molecules in minor groove is sub-diffusive. Chapter 6 presents the study of water entropy in both the grooves DNA. The average values of the entropy of water at 300K in both the grooves of DNA are found to be significantly lower than that in bulk water. We propose that the configurational entropy of water in the grooves can be used as a measure of the mobility (or micro viscosity) of water molecules in a given domain. In Chapter 7, we study the specific DNA base-water hydrogen bond lifetime (HBLT) dynamics at the major and the minor grooves of a hydrated duplex. The base-water HBLT correlation functions are in general multi-exponential and the average lifetime depends significantly on the specificity of the DNA sequence. The average HBLT is longer in the minor groove than that in the major groove by almost a factor of 2. Chapter 8 presents the solvation dynamics of constituent bases of aqueous DNA duplex. The solvation TCFs of the four individual bases display highly non-exponential decay with time. An interesting negative cross-correlation between water and counterions is observed which makes an important contribution to relaxation at intermediate to longer times. In the concluding note, Chapter 9 presents a brief summary of the outcome of the thesis and suggests several relevant problems that may prove w orthwhile to be addressed in future

Les oligonucléotides (ONs) antisens présentent un fort potentiel en tant qu’agents thérapeutiques. Toutefois, leurs propriétés physicochimiques limitent leur utilisation en thérapie génique. Pour pallier aux divers obstacles, des systèmes de vectorisation, tels que les micelles polyioniques (PICMs), ont été développés. Grâce à leur structure unique, les micelles protégent l’ON contre une dégradation prématurée et le couplage d’un ligand à leur surface augmente leur spécificité et leur internalisation. Dans d’autres systèmes, un polymère adjuvant aux propriétés pH-sensibles peut être ajouté pour faciliter la sortie de l’endosome et augmenter l’efficacité de l’ON. L’objectif général de ce mémoire était de mettre au point des PICMs ternaires ciblées pour l’administration d’ONs. Ces micelles assureraient à la fois l’internalisation cellulaire de leur cargaison en interagissant avec des récepteurs cellulaires et sa fuite de l’endosome grâce à un mécanisme de déstabilisation de la membrane endosomale. Pour cela, des PICMs composées d’un copolymère cationique de type poly(éthylène glycol)-bloc-poly(méthacrylate d’(alkylamino)éthyle) et d’un copolymère d’acide méthacrylique ont été préparées. Les propriétés physicochimiques de ces vecteurs ont démontré qu’ils permettaient une condensation efficace de l’acide nucléique et ce, indépendamment de la nature du polymère cationique et de l’acide nucléique. Finalement, une approche de couplage par pont disulfure a été développée afin de greffer au copolymère un fragment d’anticorps dirigé contre les récepteurs de la transferrine. En conclusion, ces travaux démontrent la versatilité et le potentiel des PICMs ternaires en tant que vecteurs d’acide nucléique, et proposent une méthodologie de couplage d’un ligand afin de formuler des PICMs ciblées. / Antisens oligonucleotides (ONs) present great potential as therapeutic agents. However, their physicochemical properties hinder their use in gene therapy. Targeting systems, such as polyion complex micelles (PICMs), have been proposed to circumvent the main hurdles related to ON delivery. Their unique core/shell structure can protect the ON against premature degradation and the coupling of a ligand on their surface can increase their specificity and internalization. In other systems, a polymer with pH-sensitive properties can be added to facilitate the release of the ON from the endosome and increase its efficiency. The present work was aimed at optimizing ternary PICMs targeted for the delivery of antisens ON. Such systems would provide both cellular internalization of cargo by interaction with receptors on the surface of cell membranes and escape from the endosome through a mechanism of destabilization of the endosomal membrane. PICMs composed of cationic copolymers of poly(ethylene glycol)-bloc-poly((alkylamino)ethyl methacrylate) with a methacrylic acid copolymer adjuvant were prepared. Their physicochemical properties suggest that efficient complexation of nucleic acids was obtained, regardless of the nature of the cationic polymer and the nature of the nucleic acid. Finally, a synthetic approach was developed for the conjugation of an antibody fragment directed against the transferrin receptor via a labile disulfide bond at the end of the cationic copolymer. In conclusion, the work presented herein displays the versatility and potential of ternary PICMs as vehicles for the delivery of ONs and also provides a method for the conjugation of a ligand to generate targeted ternary PICMs.