Control of vesicular morphologies through hydrophobic block length.
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Journal Article↗
Biomedical subjects
Adi Eisenberg
Publications and source records attributed to Adi Eisenberg.
Fate of micelles and quantum dots in cells.
Micelles and quantum dots have been used as experimental drug delivery systems and imaging tools both in vitro and in vivo. Investigations of their fate at the subcellular level require different surface-core modifications. Among the most common modifications are those with fluorescent probes, dense-core metals or radionucleids. Cellular fate of several fluorescent probes incorporated into poly(caprolactone)-b-copolymer micelles (PCL-b-PEO) was followed by confocal microscopy, and colloidal gold incorporated in poly 4-vinyl pyridine-PEO micelles were developed to explore micelle fate by electron microscopy. More recently, we have examined quantum dots (QDs) as the next-generation-labels for cells and nanoparticulate drug carriers amenable both to confocal and electron microscopic analyses. Effects of QDs at the cellular and subcellular levels and their integrity were studied. Results from different studies suggest that size, charge and surface manipulations of QDs may play a role in their subcellular distribution. Examples of pharmacological agents incorporated into block copolymer micelles, administered or attached to QD surfaces show how the final biological outcome (e.g. cell death, proliferation or differentiation) depends on physical properties of these nanoparticles.
Animals↗
Assessment of the integrity of poly(caprolactone)-b-poly(ethylene oxide) micelles under biological conditions: a fluorogenic-based approach.
The integrity of block copolymer micelles is important for their effectiveness and successful delivery of the incorporated drugs. Here we evaluate the integrity of poly(caprolactone)-b-poly(ethylene oxide) micelles in media of varying chemical complexity and in cells by using fluorogenic micelles. Fluorogenic dye fluorescein-5-carbonyl azide diacetate was covalently attached to the micelle-core-forming part of the block copolymer, poly(caprolactone). The fluorescence was not detectable unless the poly(caprolactone)21-b-poly(ethylene oxide)45 micelles were destroyed and the fluorogenic dye was activated by deesterification. The fluorescence of the activated dye from destroyed micelles was easily detectable in various media and in cells. Micelles were stable in simple media such as phosphate-buffered saline but disassembled to varying extents with increasing chemical complexity of the media and addition of serum. The integrity of the internalized micelles within the cells showed a time-dependent decrease but remained largely preserved (80%) after 20 h of incubation with cells. A proof of principle was also demonstrated in vivo in mice. The fluorogenic approach to micelle integrity assessment presented herein should lend itself to other block copolymer micelles and assessments of their integrity in complex biological systems in vitro and in vivo.
Animals↗
Proton diffusion across membranes of vesicles of poly(styrene-b-acrylic acid) diblock copolymers.
A study of proton diffusion across membranes of block copolymer vesicles in dilute solution is described. The vesicles were formed by the self-assembly of a diblock copolymer of poly(styrene-b-acrylic acid) (PS(310)-b-PAA(36), where the numbers represent the degree of polymerization for individual blocks). A pH gradient was created across the vesicle membrane with the interior pH (pH(in)) of ca. 2.9 and the exterior pH (pH(out)) of ca. 8.5. The permeability of the polystyrene (PS) membrane was tuned by the addition of different amounts of dioxane (0-40 wt %) to the external aqueous solution. Proton concentrations in the solution outside of the vesicles were followed by monitoring the spectrum of a pH-sensitive fluorescent dye, namely 8-hydroxypyrene-1,3,6-trisulfonate. After the start of the experiment, the proton concentrations increase linearly with the square root of time, while the slopes of the lines increase with dioxane content. To calculate the diffusion coefficients of the protons across the vesicular membrane, the concentration data were fitted using a model, which describes the diffusion of species across the membrane of a reservoir. The apparent diffusion coefficient (D*, which equals the true diffusion coefficient multiplied by the partition coefficient of protons between PS and water) increases from 1.1 x 10(-18) cm(2)/s at 7 wt % dioxane in the external solution to 1.2 x 10(-14) cm(2)/s at 40 wt %. The increase of D* with dioxane content is related to its plasticization of the PS membrane, which can be used as a gating mechanism.
Acrylic Resins↗
Self-assembly of mixtures of block copolymers of poly(styrene-b-acrylic acid) with random copolymers of poly(styrene-co-methacrylic acid).
The effects of the addition of random copolymers of poly(styrene-co-methacrylic acid) [P(S-co-MAA)] on the self-assembly of block copolymers of poly(styrene-b-acrylic acid) (PS-b-PAA) are described. The effects of variation of five factors, including the MAA content, the weight fraction and molar mass of the P(S-co-MAA), the initial concentration of the mixture, and the length of the PAA segment in the block copolymer, were investigated. With increasing MAA content, the localization of the random copolymer in the aggregate changed from the core to the interface, which led to a morphological transition from spheres to vesicles. Vesicles, mixtures of vesicles and large spheres, and large spheres alone were formed with increasing weight fraction of the random copolymer. When the molar mass of the random copolymer was high, both rods and vesicles were observed at low water contents; otherwise, only vesicles were observed. The vesicle size increased (from 100 to 140 nm) with increasing initial polymer concentration, whereas the vesicle membrane thickness remained constant. The size of the vesicles prepared from the mixtures increased with water content but decreased with the length of PAA in the diblock.
Journal Article↗
Block copolymer micelles as delivery vehicles of hydrophobic drugs: micelle-cell interactions.
One-third of drugs in development are water insoluble and one-half fail in trials because of poor pharmacokinetics. Block copolymer micelles are nanosized particles that can solubilize hydrophobic drugs and alter their kinetics in vitro and in vivo. However, block copolymer micelles are not solely passive drug containers that simply solubilize hydrophobic drugs; cells internalize micelles. To facilitate the development of advanced, controlled, micellar drug delivery vehicles, we have to understand the fate of micelles and micelle-incorporated drugs in cells and in vivo. With micelle-based drug formulations recently reaching clinical trials, the impetus for answers is ever so strong and detailed studies of interactions of micelles and cells are starting to emerge. Most notably, the question arises: Is the internalization of block copolymer micelles carrying small molecular weight drugs an undesired side effect or a useful means of improving the effectiveness of the incorporated drugs?
Drug Delivery Systems↗
Active loading and tunable release of doxorubicin from block copolymer vesicles.
Vesicles are spherical bilayers that offer a hydrophilic reservoir, suitable for the incorporation of water-soluble molecules, as well as a hydrophobic wall that protects the loaded molecules from the external solution. The permeability of a vesicle wall made from polystyrene can be enhanced by adding a plasticizer such as dioxane. Tuning the wall permeability allows loading and release of molecules from vesicles to be controlled. In this study, vesicles are prepared from polystyrene(310)-b-poly(acrylic acid)(36) and used as model carriers for doxorubicin (DXR), a weak amine and a widely used anticancer drug. To increase the wall permeability, different amounts of dioxane are added to the vesicle solution. A pH gradient is created across the vesicle wall (inside acidic) and used as an active loading method to concentrate the drug inside the vesicles. The results show that a pH gradient of ca. 3.8 units can enhance the loading level up to 10-fold relative to loading in the absence of the gradient. After loading, the release of DXR from vesicles is followed as a function of the wall permeability. The diffusion coefficient of doxorubicin through polystyrene (D) is evaluated from the initial slope of the release curves; the value of D ranges from 8 x 10(-17) to 6 x 10(-16) cm(2)/s, depending on the degree of plasticization of the vesicle wall.
Antibiotics, Antineoplastic↗
Cadmium sulphide quantum dots in morphologically tunable triblock copolymer aggregates.
Cadmium sulfide (CdS) quantum dots (QDs) are formed within poly(ethylene oxide)-block-polystyrene-block-poly (acrylic acid) (PEO-b-PS-b-PAA) triblock copolymer aggregates of different architectures. These structures are obtained starting with the same ionically cross-linked primary micelles consisting of a cadmium acrylate core, a PS shell, and a PEO corona. One morphology is a worm-shaped micelle prepared in tetrahydrofuran (THF) in which the CdS QDs are surrounded by the PAA and aligned as a loose necklace in the PS matrix. The PEO serves as a corona around the PS rod. Another structure is a multicore spherical (ca. 50 nm) water soluble PS micelle, surrounded by PEO chains. The CdS particles within these two latter structures are formed by the reaction of cadmium ions present in the acrylate cores with hydrogen sulfide. In a third structure, the CdS QDs are located on the surface of PS micelles. A fourth spherical single-core micelle structure is postulated to exist in dilute THF solutions. The dimensions in all the aggregates can be controlled by the block length.
Journal Article↗
Fluorescence anisotropy study of aqueous dispersions of block ionomer complexes.
Block ionomer complexes (BIC) of "dual hydrophilic" block copolymers containing ionic and nonionic blocks and oppositely charged surfactants spontaneously form colloidal particles of ca. 80 nm in diameter stable in aqueous dispersions at every composition of the mixture. Packing and dynamics of aliphatic groups of the surfactant in BIC were examined by using the quenching-resolved fluorescence anisotropy (QRFA) method with 1,6-diphenyl-1,3,5-hexatriene (DPH) as a probe. The values of the order parameter and rotational relaxation time in the BIC were higher than those in the surfactant micelles. Incorporation of aliphatic alcohols in the BIC decreased the order parameter and increased the rotational relaxation time. The effects on the order parameter were explained by changes in the surfactant aliphatic group conformation to "fill the gaps" induced by insertion of shorter alcohol molecules. The effects on the relaxation time were attributed to a decrease in repulsion of the surfactant headgroups and expulsion of water from the BIC hydrophobic interior as evidenced by the decrease in micropolarity. The results of this study have implications for potential use of the BIC in pharmaceutics and other fields.
Alcohols↗
Polystyrene-b-poly(acrylic acid) vesicle size control using solution properties and hydrophilic block length.
Polymeric vesicles have attracted considerable attention in recent years, since they are a model for biological membranes and have versatile structures with several practical applications. In this study, we prepare vesicles from polystyrene-b-poly(acrylic acid) block copolymer in dioxane/water and dioxane/THF/water mixtures. We then examine the ability of additives (such as NaCl, HCl, or NaOH), solvent composition, and hydrophilic block length to control vesicle size. Using turbidity measurements and transmission electron microscopy (TEM) we show that larger vesicles can be prepared from a given copolymer by adding NaCl or HCl, while adding NaOH yields smaller vesicles. The solvent composition (ratio of dioxane to THF, as well as the water content) can also determine the vesicle size. From a given copolymer, smaller vesicles can be prepared by increasing the THF content in the THF/dioxane solvent mixture. In a given solvent mixture, vesicle size increases with water content, but such an increase is most pronounced when dioxane is used as the solvent. In THF-rich solutions, on the other hand, vesicle size changes only slightly with the water concentration. As to the effect of the acrylic acid block length, the results show that block copolymers with shorter hydrophilic blocks assemble into larger vesicles. The effect of additives and solvent composition on vesicle size is related to their influence on chain repulsion and aggregation number, whereas the effect of acrylic acid block length occurs because of the relationship among the block length, the width of the molecular weight distribution, and the stabilization of the vesicle curvature.
Journal Article↗
Influence of metalation on the morphologies of poly(ethylene oxide)-block-poly(4-vinylpyridine) block copolymer micelles.
Micellization of a poly(ethylene oxide)-block-poly(4-vinylpyridine) (PEO45-b-P4VP28) copolymer in water during metalation (incorporation of gold compounds and gold nanoparticle formation) with three types of gold compounds, NaAuCl4, HAuCl4, and AuCl3, was studied using dynamic light scattering (DLS) and transmission electron microscopy (TEM). The transformations of the PEO45-b-P4VP28 block copolymer micelles in water were found to depend on a number of parameters including the thermal history of the as-prepared block copolymer, the type of the metal compound, and the metal loading. For the HAuCl4-filled PE045-b-P4VP28 micelles, the subsequent reduction with hydrazine hydrate results in a significant fraction of rodlike micelles, suggesting that slow nucleation (confirmed by the formation of the large gold nanoparticles) and facilitated migration of gold ions yields the ideal conditions for sphere-to-rod micellar transition.
Journal Article↗
Colloidal stability of aqueous dispersions of block ionomer complexes: effects of temperature and salt.
This work characterized colloidal stability of the dispersions, formed by the complexes of poly(ethylene oxide)-b-poly(sodium methacrylate) and hexadecyltrimethylammonium bromide. At room temperature, the dispersion was stabilized by the poly(ethylene oxide) (PEO) chains and did not aggregate for at least several months. Elevation of temperature caused aggregation of the dispersion because of dehydration of the PEO chains. At initial stages (minutes), the aggregation was reversible and the particles spontaneously redispersed once the temperature was decreased. However, it became irreversible at the later stages (hours), probably indicating fusion of the hydrophobic cores of the BIC particles. Addition of elementary salts led to a decrease of the aggregation temperature. The effects of various salts were dependent on the chemical nature of the ions and were consistent with the Hofmeister series. This behavior was discussed in terms of hydration and London (dispersion) interactions between the ions and the PEO.
Journal Article↗
Effect of poly(acrylic acid) block length distribution on polystyrene-b-poly(acrylic acid) block copolymer aggregates in solution. 2. A partial phase diagram.
The first paper of the series, which focused on the effect of polydispersity on the self-assembly of block copolymer vesicles, showed that an increase in the width of the poly(acrylic acid) (PAA) block length distribution resulted in a decrease in the size of the vesicles formed. In this paper, the rest of the phase diagram is explored. For the present study, a series of polystyrene-b-poly(acrylic acid) copolymers of an identical polystyrene length of 325 units but of varying degrees of polymerization of PAA was synthesized. Mixtures of the copolymers were made to artificially broaden the molecular weight distribution of PAA at a constant number average of 48 in the polydispersity index (PDI) range of 1.1-3.3. The mixtures were dissolved in dioxane, and water was added slowly to predetermined amounts. Transmission electron microscopy was used to observe aggregate morphologies at different water contents and PAA PDIs. At low water contents, dynamic light scattering was also used to measure the sizes of the aggregates. A partial phase diagram as a function of the water content and PAA PDI was obtained. Large compound micelles and spherical micelles (average diameter of 40 nm) were found at low water contents; however, at a water content of 12% (w/w), a continuum of morphologies from spheres to rods to vesicles was found with increasing PAA PDI. In addition, each copolymer was investigated by itself under identical conditions to those used for the mixtures to determine if there was any segregation of the individual polymers into separate aggregates. No evidence for such segregation was found.
Journal Article↗
Preparation and pH triggered inversion of vesicles from poly(acrylic acid)-block-polystyrene-block-poly(4-vinyl pyridine).
The aggregate morphologies of the biamphiphilic triblock PAA(26)-b-PS(890)-b-P4VP(40) have been studied by TEM as a function of pH in DMF/THF/H(2)O mixtures. The outside surfaces of the aggregates were characterized by zeta potential measurements. Starting at the apparent pH (pH) of 1, and increasing gradually to pH14, the aggregate morphologies of this triblock change progressively from vesicles (pH1), to solid spherical or ellipsoidal aggregates (pH3 approximately 11), and finally back to vesicles (pH14). Vesicles prepared at pH1 contain P4VP chains on the outside and PAA chains on the inside, while those prepared from the same triblock at pH14 contain PAA outside and P4VP inside. The segregation is based on the difference in repulsive interactions within the PAA or P4VP corona under different pH conditions. At low pH, the curvature is stabilized through increased repulsive interactions between the P4VP chains on the outside relative to the less repulsive interactions between the PAA chains on the inside. At pH14, by contrast, the PAA is preferentially segregated to the outside and the P4VP to the inside because of the increased repulsive interaction between PAA chains and the decreased repulsive interaction between P4VP chains at high pH. Most importantly, vesicles with PAA on the outside can be inverted to P4VP on the outside by changing the pH while the vesicles have swollen cores and are under dynamic conditions. The conversion mechanism is suggested to involve a whole vesicle process because the CMC is far too low for single chain reassembly to be involved.
Journal Article↗
Interfacial solubilization of model amphiphilic molecules in block copolymer micelles.
We investigate the solubilization of 2-nitrodiphenylamine, a hydrophobic but polar dye molecule, in aqueous solutions of polystyrene(310)-b-poly(acrylic acid)(47) micelles. The solubilization capacity of the micelles, which consist of a polystyrene core and poly(acrylic acid) corona, and the micelle-water partition coefficient are evaluated as a function of the solubilizate concentration. The solubilization isotherm shows a nonlinear behavior, and the partition coefficient, instead of being constant, is strongly dependent on the dye concentration. These results are explained by treating solubilization as a binding process, and by fitting the data to a Langmuir adsorption model. In addition, we examine the locus of solubilization of 2-nitrodiphenylamine using its solvatochromic properties and solubility in model solvents, and we identify the micellar interface as the solubilization site. Confirmatory studies, including the dependence of solubilization on the interfacial area of the aggregates, the role of the poly(acrylic acid) corona chains in stabilizing the solubilized molecules, and the effect of the solubilizate structure on the extent of incorporation, were also conducted. The results, consistent with surface localization, show that solubilization is dependent on the interfacial area of the aggregates, and on the affinity of the solubilizate for the micellar interface.
Journal Article↗
Micellar nanocontainers distribute to defined cytoplasmic organelles.
Block copolymer micelles are water-soluble biocompatible nanocontainers with great potential for delivering hydrophobic drugs. An understanding of their cellular distribution is essential to achieving selective delivery of drugs at the subcellular level. Triple-labeling confocal microscopy in live cells revealed the localization of micelles in several cytoplasmic organelles, including mitochondria, but not in the nucleus. Moreover, micelles change the cellular distribution of and increase the amount of the agent delivered to the cells. These micelles may thus be worth exploring for their potential to selectively deliver drugs to specified subcellular targets.
Animals↗
Synthesis of poly(tert-butyl acrylate)-block-polystyrene-block-poly(4-vinylpyridine) by living anionic polymerization.
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Journal Article↗
Synthesis of vesicles on polymer template.
Reactive single-tail cationic surfactants self-assemble on the anionic block copolymer templates. These systems spontaneously arrange in small vesicles of nanoscale size. The vesicles are further stabilized by dimerization of the assembled surfactant monomers forming double-tail surfactants bound to the block copolymer. The resulting systems are resistant to changes in environmental characteristics such as pH, ionic strength, and temperature variations. Hydrophilic macromolecules can be encapsulated in the internal aqueous volume of these vesicles. The simplicity of the preparation makes these systems promising as drug and gene delivery carriers.
Isothiuronium↗