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Solution self-assembly of amphiphilic block copolymers (BCs) is typically performed by a solvent-to-water exchange. However, BC assemblies are often trapped in metastable states depending on the mixing conditions such as the magnitude and rate of water addition. BC self-assembly can be performed under near thermodynamic control by dialysis, which accounts for a slow and gradual water addition. In this Letter we report the use of a specifically designed dialysis cell to continuously monitor by dynamic light scattering and small-angle neutron scattering the morphological changes of PDMS- b -PEG BCs self-assemblies during THF-to-water exchange. The complete phase diagrams of near-equilibrium structures can then be established. Spherical micelles first form before evolving to rod-like micelles and vesicles, decreasing the total developed interfacial area of self-assembled structures in response to increasing interfacial energy as the water content increases. The dialysis kinetics can be tailored to the time scale of BC self-assembly by modifying the membrane pore size, which is of interest to study the interplay between thermodynamics and kinetics in self-assembly pathways.

It has been shown that the use of conformationally pH-switchable lipids can drastically enhance the cytosolic drug delivery of lipid vesicles. Understanding the process by which the pH-switchable lipids disturb the lipid assembly of nanoparticles and trigger the cargo release is crucial to optimize the rational design of pH-switchable lipids. Here, we gather morphological observations (FF-SEM, Cryo-TEM, AFM, confocal microscopy), physicochemical characterization (DLS, ELS), as well as phase behavior studies (DSC, 2 H NMR, Langmuir isotherm, and MAS NMR) to propose a mechanism of pH-triggered membrane destabilization. We demonstrate that the switchable lipids are homogeneously incorporated with other co-lipids (DSPC, cholesterol, and DSPE-PEG 2000 ) and promote a liquid-ordered phase insensitive to temperature variation. Upon acidification, the protonation of the switchable lipids triggers a conformational switch altering the self-assembly properties of lipid nanoparticles. These modifications do not lead to a phase separation of the lipid membrane; however, they cause fluctuations and local defects, which result in morphological changes of the lipid vesicles. These changes are proposed to affect the permeability of vesicle membrane, triggering the release of the cargo encapsulated in the lipid vesicles (LVs). Our results confirm that pH-triggered release does not require major morphological changes, but can result from small defects affecting the lipid membrane permeability.

Hybrids, i.e., intimately mixed polymer/phospholipid vesicles, can potentially marry in a single membrane the best characteristics of the two separate components. The ability of amphiphilic copolymers and phospholipids to self-assemble into hybrid membranes has been studied until now on the submicrometer scale using optical microscopy on giant hybrid unilamellar vesicles (GHUVs), but limited information is available on large hybrid unilamellar vesicles (LHUVs). In this work, copolymers based on poly(dimethylsiloxane) and poly(ethylene oxide) with different molar masses and architectures (graft, triblock) were associated with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). Classical protocols of LUV formation were used to obtain nanosized self-assembled structures. Using small-angle neutron scattering (SANS), time-resolved Förster resonance energy transfer (TR-FRET), and cryo-transmission electron microscopy (cryo-TEM), we show that copolymer architecture and molar mass have direct influences on the formation of hybrid nanostructures that can range from wormlike hybrid micelles to hybrid vesicles presenting small lipid nanodomains.

Hybrid polymer/lipid large unilamellar vesicles (LUVs) were studied by small angle neutron scattering (SANS), time-resolved Förster resonance energy transfer (TR-FRET), and cryo-transmission electron microscopy (cryo-TEM). For the first time in hybrid vesicles, evidence for phase separation at the nanoscale was obtained, leading to the formation of stable nanodomains enriched either in lipid or polymer. This stability was allowed by using vesicle-forming copolymer with a membrane thickness close to the lipid bilayer thickness, thereby minimizing the hydrophobic mismatch at the domain periphery. Hybrid giant unilamellar vesicles (GUVs) with the same composition have been previously shown to be unstable and susceptible to fission, suggesting a role of curvature in the stabilization of nanodomains in these structures.

Polymer vesicles, also named polymersomes, are valuable candidates for drug delivery and micro- or nanoreactor applications. As far as drug delivery is concerned, the shape of the carrier is believed to have a strong influence on the biodistribution and cell internalization. Polymersomes can be submitted to an osmotic imbalance when injected in physiological media leading to morphological changes. To understand these osmotic stress-induced variations in membrane properties and shapes, several nanovesicles made of the graft polymer poly(dimethylsiloxane)-g-poly(ethylene oxide) (PDMS-g-PEO) or the triblock copolymer PEO-b-PDMS-b-PEO were osmotically stressed and observed by light scattering, neutron scattering (SANS), and cryo-transmission electron microscopy (cryo-TEM). Hypotonic shock leads to a swelling of the vesicles, comparable to optically observable giant polymersomes, and hypertonic shock leads to collapsed structures such as stomatocytes and original nested vesicles, the latter being only observed for bilayers classically formed by amphiphilic copolymers. Complementary SANS and cryo-TEM experiments are shown to be in quantitative agreement and highlight the importance of the membrane structure on the behavior of these nanopolymersomes under hypertonic conditions as the final morphology reached depends whether or not the copolymers assemble into a bilayer. The vesicle radius and membrane curvature are also shown to be critical parameters for such transformations: the shape evolution trajectory agrees with theoretical models only for large enough vesicle radii above a threshold value around 4 times the membrane thickness.

We show that the production and the geometrical shape of complex polymersomes can be predicted by varying the flow rates of a simple microdevice using an empirical law which predicts the droplet size. This device is constituted of fused silica capillaries associated with adjusted tubing sleeves and T-junctions. Studying the effect of several experimental parameters, double emulsions containing a controlled number of droplets were fabricated. First, this study examines the stability of a jet in a simple confined microfluidic system, probing the conditions required for droplets production. Then, multicompartmental polymersomes were formed, controlling flow velocities. In this work, poly(dimethylsiloxane)-graft-poly(ethylene oxide) (PDMS-g-PEO) and poly(butadiene)-block-poly(ethyleneoxide) (PBut-b-PEO) amphiphilic copolymers were used and dissolved in chloroform/cyclohexane mixture. The ratio of these two solvents was adjusted in order to stabilize the double emulsion formation. The aqueous suspension contained poly(vinyl alcohol) (PVA), limiting the coalescence of the droplets. This work constitutes major progress in the control of double emulsion formation in microfluidic devices and shows that complex structures can be obtained using such a process.

The use of poly(vinyl acetate) (PVAc) nanogels for the fabrication of patterned porous surfaces is described. These nanogels were synthesized by controlled radical cross-linking copolymerization (CRCC) involving a xanthate-mediated reversible addition-fragmentation chain transfer (RAFT) mechanism. This synthesis methodology allowed for the preparation of nanogels based on PVAc with a controlled constitutive chain length and average numbers of chains and cross-links. Solutions of these branched polymers were prepared in THF with a fixed amount of water and spin coated onto a surface of graphite. The surface porosity of corresponding films was observed by atomic force microscopy (AFM). Compared with linear PVAc homologues with a degree of polymerization (DP) sufficiently high to favor the formation of porous structures (DP = 50), a sharper and better defined porosity was observed with nanogels, the constitutive chains of which had the same DP. For nanogels differing only in their cross-link density, the pores were smaller and better defined in the case of the higher cross-link density, suggesting an enhanced stabilization of the water droplets during film formation. To explain these observations, it is postulated that PVAc nanogels can behave as compact particles providing steric stabilization of water droplets, which is referred to as a Pickering effect. The coalescence of water droplets would be better prevented as the cross-link density of the nanogels increases, resulting in a smaller size pore., (© 2011 American Chemical Society)

Vesicle response to osmotic shock provides insight into membrane permeability, a highly relevant value for applications ranging from nanoreactor experimentation to drug delivery. The osmotic shock approach has been employed extensively to elucidate the properties of phospholipid vesicles (liposomes) and of varieties of polymer vesicles (polymersomes). This study seeks to compare the membrane response for two varieties of polymersomes, a comb-type siloxane surfactant, poly(dimethylsiloxane)-g-poly(ethylene oxide) (PDMS-g-PEO), and a diblock copolymer, polybutadiene-b-poly(ethylene oxide) (PBut-b-PEO). Despite similar molecular weights and the same hydrophilic block (PEO), the two copolymers possess different hydrophobic blocks (PBut and PDMS) and corresponding glass transition temperatures (-31 and -123 °C, respectively). Dramatic variations in membrane response are observed during exposure to osmotic pressure differences, and values for polymer membrane permeability to water are extracted. We propose an explanation for the observed phenomena based on the respective properties of the PBut-b-PEO and PDMS-g-PEO membranes in terms of cohesion, thickness, and fluidity., (© 2011 American Chemical Society)

Poly(trimethylene carbonate)-b-poly(L-glutamic acid) (PTMC-b-PGA) diblock copolymers have been synthesized by ring-opening polymerization (ROP) of gamma-benzyl-L-glutamate N-carboxyanhydride (BLG) initiated by amino functionalized PTMC and subsequent hydrogenation. Self-assembly in water gave well-defined vesicles which have been studied combining light and neutron scattering techniques with electron microscopy imaging. The size and dispersity of vesicles have been tuned by varying preparation conditions, direct dissolution, or nanoprecipitation. In addition, PGA conformation could be reversibly manipulated as a function of environmental changes such as pH and ionic strength. Vesicles showed high tolerance and stability toward nonionic surfactant and pH due to a thick membrane and were revealed to be nonpermeable to water. Nevertheless, they can be rapidly degraded by enzymatic hydrolysis of the polycarbonate block. The ability to tune their size through the formation process, their stimuli responsiveness, their high stability, and their biodegradability make them suitable for biomedical applications.

Using "click chemistry" as an easy and versatile synthetic strategy to combine hyaluronan and polyglutamate blocks, we have prepared nanovesicles (polymersomes) that present a controlled size, excellent colloidal stability, and a high loading capacity for hydrophilic and hydrophobic drugs. The unique feature of our concept is the use of hyaluronan, a polysaccharide with known capacity for targeting cancer-related protein receptors, as the hydrophilic portion of a block copolymer system. The cytotoxicity and internalization mechanism of doxorubicin-loaded polymersomes have been evaluated in C6 glioma tumor cell lines. The dual purpose served by hyaluronan, as both a hydrophilic block critical to vesicle formation and a binding agent for biological targets, breaks new ground in terms of multifunctional nanomaterial design for drug delivery.

The self-assembly of dextran-block-polystyrene (dex-b-PS) block copolymers was investigated in solution. The hydrophobic PS weight fraction in these block copolymers ranges from 7 to 92% w/w, whereas the average number molar mass of dextran was kept constant at 6600 gmol(-1). Self-assembly by direct dissolution in water could be performed only for block copolymers with a low hydrophobic content (7% w/w), whereas mixtures of tetrahydrofuran and dimethylsulfoxide were required for higher PS content, before transferring the structures into water. Core-shell micelles, ovoïds, and vesicles could be identified upon characterization by light and neutrons scattering, atomic force microscopy, and transmission electron microscopy. Most of the morphologies observed were not expected considering the chemical composition of the block copolymers. Finally, the size and shape of these nanoparticles were fixed upon cross-linking the dextran block through reaction of the hydroxyl groups with divinylsulfone. The role of the dextran conformation on the self-assembly process is discussed.