Vesicle Walls Research Articles

CO2-breathing and piercing polymersomes as tunable and reversible nanocarriers.

Despite numerous studies on utilizing polymeric vesicles as nanocapsules, fabrication of tunable molecular pathways on transportable vesicle walls remains challenging. Traditional methods for building penetrated channels on vesicular membrane surface often involve regulating the solvent polarity or photo-cross-linking. Herein, we developed a neat, green approach of stimulation by using CO2 gas as “molecular drill” to pierce macroporous structures on the membrane of polymersomes. By simply introducing CO2/N2 gases into the aqueous solution of self-assemblies without accumulating any byproducts, we observed two processes of polymeric shape transformation: “gas breathing” and “gas piercing.” Moreover, the pathways in terms of dimension and time were found to be adjustable simply by controlling the CO2 stimulation level for different functional encapsulated molecules in accumulation, transport, and releasing. CO2-breathing and piercing of polymersomes offers a promising functionality to tune nanocapsules for encapsulating and releasing fluorescent dyes and bioactive molecules in living systems and also a unique platform to mimic the structural formation of nucleus pore complex and the breathing process in human beings and animals.

Mixing Water, Transducing Energy, and Shaping Membranes: Autonomously Self-Regulating Giant Vesicles.

Giant lipid vesicles are topologically closed compartments bounded by semipermeable flexible shells, which isolate femto- to picoliter quantities of the aqueous core from the surrounding bulk. Although water equilibrates readily across vesicular walls (10(-2)-10(-3) cm(3) cm(-2) s(-1)), the passive permeation of solutes is strongly hindered. Furthermore, because of their large volume compressibility (∼10(9)-10(10) N m(-2)) and area expansion (10(2)-10(3) mN m(-1)) moduli, coupled with low bending rigidities (10(-19) N m), vesicular shells bend readily but resist volume compression and tolerate only a limited area expansion (∼5%). Consequently, vesicles experiencing solute concentration gradients dissipate the available chemical energy through the osmotic movement of water, producing dramatic shape transformations driven by surface-area-volume changes and sustained by the incompressibility of water and the flexible membrane interface. Upon immersion in a hypertonic bath, an increased surface-area-volume ratio promotes large-scale morphological remodeling, reducing symmetry and stabilizing unusual shapes determined, at equilibrium, by the minimal bending-energy configurations. By contrast, when subjected to a hypotonic bath, walls of giant vesicles lose their thermal undulation, accumulate mechanical tension, and, beyond a threshold swelling, exhibit remarkable oscillatory swell-burst cycles, with the latter characterized by damped, periodic oscillations in vesicle size, membrane tension, and phase behavior. This cyclical pattern of the osmotic influx of water, pressure, membrane tension, pore formation, and solute efflux suggests quasi-homeostatic self-regulatory behavior allowing vesicular compartments produced from simple molecular components, namely, water, osmolytes, and lipids, to sense and regulate their microenvironment in a negative feedback loop.

Intermolecular exciton–exciton annihilation in phospholipid vesicles doped with [Ru(bpy)2dppz]2+

The ultrafast photophysics of [Ru(bpy)2dppz]2+ (dppz=dipyrido[3,2-a:2′,3′-c]-phenazine) embedded into the walls of phospholipid vesicles has been studied by femtosecond time-resolved pump–probe spectroscopy. While [Ru(bpy)2dppz]2+ has been studied intensively with respect to its intramolecular charge transfer processes, which are associated with the well known light-switch effect, this study focuses on intermolecular energy transfer processes taking place upon dense packing of the complexes into a phospholipid membrane composed of dipalmitoyl-l-α-phosphatidylglycerol, which can be thought of as a simplistic model of a cellular membrane. The data indicate additional quenching of excited [Ru(bpy)2dppz]2+ upon increasing the pump–pulse intensity. Hence, the observed photophysics, which is assigned to the presence of intermolecular exciton–exciton annihilation at high pump-intensities, might be related to the ultrafast photophysics of [Ru(bpy)2dppz]2+ when used as a chromophore to stain cells, an effect that may be taken into account during the employment of novel cellular markers based on Ru polypyridine complexes.

Secondary mineral assemblage as indicator of multistage alteration processes in basaltic lava flows: evidence from the Lessini Mountains, Veneto Volcanic Province, Northern Italy

The secondary mineral assemblages in the Tertiary basalts from the Lessini Mountains are mainly clay minerals and zeolites, and result from multistage alteration processes. In the earliest Stage I, clay and silica minerals precipitate along the inner walls of the vesicles, followed by the deposition of the fine-grained zeolites of the Stage II (erionite, offretite, analcime, natrolite, heulandite and stilbite). The final Stage III is marked by a new generation of large, well-shaped zeolites (phillipstite-harmotomo, gmelinite, chabazite, willhendersonite and yugawaralite), followed by extensive crystallization of calcite. New morphological and chemical data are presented herein in order to reveal the chemical compositions of Lessini zeolite species, which have never been analyzed before. Textural and chemical observations indicate that the chemical elements for Stage I and II alteration minerals derived from the alteration of the basaltic glass and the primary phases in the volcanic host rocks. The final mineral assemblages of the Stage III suggest a variation in the crystallization conditions, probably related to the presence of new, late-stage fluids enriched in Ca and (CO 3 ) 2- , leached from the surrounding calcareous rocks.

Abstract LB-227: Novel synthetic vesicle for rapid in vivo expansion of CD8 T cells can significantly improve checkpoint inhibitor therapy

Abstract Harnessing the immune system for cancer treatment offers many advantages over traditional methods as the immune system can generate tumor-specific killer cells and long-term memory cells to prevent recurrence. The success of recent clinical trials using T cell therapies has proven the potential of immunotherapy, but the ex vivo generation of T cells in these trials is costly and labor-intensive. Here, we developed wholly synthetic, pathogen-mimicking nanocapsules, Interbilayer-Crosslinked Multilamellar Vesicles (ICMVs), to deliver antigens to the lymphoid system, which prime large tumor-specific CD8 T cell populations in vivo. ICMVs use bilayer-to-bilayer crosslinks in the walls of multi-lamellar lipid vesicles to create an easily manufacturable, highly stable virus-like particle to present antigens and/or adjuvants to immune cells. ICMV carrying HPV16 E6 and E7 full-length proteins were administered alone or co-encapsulated with TLR agonists to mice. CD8 T cell responses were assessed by tetramer staining and intracellular cytokine staining (ICS) was done to assay functionality. Efficacy of ICMV treatment was demonstrated by monitoring tumor size and survival in C57BL/6 mice bearing a lethal dose of TC-1 tumor cells. ICMVs induced unprecedented antigen-specific CD8 T cell frequencies against HPV whole proteins even without added adjuvant. Repeat doses of ICMVs boosted CD8 responses resulting in 30% of the total CD8 T cell population in blood being E7-specific while treatment with free protein elicited <1% E7-specific cells, indicating that ICMVs promote strong cross-presentation of antigens. When ICMVs were combined with anti-PD-1 to treat tumor-bearing mice, 10-15% of CD8 T cells produced IFNγ+ in response to either E6 or E7 antigens, while treatment with anti-PD-1 alone elicited <1% IFNγ+ T cells. Significant tumor regression was seen with ICMV+anti-PD-1 treatment, doubling overall survival time while anti-PD-1 treatment alone delayed tumor growth only slightly. Similar results were seen when ICMV were combined with various immunomodulators including anti-PD-L1, anti-CTLA-4 and anti-CD40. These results indicate that the ICMV-induced expansion of antigen-specific CD8 T cells can significantly improve the therapeutic efficacy of checkpoint inhibitors. A triple therapy of ICMV + checkpoint inhibitor + Treg inhibiting drugs is now being assessed and eradication of >85% of established tumors was detected in preliminary experiments. These findings demonstrate the potential of ICMVs as a novel cancer immunotherapy platform for the in vivo generation of CD8 T cells. ICMV are a cost effective, easily manufactured and versatile strategy to generate T cells for immunotherapy. Citation Format: Adrienne V. Li, Jackson K. Eby, Peter C. DeMuth, Darrell J. Irvine. Novel synthetic vesicle for rapid in vivo expansion of CD8 T cells can significantly improve checkpoint inhibitor therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-227. doi:10.1158/1538-7445.AM2015-LB-227

Hydrogen‐Bond‐Regulated Distinct Functional‐Group Display at the Inner and Outer Wall of Vesicles

AbstractA unique supramolecular strategy enables the unidirectional assembly of two bola‐shaped unsymmetric π‐amphiphiles, NDI‐1 and NDI‐2, which feature a naphthalene–diimide chromophore connected to nonionic and anionic head groups on opposite arms. The amphiphiles differ only in the location of a hydrazide group, which is placed either on the nonionic or on the anionic arm of NDI‐1 and NDI‐2, respectively. The formation of hydrogen bonds between the hydrazides, which compensates for electrostatic and steric factors, promotes unidirectional alignment and the formation of monolayer vesicles. The zeta potentials and cation‐assisted quantitative precipitation reveal negatively charged and nonionic outer surfaces for NDI‐1 and NDI‐2, respectively, indicating that hydrogen bonding also dictates the directionality of the monolayer curvature, ensuring that in both cases, the hydrazides remain at the inner wall to benefit from stronger hydrogen bonding where they are in closer proximity. This is reflected in their different abilities to inhibit α‐chymotrypsin, which possesses a positively charged surface: NDI‐1 induced an inhibition of 80 % whereas hardly any inhibition was observed with NDI‐2.

Hydrogen-bond-regulated distinct functional-group display at the inner and outer wall of vesicles.

A unique supramolecular strategy enables the unidirectional assembly of two bola-shaped unsymmetric π-amphiphiles, NDI-1 and NDI-2, which feature a naphthalene-diimide chromophore connected to nonionic and anionic head groups on opposite arms. The amphiphiles differ only in the location of a hydrazide group, which is placed either on the nonionic or on the anionic arm of NDI-1 and NDI-2, respectively. The formation of hydrogen bonds between the hydrazides, which compensates for electrostatic and steric factors, promotes unidirectional alignment and the formation of monolayer vesicles. The zeta potentials and cation-assisted quantitative precipitation reveal negatively charged and nonionic outer surfaces for NDI-1 and NDI-2, respectively, indicating that hydrogen bonding also dictates the directionality of the monolayer curvature, ensuring that in both cases, the hydrazides remain at the inner wall to benefit from stronger hydrogen bonding where they are in closer proximity. This is reflected in their different abilities to inhibit α-chymotrypsin, which possesses a positively charged surface: NDI-1 induced an inhibition of 80% whereas hardly any inhibition was observed with NDI-2.

Magma fracturing and degassing associated with obsidian formation: The explosive–effusive transition

This paper explores the role of melt fracturing in degassing rhyolitic volcanic systems. The Monte Pilato-Rocche Rosse eruptions in Italy evolved from explosive to effusive in style, and H2O content in quenched glasses changed over time from relatively H2O-rich (~0.90wt.%) to H2O-poor dense obsidian (~0.10–0.20wt.%). In addition, healed fractures have been recorded in all different eruptive materials, from the glass of early-erupted tube pumice and rinds of breadcrusted obsidian pyroclasts, to the glass of late-erupted dense obsidian pyroclasts, and throughout the final effusive Rocche Rosse lava flow. These rocks show multiple fault sets, some with crenulated fault planes indicating resumption of viscous flow after faulting, complex obsidian breccias with evidence for post-brecciation folding and stretching, and centimetre- to metre-thick tuffisite preserved in pyroclasts and lava, representing collapsed foam due to fracturing of vesicle walls. These microstructural observations indicate that multiple fracturing and healing events occurred during both explosive and effusive eruptions. H2O content in glass decreases by as much as 0.14wt.% towards healed fractures/faults and decreases in stretched obsidian breccias towards regions of intense brecciation. A drop in pressure and/or increase in temperature along fractures caused diffusive H2O migration through melt towards fracture surfaces. Repetitive and pervasive fracturing and healing thereby create conditions for diffusive H2O loss into fractures and subsequent escape through permeable paths. This type of progressive magma degassing provides a potential mechanism to explain the formation of dense obsidian and the evolution from explosive to effusive eruption style.

Leaves Micromorphological Characteristics ofOpisthopappustaihangensisandOpisthopappus longilobusfromTaihang Mountain, China

Leaves Micromorphological Characteristics of Opisthopappus taihangensis and Opisthopappus longilobus from Taihang Mountain, China The micromorphological characteristics of Opisthopappus taihangensis and Opisthopappus longilobus leaves were observed using scanning electron microscope and was found that they differ in characteristics and density of glandular hairs, size and density of stomata, pattern of anticlinal wall, wax characteristics, size and density of salt vesicles. These differences mainly resulted from the microenvironment heterogeneity of these two species or different populations. The micromorphological characteristics of the leaves, stomata and salt vesicles could be regarded as important classification traits for O. taihangensis and O. longilobus. Correlation analysis indicated that there was a significant relationship between morphological characteristics, longitude and latitude. According to principal component analysis, the highest contribution came from the density of glandular hairs. All the 13 populations of Opisthopappus were gathered into two clusters based on the microstructural characteristics of their leaves. Three populations of O. longilobus were not gathered into a single cluster, but with different populations of O. taihangensis.

A conspicuous clay ovoid in Nakhla: evidence for subsurface hydrothermal alteration on Mars with implications for astrobiology.

Abstract A conspicuous biomorphic ovoid structure has been discovered in the Nakhla martian meteorite, made of nanocrystalline iron-rich saponitic clay and amorphous material. The ovoid is indigenous to Nakhla and occurs within a late-formed amorphous mesostasis region of rhyolitic composition that is interstitial to two clinopyroxene grains with Al-rich rims, and contains acicular apatite crystals, olivine, sulfides, Ti-rich magnetite, and a new mineral of the rhoenite group. To infer the origin of the ovoid, a large set of analytical tools was employed, including scanning electron microscopy and backscattered electron imaging, wavelength-dispersive X-ray analysis, X-ray mapping, Raman spectroscopy, time-of-flight secondary ion mass spectrometry analysis, high-resolution transmission electron microscope imaging, and atomic force microscope topographic mapping. The concentric wall of the ovoid surrounds an originally hollow volume and exhibits internal layering of contrasting nanotextures but uniform chemical composition, and likely inherited its overall shape from a preexisting vesicle in the mesostasis glass. A final fibrous layer of Fe-rich phases blankets the interior surfaces of the ovoid wall structure. There is evidence that the parent rock of Nakhla has undergone a shock event from a nearby bolide impact that melted the rims of pyroxene and the interstitial matter and initiated an igneous hydrothermal system of rapidly cooling fluids, which were progressively mixed with fluids from the melted permafrost. Sharp temperature gradients were responsible for the crystallization of Al-rich clinopyroxene rims, rhoenite, acicular apatites, and the quenching of the mesostasis glass and the vesicle. During the formation of the ovoid structure, episodic fluid infiltration events resulted in the precipitation of saponite rinds around the vesicle walls, altered pyrrhotite to marcasite, and then isolated the ovoid wall structure from the rest of the system by depositing a layer of iron oxides/hydroxides. Carbonates, halite, and sulfates were deposited last within interstitial spaces and along fractures. Among three plausible competing hypotheses here, this particular abiotic scenario is considered to be the most reasonable explanation for the formation of the ovoid structure in Nakhla, and although compelling evidence for a biotic origin is lacking, it is evident that the martian subsurface contains niche environments where life could develop.

Magma fracturing and degassing associated with obsidian formation: The explosive–effusive transition

This paper explores the role of melt fracturing in degassing rhyolitic volcanic systems. The Monte Pilato–Rocche Rosse eruptions in Italy evolved from explosive to effusive in style, and H2O content in quenched glasses changed over time from relatively H2O-rich (~0.90wt.%) to H2O-poor dense obsidian (~0.10–0.20wt.%). In addition, healed fractures have been recorded in all different eruptive materials, from the glass of early-erupted tube pumice and rinds of breadcrusted obsidian pyroclasts, to the glass of late-erupted dense obsidian pyroclasts, and throughout the final effusive Rocche Rosse lava flow. These rocks show multiple fault sets, some with crenulated fault planes indicating resumption of viscous flow after faulting, complex obsidian breccias with evidence for post-brecciation folding and stretching, and centimetre- to metre-thick tuffisite preserved in pyroclasts and lava, representing collapsed foam due to fracturing of vesicle walls. These textural observations indicate that multiple fracturing and healing events occurred during both explosive and effusive eruptions. H2O content in glass decreases by as much as 0.14wt.% towards healed fractures/faults and decreases in stretched obsidian breccias towards regions of intense brecciation. A drop in pressure and increase in temperature along fractures caused diffusive H2O migration through melt towards fracture surfaces. Repetitive and pervasive fracturing and healing thereby create conditions for diffusive H2O loss into fractures and subsequent escape through permeable paths. This type of progressive magma degassing provides a potential mechanism to explain the formation of dense obsidian and the evolution from explosive to effusive eruption style.

Seminal vesicle intraepithelial involvement by prostate cancer: putative mechanism and clinicopathological significance.

We have recently shown seminal vesicle intraepithelial involvement of prostate cancer in cases with seminal vesicle invasion (pT3b). Based on the manner of seminal vesicle invasion, there could be 2 possible mechanisms of seminal vesicle intraepithelial involvement: direct intraepithelial invasion from prostate carcinoma in the muscular wall of seminal vesicles or intraepithelial involvement of cancer from the invaginated extraprostatic space (IES)/ejaculatory duct system to extraprostatic seminal vesicle. We aimed to clarify the manner and clinicopathological significance of seminal vesicle intraepithelial involvement. Of 1629 consecutive radical prostatectomies, 109 cases (6.7%) showed seminal vesicle invasion in whole-mounted radical prostatectomy specimens. In these pT3b cases, 18 (17%) showed seminal vesicle intraepithelial involvement by prostate cancer. Stromal invasion of the IES/ejaculatory duct system and ejaculatory duct intraepithelial invasion by prostate cancer were identified in 62 and 5 of 109 pT3b cases, respectively. However, the presence/absence of IES/ejaculatory duct system involvement by prostate cancer does not predict seminal vesicle intraepithelial involvement. No statistically significant correlation was observed between all pathologic parameters/biochemical recurrence and the presence/absence of seminal vesicle intra-epithelial involvement in the pT3b cases. These findings suggest that seminal vesicle intraepithelial involvement is more likely due to direct invasion of carcinoma from the muscular wall of seminal vesicles rather than intraepithelial extension from the ejaculatory duct system in the IES. Further studies with a substantially greater case number are needed to clarify the clinicopathological significance of seminal vesicle intraepithelial involvement in a better manner.

Affinities of Palaeozoic encrusting ascodictyid ‘pseudobryozoans’

Small encrusting marine organisms belonging to the genera Ascodictyon, Eliasopora and Vinella were originally described as ctenostome bryozoans. Well-preserved ascodictyid specimens from the Early and Middle Devonian of Poland allow us to exclude such an affinity due to the absence of any aperture in the ascodictyid vesicles for the protrusion or withdrawal of the lophophore during feeding. The ctenostome bryozoans are soft-bodied, but the ascodictyid vesicles and filaments have calcified walls. Reinterpretation of Eliasopora stellata (Nicholson & Etheridge, 1877), Eliasopora sparsiforme (Kiepura, 1965) and ‘Ascodictyon’ venustum Kiepura, 1965, provides a basis for the recognition of a new group of extinct Palaeozoic organisms, defined by a combination of morphological features including the presence of a thread-like network of perforate branching filaments, perforate vesicles formed by swollen tips of the filaments, and the ability of filaments to fuse. This distinguishes Ascodictyidae from all other known extant microorganisms. The shape, size and perforated walls of vesicles make ascodictyids similar to the Palaeozoic tuberitinid ‘foraminifers’. It remains to be determined which morphology is plesiomorphic and which is derived.

Aqueous dispersion of metal oxide nanoparticles, using siloxane surfactants

Siloxane surfactants containing tromethamol or carboxylate groups, with very good surface properties, are tested for the first time for biocompatibility using MTT cytotoxicity test. They are used for encapsulation of superparamagnetic iron oxide nanoparticles (SPION), and of a combination of these with nystatin as model un-soluble drug, in order to obtain stable aqueous dispersions. The initial magnetite and chromite nanoparticles have been synthesized previously by thermal decomposition thus being covered by dodecylamine and oleic acid. Their aqueous dispersions were obtained by physical methods using very low concentrations of siloxane surfactants, and were investigated by DLS, TEM, cryo-TEM and EDX. One such formulation was tested by MTT method and the results showed high cell viability. The nanoparticles covered with siloxane surfactants exhibited various types of morphology: individual particles, vesicle-like aggregates or composite particles, all having diameters roughly between 20 and 200nm. The encapsulation of both SPION and nystatin confirmed our previous results on nystatin solubilization by encapsulation within the hydrophobic wall of surfactant vesicles.

Planar Multilayer Assemblies Containing Block Copolymer Aggregates

The design, preparation, and properties of planar multilayer structures composed of various combinations of sequentially deposited polyelectrolyte (PE) chains and self-assembled layers of individual block copolymer aggregates (vesicles, micelles, or large compound micelles (LCMs)) are described. The aggregates contain negatively or positively charged corona chains while the PE multilayers contain alternating polyanionic or polycationic chains deposited on silicon wafers. The final structures consist of combinations of layers of various charged species: multilayers of alternating PEs of poly(allyl hydrochloride) (PAH) and poly(acrylic acid) (PAA) as well as vesicles, micelles, or large compound micelles of ionized poly(styrene)-b-poly(4-vinylpyridine) (PS-b-P4VP) or of poly(styrene)-b-poly(acrylic acid) (PS-b-PAA). Two types of layer-by-layer (LbL) multilayer structures were studied: individual aggregate layers sandwiched between PE multilayers and layers of individual aggregates of various morphologies and of different corona chain charges, deposited on top of each other without intermediate multilayers or individual layers of PEs. The strong interactions between the successive layers are achieved mainly by electrostatic attraction between the oppositely charged layers. The planar LbL multilayers containing block copolymer aggregates could, potentially, be used as carriers for multiple functional components; each aggregate layer could be loaded with hydrophobic (in the core of the micelles, LCMs, or vesicle walls) or hydrophilic functional molecules (in the vesicular cavities). The overall thickness of such planar LbL multilayers can be controlled precisely and can vary from tens of nanometers to several micrometers depending on the number of layers, the sizes of the aggregates, and the complexity of the structure.

Alanine-rich amphiphilic peptide containing the RGD cell adhesion motif: a coating material for human fibroblast attachment and culture.

We studied the self-assembly of peptide A6RGD (A: alanine, R: arginine, G: glycine, D: aspartic acid) in water, and the use of A6RGD substrates as coatings to promote the attachment of human cornea stromal fibroblasts (hCSFs). The self-assembled motif of A6RGD was shown to depend on the peptide concentration in water, where both vesicle and fibril formation were observed. Oligomers were detected for 0.7 wt% A6RGD, which evolved into short peptide fibres at 1.0 wt% A6RGD, while a co-existence of vesicles and long peptide fibres was revealed for 2-15 wt% A6RGD. A6RGD vesicle walls were shown to have a multilayer structure built out of highly interdigitated A6 units, while A6RGD fibres were based on β-sheet assemblies. Changes in the self-assembly motif with concentration were reflected in the cell culture assay results. Films dried from 0.1-1.0 wt% A6RGD solutions allowed hCSFs to attach and significantly enhanced cell proliferation relative to the control. In contrast, films dried from 2.5 wt% A6RGD solutions were toxic to hCSFs.

Interaction between a Cationic Surfactant-like Peptide and Lipid Vesicles and Its Relationship to Antimicrobial Activity

We investigate the properties of an antimicrobial surfactant-like peptide (Ala)6(Arg), A6R, containing a cationic headgroup. The interaction of this peptide with zwitterionic (DPPC) lipid vesicles is investigated using a range of microscopic, X-ray scattering, spectroscopic, and calorimetric methods. The β-sheet structure adopted by A6R is disrupted in the presence of DPPC. A strong effect on the small-angle X-ray scattering profile is observed: the Bragg peaks from the DPPC bilayers in the vesicle walls are eliminated in the presence of A6R and only bilayer form factor peaks are observed. All of these observations point to the interaction of A6R with DPPC bilayers. These studies provide insight into interactions between a model cationic peptide and vesicles, relevant to understanding the action of antimicrobial peptides on lipid membranes. Notably, peptide A6R exhibits antimicrobial activity without membrane lysis.

Size Selective Incorporation of Gold Nanoparticles in Diblock Copolymer Vesicle Wall

A systematic study is conducted to reveal how far the polymeric vesicle wall can embed gold nanoparticles (AuNPs) with different sizes by combining experiments and self-consistent field simulations. Both the experimental and simulative results indicate that the location of AuNPs in vesicle wall or in spherical micelle is heavily size dependent. Whether the AuNPs enter the vesicle wall or not is determined by a ratio of the diameter of AuNPs (D0) to the thickness of the vesicle wall (d(w0)). The 1-dodecanethiol-coated AuNPs (Au(x)R) with D0/d(w0) < 0.3 will stably disperse in the vesicle walls. For polystyrene-coated AuNPs (Au(x)S), a criterion of D0/d(w0) is proposed based on the phase diagram; i.e., the Au(x)S with D0/d(w0) < 0.5 can be located in the vesicle wall. Otherwise, the Au(x)R and the Au(x)S prefer to locate in spherical micelles. Moreover, the contributions of enthalpy and entropy to the total free energy of the system are respectively calculated to reveal the mechanism of the size selective distribution of AuNPs. The results demonstrate that the escape of AuNPs from vesicle walls and their selective distribution in spherical micelles is an entropy-driven process. Our study provides an important guideline for fabricating nanoparticle/block copolymer hybrid vesicles in dilute solution.

Enantiomeric and Diastereoisomeric (Mixed) L/ D‐Octaarginine Derivatives – A Simple Way of Modulating the Properties of Cell‐Penetrating Peptides

Cell-penetrating peptides (CPPs) are promising vehicles for delivery of drugs, antibiotics, proteins, nucleic acid derivatives, etc. into eukaryotic and prokaryotic target cells. To prevent premature degradation, CPPs consisting of D- or β-amino acid residues have been used. We present simple models for the various modes of delivery of physiologically active cargoes by CPPs, depending on the nature of their conjugation (Fig. 1), and we describe the plasma stability of oligoarginines (OAs) 1-4, the most common unnatural CPPs. Fluorescein-labeled L-octaarginine 1 was found to have a half-life (t1/2 ) of <0.5 min, the D-enantiomer (2) of >7 d (Fig. 2). For possible medicinal applications, the former type of derivative would be too unstable, and the latter one undesirably persistent. Thus, seven of the 256 possible 'mixed' Flua-L/D-octaarginine amides, 4a-4g, were synthesized and shown to have half-lives in heparine-stabilized human plasma between 8 min and 5.5 h (Figs. 3 and 4). The cell penetration of the new OAs was investigated with 'healthy' and with apoptotic HEK cells (Figs. 5-8), and their interactions with phospholipid bilayers were studied, using anionic lipid vesicles (Figs. 9 and 10). There are surprisingly large differences in the rates of cell penetration and binding to vesicle walls between the various stereoisomeric octaarginine derivatives 1, 2, and 4a-4g (Figs. 5 and 7). - The role of D-amino acids and D-peptides in nature and in drug design is briefly discussed and referenced.

Integration of Gold Nanoparticles into Bilayer Structures via Adaptive Surface Chemistry

We describe the spontaneous incorporation of amphiphilic gold nanoparticles (Au NPs) into the walls of surfactant vesicles. Au NPs were functionalized with mixed monolayers of hydrophilic (deprotonated mercaptoundecanoic acid, MUA) and hydrophobic (octadecanethiol, ODT) ligands, which are known to redistribute dynamically on the NP surface in response to changes in the local environment. When Au NPs are mixed with preformed surfactant vesicles, the hydrophobic ODT ligands on the NP surface interact favorably with the hydrophobic core of the bilayer structure and guide the incorporation of NPs into the vesicle walls. Unlike previous strategies based on small hydrophobic NPs, the present approach allows for the incorporation of water-soluble particles even when the size of the particles greatly exceeds the bilayer thickness. The strategy described here based on inorganic NPs functionalized with two labile ligands should in principle be applicable to other nanoparticle materials and bilayer structures.