Corona Thickness Research Articles

Maintaining Hydrophobic Drug Supersaturation in a Micelle Corona Reservoir

Two poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (PND) statistical copolymers and a series of three poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide)-b-polystyrene (PND-b-PS-C12) diblock polymers were synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization, in which the molecular weight of the thermoresponsive PND corona block was held constant while the polystyrene core block length was varied. The corona thickness and density of the micelles in phosphate-buffered saline (PBS, pH = 6.5) were quantified by a combination of dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS). Two hydrophobic model drugs, phenytoin and nilutamide, were used to examine the drug–polymer interactions in aqueous solution. Intermolecular interactions between the diblock polymer micelle corona and both drugs were revealed by 2D 1H nuclear Overhauser effect spectroscopy (NOESY). The drug–polymer “binding” strength, quantified by diffusion ordered NMR spectroscopy (DOSY)...

Segmental Relaxation Dynamics of the Core and Corona in a Single Dry Micelle

The segmental relaxation dynamics of the core and the corona in a single dry spherical micelle comprising a polystyrene (PS) or poly(methyl methacrylate) (PMMA) core and a poly(acrylic acid) (PAA) corona, along with the effects of the micelle density and the chain length of the core-forming and corona-forming polymers, were investigated by AFM. The results showed that the segmental relaxation temperature in the micelle core was close to its bulk Tg and independent of the micellar structure, such as micelle size, density, and corona thickness. By contrast, the segmental relaxation temperature in the micelle corona is dependent on the micellar structure. The depressed chain mobility in the corona was enhanced as the micelle density and the length of both the corona-forming and core-forming blocks increased. This phenomenon was attributed to conformational entropy loss in the micelle corona because of the chain adopting a conformation more perpendicular to the core as the micelle size and density increased.

Complexation of Linear DNA and Poly(styrenesulfonate) with Cationic Copolymer Micelles: Effect of Polyanion Flexibility.

The complexation of linear double stranded DNA and poly(styrenesulfonate) (PSS) with cationic poly(dimethylamino ethyl methacrylate)-block-poly(n-butyl methacrylate) micelles was compared in aqueous solutions at various pH values and ionic strengths. The complexation process was monitored by turbidimetric titration, as a function of the ratio (N/P) of amine groups in the micelle corona to the number of phosphates (or sulfonates) in the polyanion. The size, structure and stability of the resulting micelleplexes were studied by dynamic light scattering (DLS) and cryogenic transmission electron microscopy (cryo-TEM). In the short chain regime, where the contour lengths of the polyanions are shorter than or comparable to the micelle corona thickness, micelleplexes with DNA oligomers show very similar behavior to complexes with short PSS chains, in terms of titration curves and structural evolution of the complexes as a function of charge ratio. However, in the long chain regime, where the contour length of the polyanion far exceeds the micelle radius, micelleplexes of linear DNA show titration curves shifted toward lower N/P ratios, reduced stability at N/P < 1, and a higher percentage of small complexes at N/P > 1 compared to complexes with long chain PSS. Furthermore, at 1 M ionic strength, the cationic micelles could still complex with long chain PSS, but not with DNA of the same total charge. These differences are attributed to the flexibility difference between the polyanion chains, and possible mechanisms are proposed. This work highlights the importance of chain flexibility in complexation of dissimilar polyelectrolyte pairs, a factor that could therefore help guide the future design of micelleplexes for various applications.

Probing Temperature- and pH-Dependent Binding between Quantum Dots and Bovine Serum Albumin by Fluorescence Correlation Spectroscopy.

Luminescent quantum dots (QDs) with unique optical properties have potential applications in bio-imaging. The interaction between QDs and bio-molecules is important to the biological effect of QDs in vivo. In this paper, we have employed fluorescence correlation spectroscopy (FCS) to probe the temperature- and pH-dependent interactions between CdSe QDs with carboxyl (QDs-COOH) and bovine serum albumin (BSA) in buffer solutions. The results have shown that microscopic dissociation constant K′D is in the range of (1.5 ± 0.2) × 10−5 to (8.6 ± 0.1) × 10−7 M, the Hill coefficient n is from 0.4 to 2.3, and the protein corona thickness is from 3.0 to 9.4 nm. Variable-temperature measurements have shown both negative values of ∆H and ∆S for BSA adsorption on QDs-COOH, while pH has a profound effect on the adsorption. Additional, FCS measurement QDs-COOH and proteins in whole mice serum and plasma samples has also been conducted. Finally, simulation results have shown four favored QD binding sites in BSA.

Limiting the protein corona: A successful strategy for invivo active targeting of anti-HER2 nanobody-functionalized nanostars.

Gold nanoparticles hold great promise as anti-cancer theranostic agents against cancer by actively targeting the tumor cells. As this potential has been supported numerously during invitro experiments, the effective application is hampered by our limited understanding and control of the interactions within complex in vivo biological systems. When these nanoparticles are exposed to a biological environment, their surfaces become covered with proteins and biomolecules, referred to as the protein corona, reducing the active targeting capabilities. We demonstrate a chemical strategy to overcome this issue by reducing the protein corona's thickness by blocking the active groups of the self-assembled monolayer on gold nanostars. An optimal blocking agent, 2-mercapto ethanol, has been selected based on charge and length of the carbon chain. By using a nanobody as a biological ligand of the human epidermal growth factor 2 receptor (HER2), the active targeting is demonstrated invitro and invivo in an experimental tumor model by using darkfield microscopy and photoacoustic imaging. In this study, we have established gold nanostars as a conceivable theranostic agent with a specificity for HER2-positive tumors.

Poly(methyl methacrylate)-block-poly(n-butyl methacrylate) Diblock Copolymer Micelles in an Ionic Liquid: Scaling of Core and Corona Size with Core Block Length

The structure of poly(methyl methacrylate)-block-poly(n-butyl methacrylate) (PMMA-b-PnBMA) micelles in the room temperature ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM][TFSI]), a selective solvent for the PMMA block, has been studied using dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS). A series of seven PMMA-b-PnBMA diblock copolymers were prepared by reversible addition–fragmentation chain-transfer (RAFT) polymerization, in which the degree of polymerization of the PMMA block was kept constant while the PnBMA block length was varied. All the polymers formed spherical micelles at ambient temperature in dilute solution; their hydrodynamic radius (Rh) and core radius (Rc) were obtained by DLS and SAXS, respectively. It was found that Rc and the degree of polymerization of the core block, NB, followed a power law relationship in which Rc ∼ NB0.71±0.01. The corona thickness (Lcorona), given by the difference of Rh and Rc, does not show any apparen...

Electron microscopy imaging of proteins on gallium phosphide semiconductor nanowires

We have imaged GaP nanowires (NWs) incubated with human laminin, serum albumin (HSA), and blood plasma using both cryo-transmission electron microscopy and synchrotron based X-ray photoemission electron microscopy. This extensive imaging methodology simultaneously reveals structural, chemical and morphological details of individual nanowires and the adsorbed proteins. We found that the proteins bind to NWs, forming coronas with thicknesses close to the proteins' hydrodynamic diameters. We could directly image how laminin is extending from the NWs, maximizing the number of proteins bound to the NWs. NWs incubated with both laminin and HSA show protein coronas with a similar appearance to NWs incubated with laminin alone, indicating that the presence of HSA does not affect the laminin conformation on the NWs. In blood plasma, an intermediate sized corona around the NWs indicates a corona with a mixture of plasma proteins. The ability to directly visualize proteins on nanostructures in situ holds great promise for assessing the conformation and thickness of the protein corona, which is key to understanding and predicting the properties of engineered nanomaterials in a biological environment.

Fluorescent gold nanoparticles with chain-end grafted RAFT copolymers: influence of the polymer molecular weight and type of chromophore

Fluorescence of gold nanoparticles functionalized with chain-end grafted RAFT copolymers increases with polymer corona thickness.

Probing Soft Corona Structures of DNA-Capped Nanoparticles by Small Angle Neutron Scattering

Soft corona structures of DNA-capped nanoparticles are crucial for their applications in diagnostics, gene delivery, and superlattice growth. While conventional X-ray techniques can only provide information on their inorganic cores, here we report substantial new insights of DNA corona structures within DNA-capped nanoparticles in this first study employing small angle neutron scattering (SANS). Using two 15-mer DNA strands with palindromic sequence and poly(dT) sequence under high number density packing on gold nanoparticle surfaces, the influence of ionic strength and temperature on DNA corona structures and resultant hybridization has been investigated. Poly(dT) sequences were found to maintain globular corona structures across a range of ionic strengths and temperatures, but the corona thickness decreased with increasing salt concentration and increased with increasing temperature. In contrast, palindromic sequenced DNA had globular corona structures in the absence of salt but quickly evolved into dim...

Synthesis and Self-Assembly of Toothbrush-like Block Copolymers

Block copolymers (BCPs) can self-assemble in selective solvents to form morphologies based on their chemistries and architectures. In this study, we investigate BCPs having both brush and linear segments in what is referred to as “toothbrush” architecture. Using anionic polymerization, we have synthesized a linear poly(styrene-block-isoprene) followed by growing poly(ethylene oxide) grafts from the isoprene block to form a brush segment. A combination of nonselective and selective solvents is used to drive the self-assembly of the toothbrush polymers. Analysis by dynamic light scattering and transmission electron microscopy show that the self-assembly is highly influenced by the density of grafts in the brush segment, with densely grafted polymers forming only spherical micelles and sparsely grafted brushes forming higher order structures including cylindrical micelles and vesicles. Additionally, calculations of micelle corona graft density and corona thickness indicate that the corona of the micelles for...

Entropic effects in mixed micelles formed by star/linear and star/star AB copolymers

The entropic effects in the comicellization behavior of amphiphilic AB copolymers differing in chain architecture of solvophilic A or solvophobic B parts are studied by means of molecular dynamics simulations. In particular, we studied linear/star and star/star copolymer mixtures. The properties of interest were the critical micelle concentration, the mean aggregation number, the shape of the micelle, which is expressed by the shape anisotropy, the thickness of the corona, and the solvophobic core radius. We found that the critical micelle concentration values for linear/star and copolymer mixtures show a positive deviation from the analytical predictions of the molecular theory of comicellization for chemically identical copolymers. This could be attributed to the effective interactions between copolymers originated from the architectural asymmetry. The effective interactions induce a small decrease in the aggregation number of preferential micelles in linear/star mixtures triggering the nonrandom mixing between the solvophilic moieties in the corona for all mixtures. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015, 53, 442–452

Effects of surface functionalization on the adsorption of human serum albumin onto nanoparticles - a fluorescence correlation spectroscopy study.

By using fluorescence correlation spectroscopy (FCS), we have studied the adsorption of human serum albumin (HSA) onto Fe–Pt nanoparticles (NPs, 6 nm radius), CdSe/ZnS quantum dots (QDs, 5 nm radius) and Au and Ag nanoclusters (1–4 nm radius), which are enshrouded by various water-solubilizing surface layers exposing different chemical functional groups (carboxyl, amino and both), thereby endowing the NPs with different surface charges. We have also measured the effects of modified surface functionalizations on the protein via succinylation and amination. A step-wise increase in hydrodynamic radius with protein concentration was always observed, revealing formation of protein monolayers coating the NPs, independent of their surface charge. The differences in the thickness of the protein corona were rationalized in terms of the different orientations in which HSA adsorbs onto the NPs. The midpoints of the binding transition, which quantifies the affinity of HSA toward the NP, were observed to differ by almost four orders of magnitude. These variations can be understood in terms of specific Coulombic interactions between the proteins and the NP surfaces.

Nanoparticle-nanoparticle interactions in biological media by atomic force microscopy.

Particle-particle interactions in physiological media are important determinants for nanoparticle fate and transport. Herein, such interactions are assessed by a novel atomic force microscopy (AFM)-based platform. Industry-relevant CeO2, Fe2O3, and SiO2 nanoparticles of various diameters were made by the flame spray pyrolysis (FSP)-based Harvard Versatile Engineering Nanomaterials Generation System (Harvard VENGES). The nanoparticles were fully characterized structurally and morphologically, and their properties in water and biological media were also assessed. The nanoparticles were attached on AFM tips and deposited on Si substrates to measure particle-particle interactions. The corresponding force was measured in air, water, and biological media that are widely used in toxicological studies. The presented AFM-based approach can be used to assess the agglomeration potential of nanoparticles in physiological fluids. The agglomeration potential of CeO2 nanoparticles in water and RPMI 1640 (Roswell Park Memorial Institute formulation 1640) was inversely proportional to their primary particle (PP) diameter, but for Fe2O3 nanoparticles, that potential is independent of PP diameter in these media. Moreover, in RPMI+10% Fetal Bovine Serum (FBS), the corona thickness and dispersibility of the CeO2 are independent of PP diameter, while for Fe2O3, the corona thickness and dispersibility were inversely proportional to PP diameter. The present method can be combined with dynamic light scattering (DLS), proteomics, and computer simulations to understand the nanobio interactions, with emphasis on the agglomeration potential of nanoparticles and their transport in physiological media.

$\hbox{MgB}_{2}$ Hollow Wires and Cables Embedded in a Mg Alloy Matrix

The brittleness of the MgB2 wires prevents performing a cable architecture with very small bending radius, similar to NbTi Rutherford cables. Consequently, it is important to reduce the thickness of the superconducting materials in order to increase its bending strain limit. In this context, thin Ni sheathed MgB2 hollow wires, having wall thickness of the order of 20 μm and length of the order of 100 m, have been produced by the Reactive Mg-Liquid Infiltration process (Mg-RLI). The latest hollow monofilament made by Mg-RLI shows very high transport properties, having an engineering critical current density at 4.2 K, 3 T of 730 A/mm2. In this wire the small thickness of the MgB2 corona allows a twisting with pass of the order of a few cm and fulfils the thermal stability criterion for MgB2. We have demonstrated that cables made by such braided or twisted wires may be conveniently reinforced, by embedding the wires in a molten Mg bath, so that the Ni sheath is almost completely dissolved and the wires are clad by an eutectic Mg10%at Ni alloy. This alloyed matrix is structurally well connected to the MgB2 material, with minimal thermal and electrical resistance at the interface. A cable prototype based on this metallic composite has been prepared with 21 mono-core MgB2 wires, twisted around a central hole, which may be useful for cooling purposes. This cable design may be applied as current leads or in short bus-bars, for high current supply.

Modeling the response of dual cross-linked nanoparticle networks to mechanical deformation

We develop a hybrid computational model for the behavior of a network of cross-linked polymer-grafted nanoparticles (PGNs). The individual nanoparticles are composed of a rigid core and a corona of grafted polymers that encompass reactive end groups. With the overlap of the coronas on adjacent particles, the reactive end groups can form permanent or labile bonds, which lead to the formation of a “dual cross-linked” network. To capture these multi-scale interactions, our approach integrates the essential structural features of the polymer grafted nanoparticles, the interactions between the overlapping coronas, and the kinetics of bond formation and rupture between the reactive groups on the chain ends. Via this model, we determine the tensile properties of the dual cross-linked samples. We find that the mechanical behavior of the network can be tailored by altering the bond energies of the labile bonds, the fraction of permanent bonds in the network and the thickness of the polymer corona. In particular, for a network with weaker labile bonds, an increase in fraction of permanent bonds and the contour length of the chain can yield a tough network that behaves like a polymeric material, which exhibits cold drawing/necking. On the other hand, similar changes to the network with stronger labile bonds lead to an increase in toughness, with the network characteristics being similar to that of a purely ductile material. Variations in the ratio between the strain rate and the bond rupture rate are also found to affect the response of the networks. Our model provides a powerful approach for predicting how critical features of the system affect the performance of cross-linked polymer-grafted nanoparticles.

An effective and controllable approach to derive polymer corona on oxide nanoparticles to enhance their compatibility in polymeric nanocomposites

Barium titanate nanoparticles were surface-functionalized by a novel polymeric surface-functionalization agent, using a rotary coating technology combined with the post-treatment bonding process. Fourier transform infrared and transmission electron microscopy results display that the nanoparticle surfaces were successfully functionalized by nitrile groups, and surrounded with a polymer corona. This can effectively prevent nanoparticles from agglomeration, and also can greatly enhance their compatibility with polymer matrices through macromolecular chains entanglement. It is important to note that the thickness of polymer corona is controllable. Furthermore, it was found that this method is also applicable to numerous other oxide nanoparticles, such as SiO2, TiO2, Fe3O4, etc.

Significance of cell “observer” and protein source in nanobiosciences

It is well understood that when nanoparticles (NPs) enter a biological medium, their surface is coated by various proteins; thus, the interaction of the living systems with the NPs depends on the composition of the protein layer, rather than the surface characteristics of the nanoparticle itself. However, there are several neglected parameters in protein–NP interactions (e.g., the key role of the protein source) that should be addressed. The composition of the protein corona is recognized as having a crucial influence on the delivery of NPs into cells, which is important in therapeutic applications and in nanotoxicology; however, the effect of “cell observer” (cell type) is poorly understood. This study probed the effects of different protein sources (fetal bovine serum [FBS] and human plasma [HP]) on the composition and protein thickness of the hard corona formed at the surface of superparamagnetic nanoparticles (SPIONs) with various sizes and surface chemistries. The results show that the hard corona can change quite considerably as one passes from the biophysicochemical properties of nanoparticles and protein sources (e.g., FBS and HP) appropriate to in vitro cell/tissue studies to those appropriate for in vivo studies. These changes in the hard corona have deep implications for in vitro–in vivo extrapolations. In addition, we probed the “cell observer” effect on the uptake and toxicity of SPIONs with the same protein corona composition to highlight the effect of cell type in nanobiosciences. The particles interacted with various cell lines. We find that without consideration of the “cell observer” effect, the cellular targeting/toxicity of NPs is inherently imprecise; thus, a deep understanding of both the protein corona composition and the “cell observer” effect offer a way to predict NP dosage for therapy and for the study of nanotoxins.

Bacterial Effects and Protein Corona Evaluations: Crucial Ignored Factors in the Prediction of Bio-Efficacy of Various Forms of Silver Nanoparticles

Because of their unique properties which are strongly dependent on the physicochemical properties of metal nanomaterials, noble metal nanostructures, particularly silver, have attracted much attention in the fields of electronics, chemistry, physics, biology, and medicine. Regarding biology and medical applications, silver nanoparticles (NPs) are recognized as a promising candidate to fight against resistant pathogens because of their significant antimicrobial activities. However, there are two major ignored issues with these NPs. First, the effect of various types of bacteria on antibacterial efficacy of silver NPs is ignored; second, there is no information on the pattern and compositions of both soft- and hard-corona proteins at the surface of NPs, which can define cellular responses to the NPs. In this article, the bacterial effect on the antibacterial capability of silver NPs with various geometries (i.e., sphere, wire, cube, and triangle) was probed; in this case, three different types of bacteria including Escherichia coli (E. coli), Bacillus subtilis, and Staphylococcus aureus were employed. The results showed that the type of bacteria can have quite a significant role in the definition of antibacterial efficacy of NPs, which has significant implications in the high yield design of NPs for antibacterial applications and will require serious consideration in the future. In addition, both soft- and hard-corona proteins were analyzed, and the effects of protein coated NPs on normal cells were evaluated. According to the results, the composition and thickness of protein coronas were strongly dependent on the physicochemical properties of silver NPs. We have found that the composition and thickness of the protein corona can evolve quite significantly as one passes from particle concentrations and shapes appropriate to in vitro cell studies to those present in in vivo studies, which has important implications for in vitro-in vivo extrapolations and will require more consideration in the future.

Size Dependent Biodistribution and SPECT Imaging of 111In-Labeled Polymersomes

Polymersomes, self-assembled from the block copolymer polybutadiene-block-poly(ethylene glycol), were prepared with well-defined diameters between 90 and 250 nm. The presence of ~1% of diethylene triamine penta acetic acid on the polymersome periphery allowed to chelate radioactive (111)In onto the surface and determine the biodistribution in mice as a function of both the polymersome size and poly(ethylene glycol) corona thickness (i.e., PEG molecular weight). Doubling the PEG molecular weight from 1 kg/mol to 2 kg/mol did not change the blood circulation half-life significantly. However, the size of the different polymersome samples did have a drastic effect on the blood circulation times. It was found that polymersomes of 120 nm and larger become mostly cleared from the blood within 4 h, presumably due to recognition by the reticuloendothelial system. In contrast, smaller polymersomes of around 90 nm circulated much longer. After 24 h more than 30% of the injected dose was still present in the blood pool. This sharp transition in blood circulation kinetics due to size is much more abrupt than observed for liposomes and was additionally visualized by SPECT/CT imaging. These findings should be considered in the formulation and design of polymersomes for biomedical applications. Size, much more than for liposomes, will influence the pharmacokinetics, and therefore, long circulating preparations should be well below 100 nm.

Reversible versus Irreversible Binding of Transferrin to Polystyrene Nanoparticles: Soft and Hard Corona

Protein adsorption to nanoparticles (NPs) is a key prerequisite to understand NP-cell interactions. While the layer thickness of the protein corona has been well characterized in many cases, the absolute number of bound proteins and their exchange dynamics in body fluids is difficult to assess. Here we measure the number of molecules adsorbed to sulfonate (PSOSO(3)H) and carboxyl-(PSCOOH) polystyrene NPs using fluorescence correlation spectroscopy. We find that the fraction of molecules bound to NPs falls onto a single, universal adsorption curve, if plotted as a function of molar protein-to-NP ratio. The adsorption curve shows the build-up of a strongly bound monolayer up to the point of monolayer saturation (at a geometrically defined protein-to-NP ratio), beyond which a secondary, weakly bound layer is formed. While the first layer is irreversibly bound (hard corona), the secondary layer (soft corona) exhibits dynamic exchange, if competing unlabeled is added. In the presence of plasma proteins, the hard corona is stable, while the soft corona is almost completely removed. The existence of two distinct time scales in the protein off-kinetics, for both NP types studied here, indicates the possibility of an exposure memory effect in the NP corona.