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Short Zwitterionic Sulfobetaine-Modified Silica Nanoparticles: Is Neutrality Possible?
... Sulfobetaine zwitterionic (ZW) and folate groups were chosen as kinetic stabilizers and targeting agents, respectively. It is worth highlighting that sulfobetaines were selected specifically for their enhanced hydration properties, effectively preventing protein adsorption on various NPs and contributing to improved colloidal stability [25,26]. Remarkably, functionalized NPs were stable in a complex medium (cell culture medium and human plasma) and showed greater potential for recognition by tumor cells. ...
Most commercial anticancer nanomedicines are administered intravenously. This route is fast and precise as the drug enters directly into the systemic circulation, without undergoing absorption processes. When nanoparticles come into direct contact with the blood, however, they interact with physiological components that can induce colloidal destabilization and/or changes in their original biochemical identity, compromising their ability to selectively accumulate at target sites. In this way, these systems usually lack active targeting, offering limited therapeutic effectiveness. In the literature, there is a paucity of in-depth studies in complex environments to evaluate nanoparticle stability, protein corona formation, hemolytic activity, and targeting capabilities. To address this issue, fluorescent silica nanoparticles (SiO 2 NPs) are here functionalized with zwitterionic (kinetic stabilizer) and folate groups (targeting agent) to provide selective interaction with tumor cell lines in biological media. The stability of these dually functionalized SiO 2 NPs is preserved in unprocessed human plasma while yielding a decrease in the number of adsorbed proteins. Experiments in murine blood further proved that these nanoparticles are not hemolytic. Remarkably, the functionalized SiO 2 NPs are more internalized by tumor cells than their healthy counterparts. Investigations of this nature play a crucial role in garnering results with greater reliability, allowing the development of nanoparticle-based pharmaceutical drugs that exhibit heightened efficacy and reduced toxicity for medical purposes.
Current research on the antifouling mechanisms of “electrically neutral” polymer brushes predominantly emphasizes thermodynamically unfavorable short-range interactions. However, our study reveals the critical importance of long-range interactions. By utilizing zwitterionic poly(carboxybetaine methacrylate) (PCBMA) and nonionic poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) brushes as model systems, we employed total internal reflection microscopy (TIRM) to directly measure interactions with contaminants. Surprisingly, even seemingly neutral polymers exhibit significant electrostatic interactions with nearby contaminants—a fact that has been largely overlooked in this field. Our findings challenge the prevailing assumption of charge absence on surfaces grafted with antifouling polymer brushes and investigate how external stimuli (such as ionic strength and polymer conformation) affect these long-range interactions. In conclusion, this study presents a novel approach to exploring long-range interactions near polymer-grafted surfaces, offering valuable insights for the development of antifouling materials and biomedical applications in the future.
The supramolecular organization of soft materials, such as colloids, polymers, and amphiphiles, results from a subtle balance of weak intermolecular interactions and entropic forces. This competition can drive the self-organization of soft materials at the nano-/mesoscale. Modeling soft-matter self-assembly requires, therefore, considering a complex interplay of forces at the relevant length scales without sacrificing the molecular details that define the chemical identity of the system. This mini-review focuses on the application of a tool known as molecular theory to study self-assembly in different types of soft materials. This tool is based on extremizing an approximate free energy functional of the system, and, therefore, it provides a direct, computationally affordable estimation of the stability of different self-assembled morphologies. Moreover, the molecular theory explicitly incorporates structural details of the chemical species in the system, accounts for their conformational degrees of freedom, and explicitly includes their chemical equilibria. This mini-review introduces the general ideas behind the theoretical formalism and discusses its advantages and limitations compared with other theoretical tools commonly used to study self-assembled soft materials. Recent application examples are discussed: the self-patterning of polyelectrolyte brushes on planar and curved surfaces, the formation of nanoparticle (NP) superlattices, and the self-organization of amphiphiles into micelles of different shapes. Finally, prospective methodological improvements and extensions (also relevant for related theoretical tools) are analyzed.
We develop a molecular thermodynamic theory to study the interaction of some proteins with a charge regulating silica-like surface under a wide range of conditions, including pH, salt concentration and protein concentration. Proteins are modeled using their three dimensional structure from crystallographic data and the average experimental pKa of amino acid residues. As model systems, we study single-protein and binary solutions of cytochrome c, green fluorescent protein (GFP), lysozyme and myoglobin. Our results show that protonation equilibrium plays a critical role in the interactions of proteins with these type of surfaces. The terminal hydroxyl groups on the surface display considerable extent of charge regulation; protein residues with titratable side chains increase protonation according to changes in the local environment and the drop in pH near the surface. This behavior defines protein-surface interactions and leads to the emergence of several phenomena: (i) a complex non-ideal surface charge behavior; (ii) a non-monotonic adsorption of proteins as a function of pH; and (iii) the presence of two spatial regions, a protein-rich and a protein-depleted layer, that occur simultaneously at different distances from the surface when pH is slightly above the isoelectric point of the protein. In binary mixtures, protein adsorption and surface-protein interactions cannot be predicted from single-protein solution considerations.
This review shows the most common and promising strategies to generate colloidally stable silica nanoparticles (NPs) in simulated biological fluids and sheds light on the latest advances in producing degradable silica-based structures. Silica NPs can be synthesized in a wide variety of morphologies, porosity levels, and sizes. This versatility makes silica NPs one of the most promising nano-platforms for imaging and disease treatment. Nonetheless, biological barriers can decrease the success of translating them for therapeutic applications since the media composition can induce their colloidal stability loss. It can, consequently, lead to the NPs aggregation and affect their degradation profile. The interplay between NPs aggregation and degradation has been scarcely explored in the literature when biological fluids are seriously taken into account. Herein we discuss the theory behind the colloidal stability of silica NPs, the processes leading to their aggregation, and some strategies to overcome this issue (mainly focused on NPs surface functionalization). Furthermore, we addressed the main issues that affect the degradability of NPs in biological fluids, and explored some strategies, such as chemical surface modification, which are able to tune these degradation-driven profiles. Thus, the understanding of the silica NPs behavior in body fluids is essential for the approval of nanomedicines and, therefore, more investigations concerning the dynamics, thermodynamics, biological response, and structural parameters of silica-based NPs are of utmost importance.
Nanoparticles (NPs) are promising platforms for the development of diagnostic and therapeutic tools. One of the main hurdle to their medical application and translation into the clinic is the fact that they accumulate in the spleen and liver due to opsonization and scavenging by the mononuclear phagocyte system. The “protein corona” controls the fate of NPs in vivo and becomes the interface with cells, influencing their physiological response like cellular uptake and targeting efficiency. For these reasons, the surface properties play a pivotal role in fouling and antifouling behavior of particles. Therefore, surface engineering of the nanocarriers is an extremely important issue for the design of useful diagnostic and therapeutic systems. In recent decades, a huge number of studies have proposed and developed different strategies to improve antifouling features and produce NPs as safe and performing as possible. However, it is not always easy to compare the various approaches and understand their advantages and disadvantages in terms of interaction with biological systems. Here, we propose a systematic study of literature with the aim of summarizing current knowledge on promising antifouling coatings to render NPs more biocompatible and performing for diagnostic and therapeutic purposes. Thirty-nine studies from 2009 were included and investigated. Our findings have shown that two main classes of non-fouling materials (i.e., pegylated and zwitterionic) are associated with NPs and their applications are discussed here highlighting pitfalls and challenges to develop biocompatible tools for diagnostic and therapeutic uses. In conclusion, although the complexity of biofouling strategies and the field is still young, the collective data selected in this review indicate that a careful tuning of surface moieties is a pivotal step to lead NPs through their future clinical applications.
Significance
Silica, conventionally known as “glass,” is a universally used material in catalysis, nanofabrication, and many other applications, but details of its surface chemistry and interactions with water are notoriously complicated and unclear––partially due to its tunable surface chemistry. We utilize this tunable surface chemistry of silica to reveal properties of surface-bound water that impact surface reactions, adhesion, and colloidal interactions. Using a combination of surface forces, hydration dynamics, and simulation techniques, we show that surface silanol groups stabilize the surface water layer, and also that variations/fluctuations are more pronounced at intermediate silanol densities on the surface. This work provides insight into fundamental interactions of water with chemically heterogeneous surfaces.
After administration of nanoparticle (NP) into biological fluids, an NP–protein complex is formed, which represents the “true identity” of NP in our body. Hence, protein–NP interaction should be carefully investigated to predict and control the fate of NPs or drug-loaded NPs, including systemic circulation, biodistribution, and bioavailability. In this review, we mainly focus on the formation of protein corona and its potential applications in pharmaceutical sciences such as prediction modeling based on NP-adsorbed proteins, usage of active proteins for modifying NP to achieve toxicity reduction, circulation time enhancement, and targeting effect. Validated correlative models for NP biological responses mainly based on protein corona fingerprints of NPs are more highly accurate than the models solely set up from NP properties. Based on these models, effectiveness as well as the toxicity of NPs can be predicted without in vivo tests, while novel cell receptors could be identified from prominent proteins which play important key roles in the models. The ungoverned protein adsorption onto NPs may have generally negative effects such as rapid clearance from the bloodstream, hindrance of targeting capacity, and induction of toxicity. In contrast, controlling protein adsorption by modifying NPs with diverse functional proteins or tailoring appropriate NPs which favor selective endogenous peptides and proteins will bring promising therapeutic benefits in drug delivery and targeted cancer treatment.
Understanding how complement proteins bind to nanoparticles and participate in their surface 'corona' can provide further insight into the relevance of the protein corona concept in medicine.
Rattle structure is a topic of great interest in design and application of nanomaterials due to the unique core@void@shell architecture and the integration of functions. Herein, we developed a novel “ship-in-a-bottle” method to fabricate upconverting (UC) luminescent nanorattles by incorporating lanthanide-doped fluorides into hollow mesoporous silica. The size of nanorattles and the filling amount of fluorides can be well controlled. In addition, the modification of silica shell (with phenylene and amine groups) and the variation of efficient UC fluorides (NaYF4:Yb,Er, NaLuF4:Yb,Er, NaGdF4:Yb,Er and LiYF4:Yb,Er) were readily achieved. The resulting nanorattles exhibited a high capacity and pH-dependent release of the anti-cancer drug doxorubicin (DOX). Furthermore, we employed these nanorattles in proof-of-concept UC-monitoring drug release by utilizing the energy transfer process from UC fluorides to DOX, thus revealing the great potential of the nanorattles as efficient cancer theranostic agent.
A zwitterionic polypeptide derivative was successfully synthesized using 3-dimethylaminopropylamine as the ring-opening reagent to react with polysuccinimide, and a poly(alpha,beta-L-dimethylamino propyl aspartamide) was obtained with tertiary amine side groups; the ring-opening reagent then reacted with 1,3-propanesultone to prepeare the poly(alpha,beta-3-dimethyl propyl ammonium propanesulfonate aspartamide) (PSBA). PSBA possessed both cationic moiety in the form of quaternary ammonium and anionic functionality in the form of a sulfo-group on the same repeat unit; it also exhibited an isoelectric point (pI) and opposite charges at pH values far high or below the pI. FT-IR and H-1 NMR spectroscopy were used to confirm the chemical structure of PSBA. Zwitterionic polypeptides were coated onto the amino functional silica wafers via electrostatic attraction. The PSBA-coated silica wafers were characterized by water contact angle analysis, X-ray photoelectron spectroscopy (XPS), and atomic force microscope (AFM). Protein adsorption measurements indicated that polypeptides with zwitterionic sulfobetaine structure had good anti-protein-fouling property. The amount of protein adsorbed on the coated surface could be controlled, depending on the pre-coated polymer concentration. Because of its good biocompatibility and anti-protein-fouling property, this zwitterionic polypeptide is a promising candidate for surface modification in many biomedical applications, such as medical implants, drug delivery carriers, and biosensors.
Nanomaterials are finding increasing use for biomedical applications such as imaging, diagnostics, and drug delivery. While it is well understood that nanoparticle (NP) physico-chemical properties can dictate biological responses and interactions, it has been difficult to outline a unifying framework to directly link NP properties to expected in vitro and in vivo outcomes. When introduced to complex biological media containing electrolytes, proteins, lipids, etc., nanoparticles (NPs) are subjected to a range of forces which determine their behavior in this environment. One aspect of NP behavior in biological systems that is often understated or overlooked is aggregation. NP aggregation will significantly alter in vitro behavior (dosimetry, NP uptake, cytotoxicity), as well as in vivo fate (pharmacokinetics, toxicity, biodistribution). Thus, understanding the factors driving NP colloidal stability and aggregation is paramount. Furthermore, studying biological interactions with NPs at the nanoscale level requires an interdisciplinary effort with a robust understanding of multiple characterization techniques. This review examines the factors that determine NP colloidal stability, the various efforts to stabilize NP in biological media, the methods to characterize NP colloidal stability in situ, and provides a discussion regarding NP interactions with cells.
Although the cytotoxicity of nanoparticles (NPs) is greatly influenced by their interactions with blood proteins, toxic effects resulting from blood interactions are often ignored in the development and use of nanostructured biomaterials for in vivo applications. Protein coronas created during the initial reaction with NPs can determine the subsequent immunological cascade, and protein coronas formed on NPs can either stimulate or mitigate the immune response. Along these lines, the understanding of NP-protein corona formation in terms of physiochemical surface properties of the NPs and NP interactions with the immune system components in blood is an essential step for evaluating NP toxicity for in vivo therapeutics. This article reviews the most recent developments in NP-based protein coronas through the modification of NP surface properties and discusses the associated immune responses.
Nanoparticles represent highly promising platforms for the development of imaging and therapeutic agents, including those that can either be detected via more than one imaging technique (multi-modal imaging agents) or used for both diagnosis and therapy (theranostics). A major obstacle to their medical application and translation to the clinic, however, is the fact that many accumulate in the liver and spleen as a result of opsonization and scavenging by the mononuclear phagocyte system. This focused review summarizes recent efforts to develop zwitterionic-coatings to counter this issue and render nanoparticles more biocompatible. Such coatings have been found to greatly reduce the rate and/or extent of non-specific adsorption of proteins and lipids to the nanoparticle surface, thereby inhibiting production of the “biomolecular corona” that is proposed to be a universal feature of nanoparticles within a biological environment. Additionally, in vivo studies have demonstrated that larger-sized nanoparticles with a zwitterionic coating have extended circulatory lifetimes, while those with hydrodynamic diameters of ≤5 nm exhibit small-molecule-like pharmacokinetics, remaining sufficiently small to pass through the fenestrae and slit pores during glomerular filtration within the kidneys, and enabling efficient excretion via the urine. The larger particles represent ideal candidates for use as blood pool imaging agents, whilst the small ones provide a highly promising platform for the future development of theranostics with reduced side effect profiles and superior dose delivery and image contrast capabilities.
Zwitterionic surfactants are relatively overlooked and some of their properties resemble those of ionic and non-ionic surfactants, but others are unique. There is unimpeachable evidence that aqueous solutions of zwitterionic micelles interact specifically with anions, forming “anionoid” micelles, which concentrate cations in the surfaces. Thus, unlike ionic micelles, both the cation and anion of the electrolyte solution can be concentrated at zwitterionic interfaces. This unique effect, known as the “Chameleon Effect”, can be used to catalyze a variety of simple reactions, as the attraction of ions to the micelle brings the reactants together. Furthermore, zwitterionic surfactants stabilize metallic nanoparticles and the magnetically stirred two-phase system could be reused 3 more times in the hydrogenation of cyclohexene (Pd:cyclohexene ratio of 1:18300), with very little loss in activity, and an average turn-over frequency of 1000 h− 1.
Surface resistance to nonspecific protein adsorption, cell/bacterial adhesion, and biofilm formation is critical for the development and performance of biomedical and analytical devices. Significant needs and efforts have been made in the development of biocompatible and bioactive materials for antifouling surfaces, but much of the work retains an empirical flavor due to the complexity of experiments and the lack of robust theoretical models. In this review, two major classes of nonfouling materials (i.e. hydrophilic and zwitterionic materials) and associated basic nonfouling mechanisms and practical examples are discussed. Highly hydrated chemical groups with optimized physical properties of the surface, along with appropriate surface coating methods, are the keys to developing effective and stable nonfouling materials for long-term biomedical applications. The zwitterionic polymers are promising nonfouling biomaterials due to the simplicity of synthesis, ease of applicability, abundance of raw materials, and availability of functional groups.
Developments of novel drug delivery vehicles are sought‐after to augment the therapeutic effectiveness of standard drugs. An urgency to design novel drug delivery vehicles that are sustainable, biocompatible, have minimized cytotoxicity, no immunogenicity, high stability, long circulation time, and are capable of averting recognition by the immune system is perceived. In this pursuit for an ideal candidate for drug delivery vehicles, zwitterionic materials have come up as fulfilling almost all these expectations. This comprehensive review is presenting the progress made by zwitterionic polymeric architectures as prospective sustainable drug delivery vehicles. Zwitterionic polymers with varied architecture such as appending protein conjugates, nanoparticles, surface coatings, liposomes, hydrogels, etc, used to fabricate drug delivery vehicles are reviewed here. A brief introduction of zwitterionic polymers and their application as reliable drug delivery vehicles, such as zwitterionic polymer–protein conjugates, zwitterionic polymer‐based drug nanocarriers, and stimulus‐responsive zwitterionic polymers are discussed in this discourse. The prospects shown by zwitterionic architecture suggest the tremendous potential for them in this domain. This critical review will encourage the researchers working in this area and boost the development and commercialization of such devices to benefit the healthcare fraternity. Here, zwitterionic polymers are introduced and their tailoring as reliable drug delivery vehicle is discussed This critical review will encourage the researchers working in this area and boost the development and commercialization of such devices to benefit the healthcare fraternity. A huge prospect is visualized in zwitterionic polymers as prospective commercialization candidates which can contribute to the healthcare sector largely.
Freeze-drying of nanoparticle suspensions is capable of generating stable nanoformulations with improved storage times and easier transportation. Nonetheless, nanoparticle aggregation is likely induced during freeze-drying, which reduces its redispersibility upon reconstitution and leads to undesirable effects such as non-specific toxicity and impaired efficacy. In this work, bovine serum albumin (BSA) is described as a suitable protectant for silica nanoparticles (SNPs), which result in solid structures with excellent redispersibility and negligible signs of aggregation even when longer storage times are considered. We experimentally demonstrated that massive system aggregation can be prevented when a saturated BSA corona around the nanoparticle is formed before the lyophilization process. Furthermore, the BSA corona is able to suppress non-specific interactions between these nanoparticles and biological systems, as evidenced by the lack of residual cytotoxicity, hemolytic activity and opsonin adsorption. Hence, BSA can be seriously considered for industry as an additive for nanoparticle freeze-drying since it generates solid and redispersible nanoformulations with improved biocompatibility.
Zwitterionic molecules are known to resist non-specific protein adsorption and have been proposed as an alternative to the widely used polyethylene glycol (PEG). Recently, zwitterionic-like nanoparticles were created from the co-immobilization of positive and negative ligands, resulting in surfaces that also prevent protein corona formation while keeping available sites for bioconjugation. However, it is unclear if they are able to keep their original properties when immersed in biological environments while retaining a toxicity-free profile, indispensable features before considering these structures for clinics. Herein, we obtained optimized zwitterionic-like silica nanoparticles from the functionalization with varying ratios of THPMP and DETAPTMS organosilanes and investigated their behavior in realistic biological milieu. The generated zwitterionic-like particle was able to resist to single-protein adsorption while the interaction with a myriad of serum proteins led to significant loss of colloidal stability. Moreover, the zwitterionic particles presented poor hemocompatibility, causing considerable disruption of red blood cells. Our findings suggest that the exposure of ionic groups allows these structures to directly engage with the environment and that electrostatic neutrality is not enough to grant low-fouling and stealth properties.
Silica nanoparticles present an enormous potential as controlled drug delivery systems with high selectivity towards diseased cells. This application is directly related to the phenomenon of protein corona, characterized by the spontaneous adsorption of proteins on the nanoparticle surface, which is not fully understood. Here, we report an investigation on the influence of pH, ionic strength and temperature on the thermodynamics of interaction of bovine serum albumin protein (BSA) with non-functionalized silica nanoparticles (SiO2NPs). Complementary, we also investigated the ability of polyethylene glycol (PEG) and zwitterionic sulfobetaine (SBS) surface-modified nanoparticles to prevent the adsorption of BSA (protein negatively charged at physiological pH) and lysozyme (protein positively charged at physiological pH). We showed that BSA interaction with SiO2NPs is enthalpically governed. On the other hand, functionalization of silica nanoparticles with PEG and SBS completely prevented BSA adsorption. However, these functionalized nanoparticles presented a negative zeta potential and were not able to suppress lysozyme anchoring due to strong nanoparticle-protein electrostatic attraction. Due to the similarity of BSA with Human Serum Albumin, this investigation bears a resemblance to processes involved in the phenomenon of protein corona in human blood, producing information that is relevant for the future biomedical use of functionalized nanoparticles.
Surface functionalization of silica nanoparticles (SiO2NPs) has been considered as a promising strategy to develop target-specific nanostructures. However, finding a chemical functionalization that can be used as an active targeting moiety while preserving the nanoparticles colloidal stability in biological fluids is still challenging. We present here a dual surface modification strategy for SiO2NPs where a zwitterion (ZW) and a biologically active group (BAG) (amino, mercapto or carboxylic functionalities) are simultaneously grafted on the nanoparticles’ surface. The rationale behind this strategy is to generate colloidally stable nanoparticles and avoid the nonspecific protein adsorption due to ZW groups insertion, while the effective interaction with biosystems is guaranteed by the BAGs presence. The biological efficacy was tested against VERO cells, E. coli bacteria and Zika viruses and a similar trend was observed for all tested particles. The desirable “stealth property” to prevent nonspecific protein adhesion also generated a ZW shielding effect of the BAG functionality hindering their proper interaction and activity in cells, bacteria and viruses.
We report direct measurements of ionic strength dependent interactions between different molecular weights of zwitterionic tri-block copolymers adsorbed to hydrophobic colloids and surfaces. Zwitterionic copolymers investigated include phosphorylcholine (PMPC) and sulfopropylbetaine (PMAPS) end blocks separated by poly(propylene oxide) (PPO) center blocks. The range of repulsion between adsorbed PMAPS copolymer layers increases with increasing NaCl from 0.01-3M, and layer thicknesses range from ~50-100% of the PMAPS block contour length. In contrast, repulsion between PMPC layers does not change for 0.01-3M NaCl, and layers remain near full extension at their contour length. NaCl dependent interactions and inferred layer dimensions correlate with hydrodynamic layer thickness and polymer second virial coefficients. These results suggest the interaction range and layer thickness of adsorbed zwitterionic copolymers arises from a balance of intramolecular dipolar attraction and repulsion possibly mediated by water solvation. The balance between these competing effects and resulting ionic strength dependence is determined by specific zwitterionic moieties.
Zwitterionic complexes in aqueous solutions have been extensively explored as the most promising candidate in drug delivery systems for targeted cancer chemotherapy. A POSS-based supramolecular AD-POSS-(sulfobetaine) 7 /CD-PLLA zwitterionic complex has been fabricated via a combination of efficient click chemistry and host-guest interaction. The well-defined POSS-based zwitterionic polymer could self-assemble into spherical nanoparticles that encapsulated a model cancer drug (DOX) and exhibited drug release in a controlled manner in a faintly acidic environment. On account of the hydrophilic block with cationic and anionic groups in the microscopic range that can form a hydration layer via electrostatic interactions, these drug-loaded nanoparticles exhibited excellent stability in a tumor intracellular microenvironment or under other pH conditions as revealed by dynamic light scattering (DLS) and zeta potential measurements. In vitro experiments demonstrated that these POSS-based nanoparticles had high resistance to non-specific protein absorption and low cytotoxicity against normal cells. Moreover, these DOX-loaded aggregates could be accumulated and effectively internalized by HeLa and MCF-7 tumor cells, exhibiting effective cellular proliferation inhibition via the release of anticancer agents. Therefore, these POSS-based supramolecular amphiphilic zwitterionic complexes, relying on the simple supramolecular interaction and efficient click reaction, could further emerge as a potential universal anticancer drug nanocarrier system for multifunctional cancer chemotherapy.
Zwitterionic groups have been widely used in anti-biofouling surfaces to resist non-specific adsorption of proteins and other biomolecules. The interactions among zwitterionic groups have attracted considerable attention in bioengineering, while the understanding of their nano-mechanical mechanism still remains limited. In this work, the interaction mechanisms between two zwitterionic groups with opposite dipoles, i.e., phosphorylcholine (PC) and sulfobetaine (SB), have been investigated via direct force measurements using atomic force microscope (AFM) and dynamic adsorption tests using quartz crystal micro-balance with dissipation monitoring technique (QCM-D) in aqueous solutions. The AFM force measurements show that the adhesion forces between contacted zwitterionic surfaces during separation under both symmetric and asymmetric configurations were close, mainly due to the enforced alignment of opposing diploe pairs via complementary orientations under confinement. The solution salinity and pH had almost negligible influence on the adhesion measured during surface separation. The QCM-D adsorption tests of PC-headed lipid on PC and SB surfaces showed some degree of adsorption of lipid molecules on SB surface while not on PC surface. The different adsorption behaviors indicate that because the outmost negatively charged sulfonic group on the SB faced the aqueous solution, this configuration could facilitate it to form attractive electrostatic interaction with the PC head of lipid molecules in the solution. This work shows that in addition to hydration and steric interactions, the zwitterionic diploe-induced interactions play an important role in the adhesion and antifouling behaviors of the zwitterionic molecules and surfaces. The improved fundamental understanding provides useful insights into the development of new functional materials and coatings with antifouling applications.
Aqueous suspensions of amidine latex (AL) and sulfate latex (SL) particles containing sodium tetraphenylborate and NaCl are studied with electrokinetic and time-resolved light scattering techniques. In monovalent salt solutions, AL is positively charged, while SL negatively. Electrophoretic mobility measurements demonstrate that adsorption of tetraphenylborate anions leads to a charge reversal of the AL particles. At higher concentrations, both types of particles accumulate negative charge. For the AL particles, the charge reversal leads to a narrow fast aggregation region and an intermediate regime of slow aggregation. For the SL particles, the intermediate slow regime is also observed. These aspects can be explained with classical theory of Derjaguin, Landau, Verwey, and Overbeek (DLVO). Another regime of fast aggregation is observed at intermediate concentrations, and the existence of this regime can be rationalized by an additional attractive non-DLVO force. We suspect that this additional force is caused by surface charge heterogeneities.
Using a molecular-level equilibrium theory where proteins are described using their crystallographic structure, we have studied protein adsorption from binary and ternary mixtures of myoglobin, lysozyme, and cytochrome c to poly(methacrylic acid) hydrogel films. The pH gradients these films induce can lead to selective protein adsorption, where the solution pH provides a sensible dial to externally control protein separation. Changing the chemical composition of the polymer network, adding either another acidic or a neutral comonomer, allows for protein localization to controlled spatial regions of the film with nanometer resolution. As pH-sensitive polymer hydrogels are promising candidates for smart, responsive biomaterials, understanding the complexity of competitive protein adsorption is essential. In this work, we highlight the decisive role of amino acid protonation in selective protein adsorption. We present conditions such that the hydrogel film will selectively incorporate the more weakly charged protein, provided that it requires less work to protonate its amino acids.
In this paper, a novel kind of zwitterion modified graphene oxide (GO) for promoting stability and reducing aggregation of GO as drug carrier was proposed and demonstrated. Specifically, the GO was functionalized with a kind of zwitterion based silane, 3-(dimethyl(3-(trimethoxysilyl)propyl)-ammonio)propane-1-sulfonate (SBS). After zwitterion modification, the SBS functionalized GO (GO-SB) shows significantly enhanced stability in both serum-free and serum-containing solution, especially after loading doxorubicin hydrochloride (DOX). According to drug release profiles, the drug-loaded GO-SB exhibits thermosensitive and sustained release behavior. Meanwhile, in vitro studies show that the DOX loaded GO-SB could be easily internalized by HepG2 cells and exhibit obvious cytotoxicity on the cells. And in vivo studies demonstrate that the GO-SB drug carrier is capable of being taken by the larvae of zebrafish and can be eliminated from the body within several days.
The negative impacts that arise from biological fouling of surfaces have driven the development of coatings with unique physical and chemical properties that are able to prevent interactions with fouling species. Here, we report on low-fouling hydrophilic coatings presenting nanoscaled features prepared from different size silica nanoparticles (SiNPs) functionalized with zwitterionic chemistries. Zwitterionic sulfobetaine siloxane (SB) was reacted to SiNPs ranging in size from 7 to 75 nm. Particle stability and grafting density were confirmed using dynamic light scattering and thermogravimetric analysis. Thin coatings of nanoparticles were prepared by spin-coating aqueous particle suspensions. The resulting coatings were characterized using scanning electron microscopy, atomic force microscopy, and contact angle goniometry. SB functionalized particle coatings displayed increased hydrophilicity compared to unmodified particle coating controls while increasing particle size correlated with increased coating roughness and increased surface area. Coatings of zwitterated particles demonstrated a high degree of nonspecific protein resistance, as measured by quartz crystal microgravimetry (QCM). Adsorption of bovine serum albumin and hydrophobin proteins were reduced by up to 91 and 94 %, respectively. Adhesion of bacteria (Escherichia coli ) to zwitterion modified particle coatings were also significantly reduced over both short and long-term assays. Maximum reductions of 97 % and 94 % were achieved over 2 and 24 h assay periods, respectively. For unmodified particle coatings, protein adsorption and bacterial adhesion were generally reduced with increasing particle size. Adhesion of fungal spores to SB modified SiNP coatings was also reduced, however no clear trends in relation to particle size were demonstrated.
Confining organic molecules to the surfaces of inorganic nanoparticles can induce intermolecular interactions between them, which can affect the composition of the mixed self‐assembled monolayers obtained by co‐adsorption from solution of two different molecules. Here, we study co‐adsorption of two thiolated ligands—a dialkylviologen and a zwitterionic sulfobetaine—that can interact with each other electrostatically, onto gold nanoparticles. Consequently, the nanoparticles favor a narrow range of ratios of these two molecules that is largely independent of the molar ratio in solution. We show that changing the solution molar ratio of two ligands by a factor of ~5,000 affects the on‐nanoparticle ratio of these ligands by only 3 times. This behavior is reminiscent of the formation of insoluble inorganic salts (e.g., AgCl), which similarly compensate positive and negative charges upon crystallizing. Our results pave the way towards developing well‐defined hybrid organic‐inorganic nanostructures.
Aim:
To study freeze-drying of silica nanoparticles (SiO2NPs) in order to find suitable conditions to produce lyophilized powders with no aggregation after resuspension and storage.
Methods:
SiO2NPs were synthesized using a Stöber-based procedure, and characterized by scanning electron microscopy, dynamic light scattering and nitrogen adsorption/desorption isotherms. SiO2NPs hydrodynamic diameters were compared prior and after freeze-drying in the presence/absence of carbohydrate protectants.
Results:
Glucose was found to be the most suitable protectant against the detrimental effects of lyophilization. The minimum concentration of carbohydrate required to effectively protect SiO2NPs from aggregation during freeze-drying is influenced by the nanoparticle's size and texture. Negligible aggregation was observed during storage.
Conclusion:
Carbohydrates can be used during SiO2NPs freeze-drying process to obtain redispersable solids that maintain original sizes without residual aggregation.
The growing need to develop surfaces able to effectively resist biological fouling has resulted in the widespread investigation of nanomaterials with potential antifouling properties. However, the preparation of effective antifouling coatings is limited by the availability of reactive surface functional groups and our ability to carefully control and organise chemistries at a materials interface. Here, we present two methods of preparing hydrophilic low fouling surface coatings through reaction of silica nanoparticle suspensions and pre-deposited silica nanoparticle films with zwitterionic sulfobetaine. Silica nanoparticle suspensions were functionalised with sulfobetaine across three pH conditions and deposited as thin films via a simple spin-coating process to generate hydrophilic antifouling coatings. In addition, coatings of pre-deposited silica nanoparticles were surface functionalised via exposure to zwitterionic solutions. Quartz crystal microgravimetry with dissipation monitoring (QCM-D) was employed as a high throughput technique for monitoring and optimising reaction to the silica nanoparticle surfaces. Functionalisation of nanoparticle films was rapid and could be achieved over a wide pH range and at low zwitterion concentrations. All functionalised particle surfaces presented a high degree of wettability and resulted in large reductions in adsorption of bovine serum albumin (BSA) protein. Prepared particle surfaces also showed a reduction in adhesion of fungal spores (Epicoccum nigrum) and bacteria (Escherichia coli) by up to 87% and 96%, respectively. These results indicate the potential for functionalised nanosilicas to be further developed as versatile fouling resistant coatings for widespread coating applications.
Adequate characterization of NPs (nanoparticles) is of paramount importance to develop well defined nanoformulations of therapeutic relevance. Determination of particle size and surface charge of NPs are indispensable for proper characterization of NPs. DLS (dynamic light scattering) and ZP (zeta potential) measurements have gained popularity as simple, easy and reproducible tools to ascertain particle size and surface charge. Unfortunately, on practical grounds plenty of challenges exist regarding these two techniques ranging from inadequate understanding of the operating principles along with critical issues like sample preparation and interpretation of the data. As both DLS and ZP have emerged from the realms of physical colloid chemistry – it is difficult for researchers engaged in nanomedicine research to master these two techniques. However, there is very little literature available in drug delivery research which can offer a simple, concise account on these techniques. This review tries to address this issue while providing the basic principles of the techniques, summarizing the core mathematical principles and offering practical guidelines on tackling commonly encountered problems while running DLS and ZP measurements. Finally, the review tries to analyze the relevance of these two techniques from translatory perspective.
The present article provides an overview of the recent progress in the direct force measurements between individual pairs of colloidal particles in aqueous salt solutions. Results obtained by two different techniques are being highlighted, namely with the atomic force microscope (AFM) and optical tweezers. One finds that the classical theory of Derjaguin, Landau, Verwey, and Overbeek (DLVO) represents an accurate description of the force profiles even in the presence of multivalent ions, typically down to distances of few nanometers. However, the corresponding Hamaker constants and diffuse layer potentials must be extracted from the force profiles. At low salt concentrations, double layer forces remain repulsive and may become long ranged. At short distances, additional short range non-DLVO interactions may become important. Such an interaction is particularly relevant in the presence of multivalent counterions.
Whereas numerous studies of stabilization of nanoparticles (NPs) in electrolytes have examined biological fluids, the interest has grown recently in media with much higher ionic strengths including seawater and brines relevant to environmental science and subsurface oil and gas reservoirs. Given that electrostatic repulsion is limited at extremely high ionic strengths due to charge screening, we have identified ligands that are well solvated in concentrated brine containing divalent cations and thus provide steric stabilization of silica nanoparticles. Specifically, the hydrodynamic diameter of silica nanoparticles with grafted low molecular weight ligands, a diol ether, [3-(2,3-dihydroxypropoxy)propyl]-trimethoxysilane, and a zwitterionic sulfobetaine, 3-([dimethyl(3-trimethoxysilyl)propyl]ammonio)propane-1-sulfonate, is shown with dynamic light scattering to remain essentially constant, indicating lack of aggregation, at room temperature and up to 80 °C for over 30 days. An extended DLVO model signifies that steric stabilization is strongly dominant against van der Waals attraction for ∼10 nm particles given that these ligands are well solvated even in highly concentrated brine. In contrast, polyethylene glycol oligomers do not provide steric stabilization at elevated temperatures, even at conditions where the ligands are soluble, indicating complicating factors including bridging of the ether oxygens by divalent cations.
A series of zwitterionic polyelectrolytes poly[3-(N-2-methacryloyloxyethyl-N,N-dimethyl)ammonatopropanesulfonate] (PMAPS) with a wide range of weight-average molecular weight (Mw) between 5.5 × 103 and 1.6 × 106 g mol-1 with narrow molecular weight distribution (Mw/Mn = 1.07-1.19) were thoroughly characterized in aqueous NaCl solutions for salt concentration (Cs) over a range from theta Cs (0.074 M) to 1.0 M by synchrotron radiation small-angle X-ray scattering (SAXS), light scattering, and viscometry at 25 °C. To determine the chain stiffness parameter (λ-1) and the excluded-volume strength (B) of PMAPS in an aqueous NaCl solution, SAXS profiles and the Mw dependences of the radius of gyration, the second virial coefficient, the interpenetration function, the hydrodynamic radius, and the intrinsic viscosity for PMAPS were analyzed on the basis of the (un)perturbed cylindrical wormlike chain model. The experimental λ-1 value for PMAPS chains in aqueous NaCl solutions barely decreased but was almost constant with the increasing Cs, whereas the value of B was increased gradually with the increasing Cs. Thus, the dominant factor for the chain dimension of PMAPS in aqueous NaCl solutions was the long-range interaction (i.e., B) than the short-range interaction (i.e., λ-1). The observed Cs dependences of λ-1 and B for PMAPS chains in aqueous NaCl solutions were fairly described by the theories of the polyampholyte with the nonrepulsive, the repulsive, and the attractive electrostatic interactions.
In the past decade, zwitterionic-based anti-biofouling layers had gained much focus as a serious alternative to traditional polyhydrophilic films such as PEG. In the area of assembling silica nanoparticles with stealth properties, the incorporation of zwitterionic surface film remains fairly new but considering that silica nanoparticles had been widely demonstrated as useful biointerfacing nanodevice, zwitterionic film grafting on silica nanoparticle holds much potential in the future. This review will discuss on the conceivable functional chemistry approaches, some of which are potentially suitable for the assembly of such stealth systems.
Hypothesis
Electrostatic interactions play an important role in adhesion phenomena particularly for biomacromolecules and microorganisms. Zero charge valence of zwitterions has been claimed as the key to their antifouling properties. However, due to the differences in the relative strength of their acid and base components, zwitterionic materials may not be charge neutral in aqueous environments. Thus, their charge on surfaces should be further adjusted for a specific pH environment, e.g. physiological pH typical in biomedical applications.
Experiments
Surface zeta potential for thin polymeric films composed of polysulfobetaine methacrylate (pSBMA) brushes is controlled through copolymerizing zwitterionic SBMA and cationic methacryloyloxyethyltrimethyl ammonium chloride (METAC) via surface-initiated atom transfer polymerization. Surface properties including zeta potential, roughness, free energy and thickness are measured and the antifouling performance of these surfaces is assessed.
Findings
The zeta potential of pSBMA brushes is -40 mV across a broad pH range. By adding 2% METAC, the zeta potential of pSBMA can be tuned to zero at physiological pH while minimally affecting other physicochemical properties including dry brush thickness, surface free energy and surface roughness. Surfaces with zero and negative zeta potential best resist fouling by bovine serum albumin, Escherichia coli and Staphylococcus aureus. Surfaces with zero zeta potential also reduce fouling by lysozyme more effectively than surfaces with negative and positive zeta potential.
The physical chemistry of dispersion may range from producing a polymer disper-sion, such as latex, where the particle dispersion is formed in situ, to pigment suspension. In preparing a latex, there is a strong element of polymerization kinetics which does not apply to pigment dispersion. On the other hand, in pigment dispersion there may be certain interfacial considerations which do not apply to latex forma-tion. However, from a colloidal point of view, once the dispersion is produced, the physical chemistry of the dispersion is the same, whether polymer or pigment. In this chapter the emphasis is on examining the physical chemistry of the dis-persion where the disperse phase is preformed, Le. from a pigment standpoint, although the same considerations apply to polymer particles if they constitute the disperse phase. Our objective is therefore to look at the physical chemistry involved in forming a dispersion; to examine the factors influencing dispersion stability; and to consider how they can be measured or assessed. For simplicity, we can define a paint as a colloidal dispersion of a pigment (the 'disperse' phase) in a polymer solution (the 'continuous' phase). Emulsion paints have both the polymer and pigment as the disperse phase. While the chemical struc-ture of the polymer is important in determining the properties of a paint, the state of dispersion of the pigment in the polymer is no less important. In practice it is fair to say that most of the problems that arise in a paint come back to the state of the pigment dispersion. The state of pigment dispersion can affect the: flow properties [2]; durability [3]; opacity [4]; gloss [5]; storage stability [6]. optical properties, e.g. colour [l]; The physical chemistry of dispersion 199 To produce a 'good' dispersion of colloidal particles from a dry powder we have to go through a number of processes which can be subdivided, arbitrarily, as separate operations, since in practice they may occur simultaneously. They are: These simple titles may mask many complex processes but are well worth consid-eration, as is the 'simple' practical question 'Is it better to disperse TiOz pigment in an alkyd solution using an aromatic or aliphatic solvent?' immersion and wetting of the pigment; distribution and colloidal stabilization of the pigment.
The functionalization of nanoparticles has primarily been used as a means to impart stability in nanoparticle suspensions. In most cases even the most advanced nanomaterials lose their function should suspensions aggregate and settle, but with the capping agents designed for specific solution chemistries, functionalized nanomaterials generally remain monodisperse in order to maintain their function. The importance of this cannot be underestimated in light of the growing use of functionalized nanomaterials for wide range of applications. Advanced functionalization schemes seek to exert fine control over suspension stability with small adjustments to a single, controllable variable. This review is specific to functionalized nanoparticles and highlights the synthesis and attachment of novel functionalization schemes whose design is meant to affect controllable aggregation. Some examples of these materials include stimulus responsive polymers for functionalization which rely on a bulk solution physicochemical threshold (temperature or pH) to transition from a stable (monodisperse) to aggregated state. Also discussed herein are the primary methods for measuring the kinetics of particle aggregation and theoretical descriptions of conventional and novel models which have demonstrated the most promise for the appropriate reduction of experimental data. Also highlighted are the additional factors that control nanoparticle stability such as the core composition, surface chemistry and solution condition. For completeness, a case study of gold nanoparticles functionalized using homologous block copolymers is discussed to demonstrate fine control over the aggregation state of this type of material.
Coating surfaces with thin or thick
films of zwitterionic material
is an effective way to reduce or eliminate nonspecific adsorption
to the solid/liquid interface. This review tracks the various approaches
to zwitteration, such as monolayer assemblies and polymeric brush
coatings, on micro- to macroscopic surfaces. A critical summary of
the mechanisms responsible for antifouling shows how zwitterions are
ideally suited to this task.
Superparamagnetic nanoparticles (NPs) are promising for biomedical applications since they can be directed toward the organ of interest using an external magnetic field. They are also good contrast agents for magnetic resonance imaging and have potential for the treatment of malignant tumors (i.e., hyperthermia). Therefore, there is a need to produce stable, non-aggregating superparamagnetic nanomaterials that can withstand the in vivo environment. In this work, the colloidal stability of a dispersion of iron oxide NPs was enhanced by functionalizing them with a short zwitterionic siloxane shell in aqueous media. The stabilization procedure yields superparamagnetic nanomaterials, ca. 10 nm in diameter, with saturation magnetization of about 54 emu/g that resist aggregation at physiological salt concentration, temperature, and pH. The loading of the zwitterionic shell was established with diffuse reflectance infrared spectroscopy and thermal gravimetric analysis. X-ray and electron diffraction verified the starting magnetite phase, and that no change in phase occurred on surface functionalization.
Zwitterionic polymers constitute a unique class of polyelectrolytes which have not been studied systematically because of the difficulty in their controlled synthesis and precise physicochemical characterization. The salt-concentration dependence of the chain dimensions and swollen brush structures of polyzwitterions, namely poly(2-methacryloyloxyethylphosphorylcholine) (PMPC) and poly[3-(N-2-methacryloyloxyethyl-N,N-dimethyl)ammonatopropanesulfonate] (PMAPS), in aqueous solutions of various ionic strengths was characterized by static light scattering, dynamic light scattering, atomic force microscopy (AFM), neutron reflectivity (NR), contact angle measurements, and macroscopic friction tests by sliding a glass ball under a load of 0.49 N. The hydrodynamic radius RH of PMPC was independent of NaCl concentration, whereas the RH of PMAPS markedly increased with the ionic strength. AFM and NR measurements also showed the independence of NaCl concentration of the swollen thickness of the PMPC brush in aqueous solution and significant changes in the swollen thickness of the PMAPS brush in aqueous NaCl solution. Both PMPC and PMAPS brushes showed oil detachment behavior in water and aqueous NaCl solutions. The PMPC brush had a significantly low friction coefficient (0.02–005) at a sliding velocity of 10−2 to 10−1 m s−1 in water even under a high normal pressure of 139 MPa.
The solution properties of zwitterionic surfactants are shown to be strong functions of the type of negatively charged center (carboxylate vs sulfonate) and the number of methylene groups separating the charged sites. For similar structures, differences such as the higher solubility and critical micelle concentration of the betaine relative to the sulfobetaine can be explained as a direct result of the carboxylate headgroup being more hydrophilic than the sulfonate. No evidence is seen of intramolecular ion-pair formation, indicating that in a polar medium such as water, the distance between the charges sites increases monotonically with increasing number of methylene units in the tether. The increasing headgroup area with tether length leads to poor foaming and aqueous solution thickening properties. The monomeric and micellar compositions of betaine surfactants as a function of pH and concentration can be determined directly from titration curves.
We develop a detailed molecular theory that describes the response of weak polyelectrolyte gels to changes in both the pH and salt concentration, c, of the solution. This approach includes specific molecular details and conformational degrees of freedom of the polymeric gel, acid−base equilibrium, and solution entropy as well as electrostatic, van der Waals, and excluded-volume interactions. Here, we study polyacid gels in good solvent. The physical properties of the gel are found to depend on the coupling between charge regulation and the molecular interactions. In particular, the gel’s degree of dissociation is not only determined by the bath pH and ionic strength but also by the polymer’s ability in regulating charge to modify the local environment and in swelling or shrinking that depends on the externally controlled variables. The gel pH can be several units smaller than the bath pH depending on the salt ion concentration. The gel pH does not respond linearly to changes in neither bath pH nor c, and its behavior results from the complex interplay between the conformational degrees of freedom and all of the interactions mentioned above. The gel system swells if pH > pKa and collapses if pH < pKa. The continuous transition between collapsed and swollen regimes occurs in a very narrow range of bath pH around pKa whose width depends on the salt concentration. In this intermediate region the volume fraction of the polyacid can be controlled by both c and pH.