Zwitterionic materials have moieties possessing cationic and anionic groups. This molecular structure leads to unique properties that can be the solutions of various application problems. A typical ...example is that zwitterionic carboxybetaine (CB) and sulfobetaine (SB) materials resist nonspecific protein adsorption in complex media. Considering the vast number of cationic and anionic groups in the current chemical inventory, there are many possible structural variations of zwitterionic materials. The diversified structures provide the possibility to achieve many desired properties and urge a better understanding of zwitterionic materials to provide design principles. Molecular simulations and modeling are a versatile tool to understand the structure–property relationships of materials at the molecular level. This progress report summarizes recent simulation and modeling studies addressing two fundamental questions regarding zwitterionic materials and their applications as biomaterials. First, what are the differences between zwitterionic and nonionic materials? Second, what are the differences among zwitterionic materials? This report also demonstrates a molecular design of new protein‐resistant zwitterionic moieties beyond conventional CB and SB based on design principles developed from these simulation studies.
There are many possible structural variations of zwitterionic materials. These diversified structures provide the possibility of achieving many desired properties for a wide range of applications. This Progress Report summarizes recent simulation and modeling studies of zwitterionic materials, providing a fundamental understanding of their nonfouling properties and design principles.
Zwitterionic polymers are generally viewed as a new class of nonfouling materials. Unlike their poly(ethylene glycol) (PEG) counterparts, zwitterionic polymers have a broader chemical diversity and ...greater freedom for molecular design. In this Minireview, we highlight recent microbiological applications of zwitterionic polymers and their derivatives, with an emphasis on several unique molecular strategies to integrate antimicrobial and nonfouling properties. We will also discuss our insights into the bacterial nonfouling performance of zwitterionic polymers and one example of engineering zwitterionic polymer derivatives for antimicrobial wound‐dressing applications.
Fighting germs: Molecular design leads to zwitterionic nonfouling polymers with surface bactericidal and bulk antimicrobial functionalities (sketched in the picture). This functional versatility makes zwitterionic polymers a promising alternative and improvement to the conventional poly(ethylene glycol) (PEG) nonfouling materials.
The technique of attaching the polymer polyethylene glycol (PEG), or PEGylation, has brought more than ten protein drugs into market. The surface conjugation of PEG on proteins prolongs their blood ...circulation time and reduces immunogenicity by increasing their hydrodynamic size and masking surface epitopes. Despite this success, an emerging body of literature highlights the presence of antibodies produced by the immune system that specifically recognize and bind to PEG (anti-PEG Abs), including both pre-existing and treatment-induced Abs. More importantly, the existence of anti-PEG Abs has been correlated with loss of therapeutic efficacy and increase in adverse effects in several clinical reports examining different PEGylated therapeutics. To better understand the nature of anti-PEG immunity, we summarize a number of clinical reports and some critical animal studies regarding pre-existing and treatment-induced anti-PEG Abs. Various anti-PEG detection methods used in different studies were provided. Several protein modification technologies beyond PEGylation were also highlighted.
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Zwitterionic carboxybetaine and sulfobetaine materials have shown an excellent ability to resist nonspecific protein adsorption. It is desirable to obtain a better understanding of zwitterionic ...materials based on their molecular structures. This work aims to understand the roles of charged groups in zwitterionic moieties and to design new protein-resistant zwitterionic moieties beyond carboxybetaine and sulfobetaine. We conducted molecular simulations to study the hydration, self-association, and protein interactions of 12 zwitterionic moieties derived from three anionic groups (carboxylic, sulfonate, and sulfate) and four cationic groups (quaternary ammonium, tertiary ammonium, secondary ammonium, and primary ammonium). The partial charges of atoms in these moieties were obtained from quantum chemical calculations. Hydration was studied by evaluating the hydration free energy of moieties and the hydration structure and dynamics of the charged groups. All zwitterionic moieties have strong hydration, but their structural and dynamic properties depend on the types of cationic and anionic groups involved. The self-association and protein interactions of zwitterionic moieties also show relationships with the charged groups. Our simulation results indicate good protein-resistant ability of several zwitterionic moieties, one of which has also been shown by recent experiments.
Treatment with therapeutic proteins is an attractive approach to targeting a number of challenging diseases. Unfortunately, the native proteins themselves are often unstable in physiological ...conditions, reducing bioavailability and therefore increasing the dose that is required. Conjugation with poly(ethylene glycol) (PEG) is often used to increase stability, but this has a detrimental effect on bioactivity. Here, we introduce conjugation with zwitterionic polymers such as poly(carboxybetaine). We show that poly(carboxybetaine) conjugation improves stability in a manner similar to PEGylation, but that the new conjugates retain or even improve the binding affinity as a result of enhanced protein-substrate hydrophobic interactions. This chemistry opens a new avenue for the development of protein therapeutics by avoiding the need to compromise between stability and affinity.
Zwitterionic carboxybetaines (CBs) are ubiquitous in nature and considered promising materials for biological and chemical applications. A thorough understanding of the effect of carbon spacer length ...(CSL) on molecular properties is important. In this work, using molecular dynamics simulation and quantum chemical calculation, we investigated the effect of CSL on the molecular properties of CB molecules. The hydration number, structure, and dynamics of carboxylic and trimethyl ammonium groups were investigated and found to present different behaviors in regards to the variation of CSL. The simulation results with partial charges developed from quantum chemical calculations were compared with those with partial charges from the OPLS all atom (OPLSAA) force field. The hydration free energy of CB molecules and CB–Na+ association was also studied as a function of CSL.
Nonfouling materials are of great importance for numerous applications. A simple method is introduced to prepare nonfouling materials and surfaces (see figure) with unique properties from a variety ...of desirable functional groups. Materials with a uniform distribution of mixed charged groups at the nanometer scale, similar to zwitterionic materials, are excellent candidates for use as nonfouling materials.
Nonfouling zwitterionic polymers have wide applications ranging from the naval industry to biomedical engineering. Strong hydration at polymer surfaces has been proven to be crucial to their ...nonfouling property, but the absolute orientations of water molecules on the polymers and the competition between water and salt binding have not been elucidated. In this work, the absolute orientations of water molecules on two zwitterionic polymer brushes, poly(carboxybetaine methacrylate) (pCBMA) and poly(sulfobetaine methacrylate) (pSBMA), were measured using regular and phase-sensitive sum frequency generation (SFG) vibrational spectroscopy. The pH-dependent studies in a pH range from 2 to 12 showed that at a pH of 7, the water absolute orientations are different on the pCBMS and pSBMA surfaces. Phase-sensitive SFG studies confirmed the results obtained from the pH-dependent measurements. Salt effects on the hydration of zwitterionic polymers were examined as a function of time, which indicated that the pCBMA surface and the associated interfacial water exhibit a slow restructuring process after salt binding (likely due to the strong binding of pCBMA with water), whereas the surface of pSBMA and the associated water have a fast change after salt binding.
This work describes the superlow fouling properties of glass slides grafted with zwitterionic polymers to highly resist the adsorption of proteins and the adhesion of mammalian cells. Glass slides ...were first silanized using 2-bromo-2-methyl-N-3-(triethoxysilyl)propylpropanamide (BrTMOS). Two zwitterionic polymers, poly(sulfobetaine methacrylate) (polySBMA) and poly(carboxybetaine methacrylate) (polyCBMA), were then grafted from the silanized glass substrates using the atom-transfer radical polymerization (ATRP) method. X-ray photoelectron spectroscopy (XPS) was used to analyze the surfaces of the silanized glass substrates and the substrates grafted with the polymers. An enzyme-linked immonosobrbent assay (ELISA) using polyclonal antibodies was used to measure fibrinogen adsorption on these surfaces. The surfaces with polySBMA or polyCBMA layers were shown to reduce fibrinogen adsorption to a level comparable with that of adsorption on poly(ethylene glycol)-like films. Bovine aortic endothelial cells (BAECs) were seeded on these surfaces. The attachment and spreading of the cells were observed only on unpolymerized glass surfaces. This work further demonstrates that zwitterionic polymers highly resist nonspecific protein adsorption and cell adhesion and provides an effective method to modify glass slides or other oxide surfaces to achieve superlow fouling.
Extreme ultraviolet (EUV) lithography currently dominates the frontier of semiconductor fabrication. Photoresists must satisfy increasingly strict pattern fidelity requirements to realize the ...significant enhancements in resolution offered by EUV technology. Traditional chemically amplified resists (CARs) have hit a barrier in the form of the resolution, line edge roughness, and sensitivity trade-off. This has been compounded by a lack of understanding of the chemical mechanism associated with the EUV process. Here, we synthesize a series of novel EUV photoresists based on a self-immolative, acid-labile poly(acetal) system. These systems are shown to be commercially viable under current EUV requirements. Careful study of the resists’ degradation pathways has enabled the identification of a remarkable photoacid generator (PAG) that functions as both an acid generator and base quencher, enabling further improvements over previous resists. density functional theory calculations reveal, for the first time, the connection between the PAG activation barrier and resist sensitivity and suggests why attempts to use electron-beam lithography to predict EUV performance have failed.
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