Recent Advances in Zwitterionic Hydrogels: Preparation, Property, and Biomedical Application.

Nonspecific protein adsorption impedes the sustainability of materials in biologically related applications. Such adsorption activates the immune system by quick identification of allogeneic materials and triggers a rejection, resulting in the rapid failure of implant materials and drugs. Antifouling materials have been rapidly developed in the past 20 years, from natural polysaccharides (such as dextran) to synthetic polymers (such as polyethylene glycol, PEG). However, recent studies have shown that traditional antifouling materials, including PEG, still fail to overcome the challenges of a complex human environment. Zwitterionic materials are a class of materials that contain both cationic and anionic groups, with their overall charge being neutral. Compared with PEG materials, zwitterionic materials have much stronger hydration, which is considered the most important factor for antifouling. Among zwitterionic materials, zwitterionic hydrogels have excellent structural stability and controllable regulation capabilities for various biomedical scenarios. Here, we first describe the mechanism and structure of zwitterionic materials. Following the preparation and property of zwitterionic hydrogels, recent advances in zwitterionic hydrogels in various biomedical applications are reviewed.

Determination of non-freezing water in different nonfouling materials by differential scanning calorimetry.

Nonfouling materials have attracted increasing interest for their excellent biocompatibility and low immunogenicity. Strong hydration is believed to be the key reason for their resisting capability to nonspecific protein adsorption. However, little attention has been paid to quantifying their strong water binding capacity. In this study, we synthesized four zwitterionic polymers, including poly(sulfobetaine methacrylate) (pSBMA), poly(carboxybetaine methacrylate) (pCBMA), poly(carboxybetaine acrylamide) (pCBAA) and poly(2-methacryloyloxyethyl phosphorylcholine) (pMPC), and compared non-freezing water of these zwitterionic polymers with typical antifouling polymer poly(ethylene glycol) (PEG) using differential scanning calorimetry (DSC). Non-freezing water of their monomers was also investigated. The non-freezing water of the polymers (per unit) is pMPC (10.7 ± 1.4) ≈ pCBAA (10.8 ± 1.5) > pCBMA (9.0 ± 0.6) > pSBMA (6.6 ± 0.4) > PEG20000 (0.60 ± 0.04). Similar trend is observed for their monomers. For all studied zwitterionic materials, they showed higher binding capacity than PEG. We attribute the stronger hydration of zwitterionic polymers to their strong electrostatic interactions.

Development of Robust and Recoverable Ultralow-Fouling Coatings Based on Poly(carboxybetaine) Ester Analogue.

Polyurethane with zwitterionic side chains (PCB-ester-PU) based on a poly(carboxybetaine) ester analogue is developed for marine coatings and biomedical applications by introducing dihydroxy-terminated PCB-ester(OH)2 with different polymerization as the macrodiol, 4,4'-diphenylmethane diisocyanate (MDI) as the diisocyanate, and 1,4-butanediol (1,4-BD) as the chain extender. Robust coatings are obtained and exhibit long-term excellent resistance to nonspecific protein adsorption, bacterial adhesion, and human umbilical vein endothelial cell (HUVEC) attachment after hydrolysis. Tests of adhesion on different substrates and film hardness indicate that the material possesses far more stable mechanic properties than hydrogel coatings. Moreover, such a resistance can be generated not only by alkaline solution, but also by a physiological buffer (such as phosphate-buffered saline (0.15 M pH 7.4 PBS)) or by steam in an autoclave. Ultimately, its excellent long-term nonfouling property, its healing capability through self-regeneration and superior mechanic properties (such as hardness and elasticity), and its good adhesiveness as a paint on both polar and nonpolar substrates make this material an ideal candidate as a coating for marine and medical devices.

Biocompatible long-circulating star carboxybetaine polymers.

Polyethylene glycol (PEG) is considered to be the most effective material to prolong the circulation time of nanoparticles by reducing non-specific protein adsorption in blood. However, it is recognized that PEG decomposes in most physiological solutions, and an anti-PEG antibody has been detected in some normal blood donors as a response to injection with PEGylated polymer particles. Zwitterionic polymers are potential alternatives to PEG for biomedical applications because of their super resistance to non-specific protein adsorption. Thus, finding one polymer with a long circulation time and resistance to the immune response is of significant importance. Here, we prepared four star carboxybetaine polymers of different molecular weights via atom transfer radical polymerization (ATRP) from a ß-cyclodextrin (ß-CD) initiator for investigating the biocompatibility of carboxybetaine polymer, a typical zwitterionic polymer. The circulation half-life of the largest star polymer (123 kDa) in mice was prolonged to 40 h in vivo, with no appreciable damage or inflammation observed in the major organ tissues. Furthermore, the circulation time of repeat injections showed similar results to the first injection, with no obvious increase in the amount of antibody in blood. The internalization of the star carboxybetaine polymers by macrophage cells was a relatively slow process. The high cell viability in the presence of star carboxybetaine polymers up to 2 mg mL-1 was maintained. The hemolytic activity of the star carboxybetaine polymers at 5 mg mL-1 was almost undetectable. In vitro results prove a key prediction of excellent biocompatibility in vivo. All the results suggest that the carboxybetaine polymer, perhaps even most of the zwitterionic ones, might be a good alternative to PEG in the development of a drug delivery system.

Development of zwitterionic polymer-based doxorubicin conjugates: tuning the surface charge to prolong the circulation and reduce toxicity.

Polymer-drug conjugates are commonly used as nano drug vehicles (NDVs) to delivery anticancer drugs. Zwitterionic polymers are ideal candidates to conjugate drugs because they show higher resistance to nonspecific protein adsorption in complex media than that of nonionic water-soluble polymers, such as poly(ethylene glycol). However, the charge balance characteristics of zwitterionic polymers used as NDVs will be broken from the inclusion of additional charged groups brought by conjugated drugs or functional groups, leading to the loss of resistance to protein adsorption. Consequently, the nonspecific protein adsorption on drug carriers will cause fast clearance from the blood system, an immune response, or even severe systemic toxicity. To overcome this drawback, a model zwitterionic polymer, poly(carboxybetaine methacrylate) (pCBMA), was modified by the introduction of a negatively charged component, to neutralize the positive charge provided by the model drug, doxorubicin (DOX). A DOX-conjugated NDV which possesses excellent resistance to nonspecific protein adsorption was achieved by the formation of a strongly hydrated pCBMA shell with a slightly negative surface charge. This kind of DOX-conjugated NDV exhibited reduced cytotoxicity and prolonged circulation time, and it accelerated DOX release under mild acid conditions. In tumor-bearing mouse studies a 55% tumor-inhibition rate was achieved without causing any body weight loss. These results indicate the importance of charge tuning in zwitterionic polymer-based NDVs.

Highly hemocompatible zwitterionic micelles stabilized by reversible cross-linkage for anti-cancer drug delivery.

Both blood stability and intelligent-responsiveness after reaching the drug-targeting site are very important features to make desirable nano-drug vehicles (NDVs). Here, a highly nonfouling cross-linked micelle based on a copolymer composed of carboxybetaine methacrylate (CBMA) as hydrophilic segment and 2-(methacryloyloxy)ethyl lipoate (MAEL) as hydrophobic and cross-linked segment is reported. Furthermore, a simple method to evaluate the hemocompatibility of NDVs through examining the activation of a blood-clotting protein (fibrinogen) was introduced. The micelles can encapsulate anticancer drug doxorubicin (DOX) conveniently and release DOX quickly in response to an intracellular reductive environment. With the advantages of excellent stability in fibrinogen (1 mg/mL) PBS solution and 50% fetal bovine serum (FBS), and accelerated intracellular drug release, the biocompatible zwitterionic micelles stabilized by reversible cross-linkage might be a promising drug carrier for cancer chemotherapy.

Development of nonstick and drug-loaded wound dressing based on the hydrolytic hydrophobic poly(carboxybetaine) ester analogue.

A novel biocompatible polymer is developed for antimicrobial and nonstick coatings of wound dressing. The polymer is formed by copolymerization of carboxybetaine ester analogue methacrylate (CB-ester) and small partial poly(ethylene glycol) methacrylate (PEGMA) for cross-linking by hexamethylene diisocyanate (HDI), which is highly resistant to nonspecific protein adsorption and mammalian cell attachment after a quick hydrolysis. A small hydrophobic drug, aspirin, can be incorporated into the new polymer and slowly released to inhibit microorganism growth while the new polymer shows very low cytotoxicity. Moreover, the wound dressing, the new polymer coated medical gauze, shows good mechanic properties, such as flexibility and strength, for medical application. After all, this new nonfouling polymer offers great potential for an antimicrobial wound dressing and other applications.