Antibiotic Zwitterionic Nanogel Membrane: from Molecular Dynamics Simulation to Structure Manipulation.

Membrane separation has been considered as one of the most revolutionary technologies for the removal of oils, dyes, or other pollutants from wastewater. However, most membranes still face great challenges in water permeability, antifouling property, and even antibiotic ability. Possessing a pathogen-repellent surface is of great significance as it can enable membranes to minimize the presence of active viral pathogens. Herein, we demonstrate a distinct design with a molecular dynamics simulation-guided experiment for the surface domination of antibiotic zwitterionic nanogel membranes. The zwitterionic nanoparticle gel (ZNG)/Cu2+/glutaraldehyde (GA) synergy system is first simulated by introducing a ZNG into a preset CuCl2 brine solution and into a GA ethanol solution, in which the nanogel is observed to initially swell and subsequently shrink with the increase of GA concentration, leading to the membrane surface structure transition. Then, the corresponding experiments are performed under strict conditions, and the results suggest the surface structure transition from nanoparticles to network nanoflowers, which are consistent with the simulated results. The obtained network structure membrane with superhydrophilic and underwater superoleophobic abilities can significantly enhance the water permeability as high as almost 40% with its original rejection rate in comparison with unoptimizable ZNG-PVDF (polyvinylidene difluoride) membranes. Moreover, the obtained membrane achieves additional excellent antibiofouling capacity with the antibiotic efficiency exceeding 99.3%, manifesting remarkable potential for disinfection applications. By comparison, the conventional antibiotic methods generally improve the membrane's antibiotic property solely but can hardly improve the other properties of the membrane. That is to say, our simulation combined with the experimental strategy significantly improved the zwitterionic membrane property in this work, which provides a new perspective on the design of high-performance functional materials.

Hypoxia-degradable and long-circulating zwitterionic phosphorylcholine-based nanogel for enhanced tumor drug delivery.

Tumor microenvironment has been widely utilized for advanced drug delivery in recent years, among which hypoxia-responsive drug delivery systems have become the research hotspot. Although hypoxia-responsive micelles or polymersomes have been successfully developed, a type of hypoxia-degradable nanogel has rarely been reported and the advantages of hypoxia-degradable nanogel over other kinds of degradable nanogels in tumor drug delivery remain unclear. Herein, we reported the synthesis of a novel hypoxia-responsive crosslinker and the fabrication of a hypoxia-degradable zwitterionic poly(phosphorylcholine)-based (HPMPC) nanogel for tumor drug delivery. The obtained HPMPC nanogel showed ultra-long blood circulation and desirable immune compatibility, which leads to high and long-lasting accumulation in tumor tissue. Furthermore, HPMPC nanogel could rapidly degrade into oligomers of low molecule weight owing to the degradation of azo bond in hypoxic environment, which leads to the effective release of the loaded drug. Impressively, HPMPC nanogel showed superior tumor inhibition effect both in vitro and in vivo compared to the reduction-responsive phosphorylcholine-based nanogel, owing to the more complete drug release. Overall, the drug-loaded HPMPC nanogel exhibits a pronounced tumor inhibition effect in a humanized subcutaneous liver cancer model with negligible side effects, which showed great potential as nanocarrier for advanced tumor drug delivery.

Hypoxia-degradable and long-circulating zwitterionic phosphorylcholine-based nanogel for enhanced tumor drug delivery

Tumor microenvironment has been widely utilized for advanced drug delivery in recent years, among which hypoxia-responsive drug delivery systems have become the research hotspot. Although hypoxia-responsive micelles or polymersomes have been successfully developed, a type of hypoxia-degradable nanogel has rarely been reported and the advantages of hypoxia-degradable nanogel over other kinds of degradable nanogels in tumor drug delivery remain unclear. Herein, we reported the synthesis of a novel hypoxia-responsive crosslinker and the fabrication of a hypoxia-degradable zwitterionic poly(phosphorylcholine)-based (

Biodegradable phosphorylcholine-based zwitterionic polymer nanogels with smart charge-conversion ability for efficient inhibition of tumor cells.

Zwitterionic polymer nanocarriers have attracted much attention in recent years due to their desirable biocompatibility and anti-fouling properties. However, the super-hydrophilic and neutral charge of zwitterionic polymer results in weak interactions with negatively charged cell membranes, which leads to suboptimal uptake by tumor cells. Herein, a series of biodegradable poly(2-methacryloyloxyethyl phosphorylcholine-s-s-vinylimidazole) (PMV) nanogels with uniform spherical shape was fabricated by one-step reflux precipitation polymerization, which was clean and efficient. The PMV nanogels remained in zwitterionic state at physiological pH (pH 7.4) and were converted rapidly to positive charged state at tumor extracellular pH (pH 6.5). Proton nuclear magnetic resonance spectra and acid-base titration experiment proved that the charge-conversion ability of PMV nanogels was attributed to protonation of the imidazole ring in an acidic environment. Protein stability experiment showed that PMV nanogels exhibited a protein-adsorption resistance at pH 7.4 for as long as 7 days while adsorbed protein rapidly at pH 6.5. Moreover, PMV nanogels showed a reducing-labile property, which was able to degrade into short linear polymer chains in the presence of reduction agents. Therefore, the doxorubicin (DOX) release profile was controlled finely with a low DOX leakage under physiological conditions (7.8% in 48 h) and a rapid DOX release in 10 mM glutathione at pH 7.4 (78.9% in 48 h). Confocal laser scanning microscope and flow cytometry showed that the PMV nanogels exhibit an enhanced cellular uptake by tumor cells at pH 6.5 compared with pH 7.4, which allows for a severe cytotoxic effect of DOX-loaded PMV nanogels against tumor cells.

Biodegradable Zwitterionic Nanogels with Long Circulation for Antitumor Drug Delivery.

Zwitterionic nanocarriers have emerged as a new class of biocompatible nanomaterials with outstanding stealth capability in blood circulation. In this work, a novel biodegradable zwitterionic nanogel based on poly(sulfobetaine methacrylate) (PSBMA) was developed for reduction-responsive drug delivery to tumors. PSBMA nanogels were facilely fabricated by one-step reflux precipitation polymerization with the advantage of being surfactant-free and time-saving. The disulfide bond not only endowed the nanogels degradability in a reduction environment but also be modified with a fluorescent group after partial reduction. In vitro release experiments disclosed that doxorubicin (DOX)-loaded PSBMA nanogels could hold the drugs firmly in physiological conditions (only 7% release in 24 h) and release the drugs rapidly and sufficiently in 10 mM glutathione (85% in 8 h). More interestingly, PSBMA nanogels displayed long circulation in blood after intravenous injection, and small change was found in half-life of nanogels between the first (34.1 h) and the second injection (30.5 h), indicating that there was no accelerated blood clearance phenomenon for these nanogels. Meanwhile, no obvious immunogenic response was detected after PSBMA nanogels were injected into BALB/c mice. Furthermore, PSBMA nanogels showed a high accumulation of 9.5 and 10.7% of injected dose per gram of tissue in tumors at 24 and 48 h post intravenous injection, respectively. With outstanding long circulation time, high tumor accumulation, and sufficient drug release in a reduction environment, DOX-loaded PSBMA nanogels demonstrated the strongest tumor growth inhibition effect among all of the treatment groups in human hypopharyngeal carcinoma-bearing mouse models. Therefore, our study provided a facile drug delivery platform based on biodegradable zwitterionic nanogels and may have great potential in tumor drug delivery.