Vinylsulfone-PEG-NHS (VS-PEG-NHS) is a polymer formed by functionalizing polyethylene glycol (PEG) with an N-hydroxysuccinimide (NHS) active ester group at the end with vinylsulfone. Its thiol-binding molecule will bind or react with biomolecules or any other substance through its thiol (-SH) reactive group. VS-PEG-NHS is available in sizes ranging from 1000-20000 Daltons and can be customized. VS-PEG-NHS is a bioconjugate. The compound provides a nifty basis for therapeutic aimed delivery. The vinylsulfone molecule is further reinforced reactivity by N-hydroxysuccinimide (NHS), which leads to effective covalent ligature to proteins, peptides and small molecules. It can react, for instance, with thiol-based peptides through Michael addition reactions to form solid PEG-Thiol bonds. VS-PEG-NHS is also applicable to making hydrogels, important for regenerative medicine and prolonged drug release. Combining these properties allows us to build highly effective drug delivery systems with minimal side-effects. VS-PEG-NHS must be stored under -20°C, away from light and moisture, when not in use to maintain activity. As the VS group easily reacts with free thiols in buffer solutions of pH 6.5-8.5, the reaction conditions are easy at room temperature.
Figure 1. Reaction scheme of NHS–PEG conjugation. (Gaziova Z, et al.; 2014)
Especially the vinyl sulfone group is interesting as it is electrophilic, so that it can be nucleophilic in its reaction with primary amines. This is an important feature in the drug conjugation reactions since it makes it possible to bind to amide bonds that stay. The NHS group, a favourite to activate carboxylic acids for nucleophilic oxidation, is a supplement to the vinyl sulfone. This synergy leads to a strong and biocompatible association that does not deteriorate via hydrolysis or other degradation. These conjugates must be stable – particularly in physiological environments, where early delivery of the drug may reduce therapy. With VS-PEG-NHS, scientists can engineer drug delivery systems that do not lose integrity in the bloodstream, which will make the therapeutics more bioavailable. PEG's biocompatibility is a further strength of vinyl sulfone-PEG-NHS. PEG is known for its immunogenicity inhibition and time delay of blood circulation. Because PEG is hydrophilic, the drug can escape from the immune system, which enables the drug to be administered into the entire body and better targeted at infected tissues. This is especially useful when chemotherapeutic agents must be precisely targeted so as to be least toxic to normal cells. With vinyl sulfone-PEG-NHS, pharmaceutical companies can optimize their pharmacokinetics so the therapeutic hits its target and minimises side effects. The design freedom of vinyl sulfone-PEG-NHS makes it useful in a variety of drug delivery systems. The chemists can extend the PEG chain or add functional groups to adjust the physical and chemical makeup of the conjugate for individual therapeutic requirements. For instance, the length of PEG chains can alter solubility, viscosity, and clearance from the body, and thus the pharmacodynamics of the drug. Moreover, by incorporating multiple drug molecules into the same carrier via VS-PEG-NHS, there are novel potential combinations for treatment. This could be especially effective for a disease like cancer, where multiple pathways can have to be engaged in concert to yield therapeutic benefit. Besides, vinylsulfone-PEG-NHS is increasingly being used in prodrugs, pharmacologically inert substances that are converted into active substances in the body. With this bioconjugate, scientists could develop prodrugs that released their active constituents in a controlled way to increase therapeutic activity and reduce side-effects. The selective release can be activated by environmental conditions (pH, specific enzymes in target tissues) and this approach is ideal for localized delivery of drugs. This schedulability of drug release at the right place and time is one of the most important features of contemporary drug delivery systems and has the potential to revolutionise treatment.
The second major application of vinylsulfone-PEG-NHS involves nanocarrier building. Nanoparticles can be used as carrier particles for various therapeutic molecules, which are resistant to degradation and deliver them more effectively. Vinylsulfone-PEG-NHS can be used to reshape the surface of these nanoparticles to give them a stable and effective target. By chemistry nanoparticles with VS-PEG-NHS, scientists could design systems that release drugs in response to biological signals or ambient environments. This specific treatment enhances both the therapeutic index of the drugs that are delivered and the off-target side effects, which is a promising option for personalized medicine. Further, the incorporation of vinylsulfone-PEG-NHS in drug delivery systems can be used to develop diagnostic instruments. When imaging agents can be bound to this bioconjugate, personalised imaging probes can be designed to allow the visualization of diseases like cancer. Through the addition of imaging agents to vinylsulfone-PEG-NHS, scientists can record biodistribution and pharmacokinetics of therapeutic molecules in real-time, which is critical information about treatment response and effectiveness. This duality of use of vinylsulfone-PEG-NHS as a drug delivery vehicle and diagnostic device is another example of multifunctional platform in modern medicine.
Alternate Names:
Vinylsulfone-PEG-NHS
NHS-PEG-Vinylsulfone
NHS-Activated PEG-Vinylsulfone
Vinylsulfone-Activated PEG-NHS
Vinyl Sulfone-PEG-NHS Ester
NHS-PEG-VS
References:
1. Gaziova Z, et al.; Chemically defined polyethylene glycol siRNA conjugates with enhanced gene silencing effect. Bioorg Med Chem. 2014, 22(7):2320-6.
Injectable Gel-PEG hydrogels as promising delivery system for intravitreal PACAP release: Novel therapeutics for unilateral common carotid artery occlusion induced retinal ischemia
Biomed Pharmacother
Authors: Chen M, Liang X, Chen X, Yang Y, Shu Q, Ju Y, Nie W, Yang X, Guo Y, Li X, Gu P, Li L
Abstract
Retinal ischemia is an ophthalmic emergency often caused by cardiovascular diseases, leading to irreversible vision loss and even blindness. Innovative retinal ischemia treatments are needed due to limited options. The pathological mechanisms involve retinal cell apoptosis and microglial activation. The pituitary adenylate cyclase-activating polypeptide (PACAP) is a well distributed neuropeptide found in both central nervous system and peripheral organs. Though it shows great anti-apoptosis and anti-microglia activation properties, it is rapidly cleared by intravitreal injection. Herein, we established a novel poly(ethylene glycol) (PEG) hydrogel system by cross-linking 4arm-PEG-NHS and 4arm-PEG-NH2 to load PACAP (PACAP@Gel-PEG), which exhibited great fluidity, injectability, structural recovery ability, moderate swelling ratio and drug release ability that were appropriate for drug delivery. Then the safety and effectiveness of the PACAP@Gel-PEG were evaluated in vitro in three retinal cell lines (ARPE-19, 661 W and rRMC) and in vivo using the unilateral common carotid artery occlusion (UCCAO) mice model. The CCK-8 test and live/dead staining demonstrated that PACAP@Gel-PEG exhibited excellent biocompatibility in three retinal cell lines. Furthermore, after PACAP@Gel-PEG treatment, a great anti-apoptotic effect was observed in cells treated by CoCl2. Application of PACAP@Gel-PEG greatly improved the therapeutic efficacy of PACAP in restoring retinal function, maintaining retinal integrity, and suppressing apoptosis and microglia activation in retinal tissues. Moreover, in mice, the biosafety of PACAP@Gel-PEG was confirmed by H&E staining of systemic organs. Taken together, our results demonstrated PACAP@Gel-PEG as a promising therapeutic option for retinal ischemia, providing new strategies for vision restoration.
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