The exposure of humans to PEG occurs during their first days of life via lotions, soaps, toothpaste, food packaging and, later, over-the-counter laxatives

The exposure of humans to PEG occurs during their first days of life via lotions, soaps, toothpaste, food packaging and, later, over-the-counter laxatives. well as in drug products and vaccines stimulated research which uncovered that PEG is not as immunologically inert as it was initially expected. Herein, we review the current understanding of PEGs immunological properties and discuss them in the context of synthesis, biodistribution, safety, efficacy, and characterization of PEGylated nanomedicines. We also review the current knowledge about immunological compatibility of other polymers that are being actively investigated as PEG alternatives. Graphical Abstract 1.?Introduction 1.1. Chemical structure and varieties of PEG Itgbl1 Polyethylene glycol (PEG) is produced from polymerization of ethylene oxide, ethylene glycol, or diethylene glycol VX-770 (Ivacaftor) in the presence of alkaline catalysts and the reaction is ended by neutralizing the catalyst when polymer reaches the desired molecular weight [1, 2]. The chemical structure of PEG is HO-[CH2-CH2-O]n-H, where n is the number of ethylene oxide units and the molecular weight is calculated by (44 g/mol)*n. PEG is hydrophilic and each ethylene glycol subunit surrounded by 2C3 water molecules [3, 4]. PEG is soluble in water, methanol, ethanol, acetonitrile, glycerin, glycols, benzene, and dichloromethane, and this property makes PEG useful in many formulations and products [1]. PEG can have different geometries, including linear, tube, branched, star, and comb [5]. Modifications can be made to PEG to allow for further customization. A methyl VX-770 (Ivacaftor) ether cap (mPEG) can be added to PEG to prevent hydrogen bonding at the cap end, which can restrict nonspecific interactions with proteins and with other PEG chains [2]. Some VX-770 (Ivacaftor) PEGylated nanomaterials will have many opportunities for multiple hydrogen bonds; a methoxy-PEG will have significantly less risk of non-covalent crosslinking in such an environment. PEG is also very flexible and exhibits high chain mobility that results in a large number of polymer chain conformations, and a reduction in chain conformational freedom is thermodynamically unfavorable [6C8]. PEG can be used to form a shell around micelles [9]. PEG shells have a hydration sheath that sterically prevents biomacromolecules from penetrating the polymer layer and binds to the core by hydrophobic or electrostatic interactions [10C12]. PEG is a common product in drug formulations, pharmacological and food products [1, 2, 13, 14]. PEG units used in drug formulations and consumables generally range between molecular weights of 200C60,000 Da VX-770 (Ivacaftor) [2, 13, 15]. The molecular weight of PEG used in nanomedicines such as Doxil, and in recent lipid-nanoparticles mRNA-based COVID-19 vaccines is 2000 [16]; that of nanomedicine CYT6091 is 20,000 [17]. Conjugation of the end hydroxyl group on PEG to reactive groups on compounds to make formulations and larger PEG-matrices is also a common use for PEG, in the form of PEGylated nanoparticles or medicine that allows for improved circulation, sustained release, improved efficacy and/or dissolution of drug, or production of artificial PEG-environment [18C21]. Stealth characteristics of PEG require large amounts of PEG coating and may depend on the type nanoparticle to which it is conjugation (i.e., more for metals or polymers) [22, 23]. 1.2. Hydrophilic and stealth properties of PEG One of the early examples of using PEG to modify biomolecules include the conjugation of PEG-1900 and bovine albumin that resulted in changes in the proteins physical and chemical properties, including greater solubility in a wider pH range, from 1C12; prevented interaction of ion exchangers with the protein, and allowed the PEGylated-albumin to remain in circulation longer than unconjugated albumin [24]. Intravenous (i.v.) and intramuscular (i.m.) injection of unconjugated albumin resulted in antibody production whereas reduced antibody levels were observed with PEGylated albumin [24]. This study suggested that PEGylation masked antigenic sites on albumin thereby inhibiting their recognition and an immune response. Conjugation of PEG to a nanoparticle surface reduces opsonization (the binding of plasma proteins) and stalls clearance of PEGylated nanoparticles by the mononuclear phagocyte system [25C27]. As such, PEGylated nanoparticles have longer circulation.