1). This allows manufacturing of PEG molecules of various sizes and molecular weights depending on the number of subunits needed. Polyethylene glycol molecules are inert, amphiphilic and soluble in water. They remain uncharged and do not contain any specific moieties that would enhance interaction with biological structures in the body, such as receptors or membranes [4]. Polyethylene glycols are more or less polydispers with a range of molecular weights and only an average molecular weight is usually reported. For pharmaceutical use, PEG molecules are produced under well-controlled Good Manufacturing Practice conditions. Current experience PF-02341066 purchase with PEGylated therapeutics demonstrates

that they exhibit superior clinical properties when compared with their unmodified parent molecules. They can show reduced toxicity, better physical and thermal stability, greater protection against proteolytic degradation, higher solubility, longer in vivo circulation half-life, lower clearance and therefore enhanced efficacy [1, 13, 19]. The PEG molecule itself is generally considered non-immunogenic, but the immunogenicity of the PEG molecule coupled to a protein may ZD1839 in vitro reflect the immunogenicity of the protein [4, 12, 13]. Webster et al. conclude that the risk of a severe immune reaction due to the generation

of anti-PEG antibodies is practically negligible due to the weak immunogenicity of PEG and the low amounts of the polymer-protein conjugate usually given as therapy. Several authors have reported that PEGylated proteins show reduced immunogenicity when compared with their unmodified parent molecule

Erastin manufacturer [4, 12, 13, 20]. Preclinical studies with BAY 94–9027 molecule similarly showed consistently less neutralizing antidrug antibody development in rats, haemophilia A mice and rabbits and in vitro studies indicated that the PEG moiety decreased presentation of the rFVIII to antigen presenting cells, thereby potentially reducing the immunogenicity of FVIII itself [21]. All PEGylated therapeutic proteins undergo preclinical programmes and clinical trials mandated by regulatory authorities. No PEG-specific risk for human health or any safety concerns were identified, when reviewing toxicology and other PEG safety data from a wide molecular range (2–60 kDa) of PEG molecules [12, 13]. The only reported findings were ‘foamy macrophages’ seen in some toxicology studies at high doses, which did not result in any toxicity [13, 22, 23]. Small PEGs and PEG derivatives find many applications in cosmetics and consumer products due to their low toxicity, good solubility and low viscosity. Polyethylene glycols are used in laxatives, toothpastes, hair shampoos, excipients in oral and intravenous (iv) formulations (e.g. Busulfan®) and in hydrogels for tissue engineering [12, 13, 24]. At least 10 PEGylated protein therapeutics have been approved by regulatory agencies (FDA, EMA), and several others are in development [1, 22-29].