PEGylation specificity

Villa et al. 1996). Recent reports from Japan suggest that daily IFN-p administration is highly effective in patients with low or moderate HCV RNA levels (Horiike and Onji 2003 Shiratori et al. 2000). Twice-daily administration of IFN-P as induction therapy has also been reported to be effective (Kim et al. 2005 Naka-jima et al. 2003). It is unlikely, however, that IFN-p will be used in routine clinical practice unless it is pegylated or otherwise modified, and until specific clinical trials are done. 

The results of IFN-a-based therapy can theoretically be improved by using better-tolerated drugs that mimic the action of ribavirin and/or by using HCV inhibitors that, when combined, substantially reduce HCV replication. Since the mechanism of action of ribavirin is still unknown, no credible alternative approach is currently available. In contrast, many specific inhibitors of the HCV replication cycle are in preclinical development and several have reached chnical development (Pawlotsky et al. 2007). A number of them are being tested in combination with pegylated IFN-a, with or without ribavirin. 

Fig. 1 PEGylation technologies. Nonspecific and irreversible PEGylation is associated with several limitations, such as altered drug properties. To overcome this problem, a new generation of PEGylation technologies that enable highly specific and reversible PEGylation have been developed...

Fig. 3 Chemistry of site-specific PEGylation developed by Brocchini et al. [5, 6]. After cleavage of the native disulfide bond between two cysteine thiols by reduction, the free cysteines are reacted with an a, (3-unsaturated PEG derivative to produce a PEG conjugate via a three-carbon bridge...

Fig. 4 PEGylation at the N-terminal methionine residue. The difference in pKa. between the N-terminal amine and other amines in the protein enables site-specific PEGylation. After reaction with aldehyde-terminated PEG at low pH, reduction of the resultant imine produces PEGylated protein...

Fig. 5 Enzymatic site-specific PEGylation by transglutaminase (TGase). The alkylamine derivative of PEG can be introduced into proteins in a site-specific manner...

Fig. 9 Utility of de-PEGylation technology in liposomes, (a) PEG derivative possessing a lipid moiety. The covalent bond between PEG and the lipid moiety can be cleaved by stimuli such as those within the acid environment of cancer and inflammation, (b) After binding the target cell via specific recognition of the receptor by the ligand, PEG molecules on the surface of the liposome are cleaved. The release of PEG facilitates membrane fusion of the liposome and liposome decomposition, resulting in efficient drug delivery...

Hu J, Sebald W (2011) N-terminal specificity of PEGylation of human bone morphogenetic protein-2 at acidic pH. Int J Pharm 413 140-146... 

Lee H, Jang IH, Ryu SH, Park TG (2003) N-terminal site-specific mono-PEGylation of epidermal growth factor. Pharm Res 20 818-825... 

Sato H (2002) Enzymatic procedure for site-specific pegylation of proteins. Adv Drug Deliv Rev 54 487-504... 

Fontana A, Spolaore B, Mero A, Veronese FM (2008) Site-specific modification and PEGylation of pharmaceutical proteins mediated by transglutaminase. Adv Dmg Deliv Rev... 

Ferrying of molecules into cells via entry through caveolae may represent a way to traffic specifically cytotoxic molecules to specific action sites. For example, elevating the intracellular level of the sphingolipid ceramide is known to exert antimitogenic and proapoptotic effects. While ceramide is cell-permeable and displays antiapoptotic properties in vitro, systemic in vivo use of ceramide is hampered by its hydrophobicity. Using a C6-ceramide formulation in pegylated liposomes was shown to elicit a sixfold reduction in solid phase tumors, when compared to unloaded liposomes in a mouse model of breast adenocarcinoma [68],... 

These polymers have been designed to achieve serum stability and sustained circulation with the PEGylated peptide, specific targeting to hepatocytes with... 

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