PEG/pegylation

Several of these problems can be solved by polyplex modification with polyethylene glycol (PEG). PEGylation has been broadly explored for surface shielding ( stealthing ) of many liposomal and nanoparticulate carriers. In the case of cationic polymers, Plank et al. [62] demonstrated that complement activation can be reduced when the polymers are PEGylated. Such a modification can be... 

PEG drug in formation PEG PEGylation PEG size (kDa) Year of approval... 

Natural interferons produced by human leukocytes, recombinant interferons produced in bacteria, and recombinant interferons conjugated to monomethoxy polyethylene glycol (PEG pegylated interferons) are available in the United States. The various preparations may be administered subcutaneously, intramuscularly, intravenously, or intralesionally (e.g., into genital warts). Natural or recombinant interferons typically achieve peak plasma levels within 4 to 8 hours of subcutaneous... 

Interferon alfa-2a, rDNA, PEG-PEGylated-40K interferon [SY used by Roche]... 

The covalent attachment of PEG, PEGylation, is a well-established technique of overcoming several problems associated with the therapeutic uses of proteins. This technique has demonstrated reduced immunogenicity, extended circulating half-life, and improved stability for these therapeutic agents [125-127]. 

Keywords PEG PEGylation PEG-protein PEG-drugs Polymer therapeutics... 

Polyethylene glycol (PEG) consists of repeating units of ethylene glycol forming linear or branched polymers with different molecular masses. Pegylation is the process by which PEG chains are covalently attached to lEN molecules. Pegylation confers a number of properties on lEN-a molecules, such as sustained blood levels that enhance antiviral effectiveness and reduce adverse reactions, as well as a longer half-life and improved patient compliance (Kozlowski et al. 2001). 

The development of pegylated (peg) interferons that possess a sustained absorption, a slower rate of clearance, and a longer half life than unmodified interferons led to further improvement of sustained virologic response rates especially for patients infected with genotype 1 (Fig. 1) (Fried et al. 2002 Manns et al. 2001 Zeuzem et al. 2000). 

Interestingly, this behavior of the reaction mixture can be prevented by employing another principle of particle stabilization steric protection. Inclusion of pegylated comonomer (PEG-AEPD) into the reaction mixture did enable the formation of nonaggregating DNA particles. It also caused the particles to form worm -like structures (as judged by transmission electron microscopy) that have previously been observed with DNA complexes formed from block copolymers of PEL and PEG [98]. 

At present, the most frequently used methods for PEGylation are chemical conjugation between reactive groups in the drug, such as the primary amine of lysine in protein, and end-reactive PEG derivatives, such as the A-hydroxysuccinimide-... 

Fig. 2 Examples of activated PEG derivatives commonly used for PEGylation...

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...

The N-terminal methionine residue of protein can also be employed for selective PEGylation using aldehyde-terminated PEG via a reductive amination reaction, because the N-terminal primary amine has a lower pAa of 7.8 than other amines such as lysines, whose pZa is 10.1 [7]. After reaction with aldehyde-terminated PEG at low pH, the resultant imine is reduced with sodium cyanoborohydrate to provide PEGylated protein (Fig. 4) [8, 9]. This technique was used for the production of Neulasta, which was approved for use by the FDA in 2002 [10]. 

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...

Although the detailed mechanism of the longer circulation time of branched PEGylated protein is unclear, the architecture of PEG affects the release profile, the pharmacokinetics of the chug [29], and the behavior of the protein at the interface (e.g., protein absorption on hydrophobic surfaces [30]). 

The concept of de-PEGylation can be applied to the development of nanoparticle-based drug delivery systems. PEG is used for the modification of liposomes to increase their blood circulation time [38], However, it also prevents cellular uptake, resulting in a decrease in therapeutic efficiency thus, modifications of the liposome surface with PEG interfere with membrane fusion to the cell membrane and liposome decomposition [39]. One of the possible strategies to solve this problem is to cleave the PEG chains after the nanoparticle reaches the target site (Fig. 9). This system of de-PEGylation of liposomes is also useful in avoiding the immune... 

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