Figure 8 Synthesis of PEG-Intron by conjugating activated PEG with free amino groups in the interferon. R is lower alkyl group, R1, R2, R3, R4, R1′, R2′, R3′, R4′, R5 is H or lower alkyl; and x, y, and z are selected from any combination … In other instance, pegvisomant (Somavert) prodrug conjugate is synthesized by covalent attachment of four to six Mw 5000Da PEG units via NHS displacement to several lysine residues available on hGH antagonist Inhibitors,research,lifescience,medical B2036, as well as the N-terminal phenylalanine residue is used
for acromegaly treatment [41–43]. Similarly, Amgen’s pegfilgrastim (Neulasta®) is used to decrease febrile neutropenia manifested this website infection and this prodrug is a covalent conjugation of Mw 20000Da monomethoxy PEG aldehyde by reductive amination with the N-terminal methionine residue of the filgrastim protein . On the other hand, Krystexxa (pegloticase) by Savient, used for the treatment of chronic gout, is synthesized by using PEG p-nitrophenyl Inhibitors,research,lifescience,medical carbonate
ester . The primary amine lysine side chain is replaced by p-nitrophenol to form carbamates, Inhibitors,research,lifescience,medical which are further subjected to decrease hydrolysis under mild basic conditions. From the total of 28-29 lysines, approximately 12 lysines on each subunit of urate oxidase are surface accessible in the native tetrameric form of the complete enzyme. In fact, due to the close proximity of some of the lysine residues, PEGylation of one lysine may sterically hinder the addition of another PEG chain [45, 46]. 5.2. PEG-Drug Conjugates PEGylation of drugs does influence the pharmacokinetic properties of drugs and drug carriers
and therefore is emerging as an important area in pharmaceutics. PEG has been successful for protein modification but in the case of low-molecular-weight Inhibitors,research,lifescience,medical drugs it presents a crucial limit, the low drug payload accompanying the available methoxy or diol forms of this polymer. This intrinsic limitation had for many years prevented the development of a small drug-PEG conjugate, and also because the conjugates extravasation into tumors by EPR effect Inhibitors,research,lifescience,medical is directly proportional to the conjugate’s molecular weight. Unfortunately, in case of PEG the use of larger polymer does not correlate mafosfamide well with an increase in the amount of drug selectively delivered into the tumor. In case of PEG, the number of available groups for drug coupling does not change with the length of polymeric chain, as happens instead with other polymers (e.g., polyglutamic acid, and dextran) or copolymers (e.g., HPMA). The latter can have several functional groups along the polymeric backbone: longer polymer chains correspond to an increased number of functional groups [22, 47–49]. A few studies have been conducted recently to overcome the low PEG loading by using multiarm PEGs either branched at the end chain groups or coupling on them small dendron structures (Figure 9) [47, 49–51].