PEG-drug conjugates can therefore be tailored for activation by extra- or intracellular enzymes releasing the parent drug in situ (Figure 3) [7]. In this paper, we represent an overview on the advances of PEG prodrug conjugates which are being currently used as therapeutics. A short discussion with particular emphasis on the derivatives in clinical Idelalisib clinical trial practice or still under clinical Inhibitors,research,lifescience,medical trials is also provided. Figure 3 A schematic illustration of prodrug concept. 2. Properties of PEG PEG in its most common form is a linear or branched polyether terminated with hydroxyl groups. PEG is synthesized by anionic polymerization of ethylene

oxide initiated by nucleophilic attack of a hydroxide ion on the epoxide ring. Most useful for polypeptide modification is monomethoxy PEG (mPEG). On the other hand, mPEG is synthesized by anionic ring opening polymerization initiated with methoxide ions. Successful conjugation

of PEG with biomolecule depends upon the chemical structure, molecular weight, steric hindrance, and the reactivity Inhibitors,research,lifescience,medical of the biomolecule as well as the polymer. In order to synthesize a bioconjugate, both chemical entities (i.e., the bioactive as well as the polymer) need to possess a Inhibitors,research,lifescience,medical reactive or functional group such as –COOH, –OH, –SH, or –NH2. Therefore, the synthetic methodology to form a conjugate involves either protection or deprotection of the groups [18]. 3. PEG-Based Nanocarrier Architectures and Designs There is need to design simple and yet appropriate PEG-conjugation methodology. Most commonly used strategies for conjugation involve use of both coupling agents such as dicyclohexyl carbodiimide (DCC) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Inhibitors,research,lifescience,medical (EDC) or use of N-hydroxysuccinimide (NHS) esters. Chemical conjugation of drugs or other biomolecules to polymers and its modifications can form stable bonds Inhibitors,research,lifescience,medical such as ester, amide, and disulphide. The resulting bond linkage should be relatively stable to prevent drug release during its transport until it reaches

the target. Covalent bonds (e.g., ester or amide) are comparatively stable bonds and could deliver the drug at the targeted site. However, in some instances such bonds may not easily release targeting agents and peptides under the influence of acceptable environmental changes [19]. In the past, either PEG prodrugs have been designed mostly for the delivery of anticancer agents due to its overall implications in the treatment. However it should be noted that PEG-antitumor prodrug is expected to be stable during circulation and degrade/hydrolyze only on reaching the targeted site. PEG-drug conjugates can therefore be tailored to release the parent drug in situ on activation by extra- or intracellular enzymes or pH change. PEG has limited conjugation capacity since it possesses only one (two in case of modified PEGs) terminal functional group at the end of the polymer chain.