PEGylation

Polyethylene glycol), PEG compounds are also known as PEO (polyethylene oxide) and POE (polyoxyethylene): Properties of Polyethylene Glycol Poly(ethylene glycol) has several chemical properties that make it especially useful in various biological, chemical and pharmaceutical settings:
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Non-toxic and non-immunogenic can be added to media and attached to surfaces and conjugated to molecules without interfering with cellular functions or target immunogenicities. Hydrophilic (aqueous-soluble) attachment to proteins and other biomolecules decreases aggregation and increases solubility. Highly flexible provides for surface treatment or bioconjugation without steric hindrance.

Defination of PEGylation: PEGylation is the process of covalent attachment of polyethylene glycol polymer chains to another molecule, normally a drug or therapeutic protein. -PEGylation is routinely achieved by incubation of a reactive derivative of PEG with the target macromolecule. -The covalent attachment of PEG to a drug or therapeutic protein can "mask" the agent from the host's immune system(reduced immunogenicity and antigenicity), increase the hydrodynamic size (size in solution) of the agent which prolongs its circulatory time by reducing renal clearance. - PEGylation can also provide water solubility to hydrophobic drugs and proteins.

-PEGylation is a process in which one or more units of chemically activated polyethylene glycol reacts with a biomolecule, usually a protein, peptide, small molecule or oligonucleotide, creating a putative new molecular entity possessing physicochemical and physiological characteristics that are distinct from its predecessor molecules. - In recent years, PEGylation has been used not only as a drug delivery technology but used also as a drug modification technology to transform existing biopharmaceuticals clinically more efficacious than before their PEGylation. -PEGylation bestows several useful properties upon the native molecule, resulting in improved pharmacokinetic and pharmacodynamic properties, which in turn enable the native molecule to achieve maximum clinical potency. -In addition, PEGylation results in sustained clinical response with minimal dose and less frequency of dosing, leading to improved quality of life via increased patient compliance and reduced cost. -PEGylation can help to improving the safety and efficiency of many therapeutics. - It produces alterations in the physiochemical properties including changes in conformation, electrostatic binding, hydrophobicity etc. These physical and chemical changes increase systemic retention of the therapeutic agent. Also, it can influence the binding affinity of the therapeutic moiety to the cell receptors and can alter the absorption and distribution patterns. -PEGylation, by increasing the molecular weight of a molecule, can impart several significant pharmacological advantages over the unmodified form, such as: 1)Improved drug solubility. 2)Reduced dosage frequency, without diminished efficacy with potentially reduced toxicity 3)Extended circulating life 4)Increased drug stability

5)Enhanced protection from proteolytic degradation

PEGylated drugs :
a) ADAGEN :(PEG- bovine adenosine deaminase) manufactured by Enzon Pharmaceuticals, Inc., US was the first PEGylated protein approved by the U.S. Food and Drug Administration (FDA) in March 1990, to enter the market. USE: It is used for treatment of severe combined immune deficiency in children and Adolescents(SCID disease), caused mainly by lack of the bodys own Adenosine deaminase and also for bone marrow tansplantation ADADEN was approved under the orphan drug Act in 1990 on the basis of a clinical trial with 6 patients, this method of therapy called Enzyme replacement therapy which is the starting point for the treatment of many genetically caused disease of the metabolism. b)PEGASYS: ( PEG- -Interferon 2a) for use in the treatment of chronic hepatitis C and hepatitis B (Hoffmann-La Roche) b)PEGINTRON: (PEG- -Interferon 2b) for use in the treatment of chronic hepatitis C and hepatitis B (Schering-Plough / Enzon) both PEGASYS and PEGINTRON are the protein have a very similar amino acid sequence. They may be distinguished by the kind of PEG chains used for PEGylation.  PEGASYS has been modified with a branched reagent consisting of two 20kDa PEG chains.  PEGINTRON has been conjugated with a linear PEG molecule with a molecular weight of 10kDa. c)Oncaspar: PEGylated L-asparaginase (PEGylated enzyme drug) USE:for the treatment of acute lymphoblastic leukemia in patients Advantage of this drug is to prolong plasma half life and strongly reduced immunogenicity as compared to non PEGylated-asparaginase. This drug was recently approved for front line use.

Other PEGylated enzymes to be mentioned are Uricase,Glutaminase,Arginine deaminase and Glucocerebrosidase, these drugs are still under clinical development. d)Neulasta: PEGylated recombinant methionyl human granulocyte colonystimulating factor for severe cancer chemotherapy-induced neutropenia (Amgen) e)Doxil/Caelyx: PEGylated liposome containing doxorubicin for the treatment of cancer (Ortho Biotech / Schering-Plough) f)Pegloticase (Krystexxa) - PEGylated Uricase for the treatment of gout (Savient) PEG moiety properties: PEG is a particularly attractive polymer for conjugation. The specific characteristics of PEG moieties relevant to pharmaceutical applications are:
    

Water solubility High mobility in solution Lack of toxicity and immunogenicity Ready clearance from the body Altered distribution in the body

Reference: 1. Veronese, F. M. ; Pasut, G. (2005), "PEGylation, successful approach to drug delivery", Drug Discovery Today 10 (21): 1451 1458, http://dx.doi.org/10.1016/S1359-6446(05)03575-0 2. Veronese, F. M.; Harris, J. M. (2002), "Introduction and overview of peptide and protein pegylation", Advanced Drug Delivery Reviews 54 (4): 453456, PMID 12052707 3. Fee, C. J. ; Van Alstine, J. M. (2006), "PEG-proteins: Reaction engineering and separation issues", Chemical Engineering Science 61 (3): 924939, http://dx.doi.org/10.1016/j.ces.2005.04.040 4. Fee, C. J.(2009), Protein conjugates purification and characterization, PEGylated Protein Drugs: Basic Science and Clinical Applications, Veronese, F. M., Ed. Birkhauser Publishing: Basel, 113-125.

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Fee, C. J.(2008), Size-exclusion reaction chromatography (SERC): A new technique for protein PEGylation. Biotechnology and Bioengineering, 82 (2): 200-206, http://dx.doi.org/10.1002/bit.10561 6. Ryan, S. M.; Giuseppe, M.; Wang, X.; Haddleton, D. M.; Brayden, D. J.(2008), "Advances in PEGylation of important biotech molecules: delivery aspects", Expert Opinion on Drug Delivery 5 (4): 371383.http://dx.doi.org/10.1517/17425247.5.4.371 7. Damodaran V. B. ; Fee C. J. (2010), "Protein PEGylation: An overview of chemistry and process considerations", European Pharmaceutical Review 15 (1) : 1826,http://www.europeanpharmaceuticalreview.com/articles/20100222_7