Biomedical Engineering Reference
In-Depth Information
may include changes in level of hydration, conformation, electrostatic
binding, and hydrophobicity/hydrophilicity balance. Covalently
attached highly flexible and highly hydratedhydrated PEG [three to
four molecules of water per 1 ethylene oxide oxygen (Tirosh et al.,
1997, 1998)] induce changes in structure and lead to increase in size
and bulkiness. All together this results in “steric stabilization,” which
reduces nonspecific protein-protein interaction and nonspecific
protein-cell interactions. 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.
PEG polymer has only two reactive OH groups (one at each end of the
PEG molecule); in order to prevent the PEG from inducing intra- and
inter-cross linkages, one of these hydroxyl groups was methylated.
Pegylation, by increasing the molecular weight of a molecule and
its level of hydration, can impart several significant pharmacological
advantages over the native unmodified molecule, such as
•
Improved agent solubility
•
Extended circulating life
•
Therefore, reducing dosage frequency, without diminished
efficacy with potentially reduced toxicity
•
Increased drug stability
•
Enhanced protection from proteolytic degradation
•
Reduced immunogenicity
In addition, pegylated drugs may have the following commercial
advantages:
•
Opportunities for new delivery formats and dosing regimens
•
Extended patent life of previously approved drugs
This resulted in the development of many pegylated proteins and
peptide drugs, (only a few of which made it to the market), so now the
clinical value of pegylation is well established. ADAGEN (PEG-bovine
adenosine deaminase), manufactured by Enzon Pharmaceuticals,
Inc., was the first pegylated protein (approved by the FDA in March
1990) to enter the market. It is used to treat X-chromosome-linked
severe combined immunogenicity syndrome, as an alternative to
bone marrow transplantation and enzyme replacement by gene
therapy. Now a large number of pegylated protein and peptide
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