Chemical modification is an effective way to extend the half-life of protein drugs. It is the covalent attachment of a small molecular weight protein drug to a larger molecule, such as polyethylene glycol, which reduces immunogenicity, improves solubility and bioavailability, and increases anti-protein hydrolysis, while also extending the half-life.
PEG is non-toxic, non-immunogenic, non-antigenic, and water-soluble. The PEGylated modification changed the physicochemical properties of the drug, including conformation, electrostatic binding and hydrophobicity. These physical and chemical changes increase the in vivo retention time, improve plasma half-life and prolong absorption time of the drug, and also affect the binding affinity of the drug to cell receptors and improve tumor targeting. Drug modification by PEG can reduce the number of dosing, increase efficacy, improve tolerability, and reduce the severity and incidence of adverse events. PEG also increases the solubility and stability of proteins, which also facilitates drug production and storage. Therefore, PEG is often used as a drug delivery and drug modification technology, either directly coupled to a drug or attached to the drug surface and encapsulated together in a nanomaterial.
The modification pathways of PEGylated protein drugs mainly include amino modification, carboxyl modification and sulfhydryl modification.
Chemical modification of peptides with PEG can improve a variety of physicochemical and pharmacokinetic properties of peptides with minimal increase in manufacturing cost. The effects of PEG modification on peptide pharmacokinetics have potentially beneficial biodistribution changes, including avoidance of reticuloendothelial system (RES) clearance, reduced immunogenicity, and reduced enzymatic and renal filtration losses. Peptide compounds are more readily available than proteins in targeted modifications of PEG. The most common application in PEGylation studies of peptide compounds is mPEG.
PEG-loaded small molecules can transfer many of their excellent properties to the coupling compound, making the polymer biocompatible. Not only can their solubility and biodistribution be improved, but also their metabolism and toxicity can be reduced by altering the exposure of the drug to enzymes and vital organs. Many antitumor drugs are modified by high molecular weight PEGs to achieve targeted delivery to tumor tissue.
After PEGylation of liposomes, the PEG chain increases the hydrophilicity of the liposome surface by creating a hydrophilic protective film on the liposome surface, decreasing the affinity with mononuclear phagocytes, thus evading the recognition of RES, reducing the capture of liposomes, and preventing the interaction of liposomes with other molecules.
PEG minimizes antigenic determinant cluster exposure and reduces or prevents neutralizing antibody production Reduces antigenicity and immunogenicity, maximizing retention of biological activity
The flexible chain of PEG can produce a spatial site blocking effect that protects the modifier from protease attack and increases the stability of the modification. PEGylation also improves the thermal and mechanical stability of the molecule.
PEGylation improves the stability of body circulation and prolongs the retention time, which is conducive to improving the distribution of drugs in the body, especially the accumulation of large molecules in tumor and inflammation sites.