A Brief Introduction to Functional PEGs

Due to its biological inertness and good biocompatibility, polyethylene glycol (PEG) has a wide range of applications in the pharmaceutical industry, biological materials, cosmetics, and analytical science. A number of compounds, such as proteins, peptides, oligonucleotides, drugs and liposomes, after being modified by PEG covalent bonding, can effectively extend the circulation time in the body, increase stability, optimize pharmacokinetics and reduce side effects.

Functional PEG has huge potentials in different scenarios. According to MarketsandMarkets, the global PEG-modified drug market in 2017 was 10.388 billio
U.S. dollars, and is expected to reach 17.813 billio
U.S. dollars by 2025, with a significant growth rate. As of the end of 2019, 26 PEGylated drugs have been approved by the FDA or the European Union. Except for 2 small molecule drugs and 1 liposome drug, the remaining 23 are all PEGylated protein/peptide drugs.

On the whole, PEGylation can be used for PEGylated protein drugs, PEGylated peptide chain compounds, PEGylated small molecule drugs, PEGylated liposomes, etc. At the earliest, it was also used for producing long-acting protein and peptide drugs. Generally speaking, the common techniques for the long-lasting potency of protein and peptide drugs include polyethylene glycol modification, fusion proteins, microspheres, liposomes, and site-directed mutagenesis.

In addition, amphiphilic block-terminated copolymers (BCPs) synthesized based on PEG initiators are widely used to construct nanocarriers for drug delivery. Via the terminal functionalization of PEG, longer blood circulation time can be achieved.

Conventional protein and peptide drugs are composed of multiple amino acids. Such drugs are often excreted quickly through the kidneys after acting on the human body, or are deactivated by enzymes and proteins that are abundant in the human body. Therefore, the effective time of such drugs is short, and the concentration of the drug in the blood changes greatly in a short period of time. In contrast, PEG-modified protein drugs have a longer half-life compared with conventional similar drugs.

Advantages of PEGylated protein drugs

1) The relative molecular weight of the PEGylated drug can be increased, so that it is not easy to be degraded and filtered out by the kidneys, and the effective concentration time of the drug in the body can be prolonged;

2) The long-chai
PEG derivative wraps the drug to prevent the drug from being rapidly enzymatically digested or recognized by the immune system.

Both reduce the total clearance rate of the drug, allow the drug to be slowly released in the human body, stabilize the blood drug concentration, and reduce the number of drug use.

Traditional PEG functionalization relies on esterification and etherification reactions. There are problems such as incomplete conversion, harsh reaction conditions, and incompatibility of functional groups. In addition, due to the synthesis route and the storage stability issues that have been neglected, The GPC and macromolecular mass spectrometry analysis results of commercially sold functionalized polyethylene glycol (PEG-NH2) are very unsatisfactory. Therefore, it is impossible to achieve precise polymer synthesis chemistry with commercial PEG-NH2 as the starting material. Some materials scientists have proposed an effective strategy for efficient functionalization of PEG through carbamate linkages. According to the characterization results of macromolecule mass spectrometry, PEG-NH2 with high storage stability and high fidelity end groups was successfully prepared by fine-tuning the basicity of the terminal amino group and the length of the spacer.

Globally, the approved PEG-modified drugs are still concentrated in macromolecular drugs. At present, the number of PEG-modified small molecule drugs approved for marketing is relatively small. With the increasing maturity of PEGization technology, it will be extended to smaller molecule drugs. The future market size of PEG-modified small molecule drugs is expected to exceed that of PEG-modified protein/peptide drugs.