Application of PEGylation in Medicine



The applications of PEGylation modification in medicine are mainly PEGylated protein drugs, PEGylated peptide chain compounds, PEGylated small molecule drugs, PEGylated liposomes and so on.

1. PEGylated protein drugs

The modification methods of PEGylated protein drugs mainly include amino modification (including acylation of N-terminal amino group, acylation of lysine side chain amino group, alkylation modification of N-terminal amino group), carboxyl group modification, sulfhydryl group modification, etc. The research of PEGylated protein drugs mainly focuses on adenosine deaminase, asparaginase, interferon, granulocyte colony stimulating factor, interleukin and so on. PEGylated macromolecular drugs are currently mainly used for the treatment of cancer, chronic kidney disease, hepatitis, multiple sclerosis, hemophilia and gastrointestinal diseases.

2. PEGylated peptide-based compounds

Polypeptides generally have a short plasma half-life and low oral bioavailability, which is due to the presence of a large number of peptidases and their excretion mechanisms in the body, which inactivate and clear the peptides. This instability allows the body to rapidly adjust hormone levels to maintain homeostasis, but is detrimental to many therapeutic developments. In addition, the low bioavailability of oral peptides is due to the fact that digestive enzymes in the oral cavity can decompose the amide bonds of ingested proteins, and can also effectively cut the same bonds of peptide hormones. At the same time, the high polarity and large molecular weight of peptides also severely limit intestinal permeability. sex. Chemical modification of peptides with PEG can improve various physicochemical and pharmacokinetic properties of peptides with minimal increase in manufacturing costs. The effect of PEGylation on peptide pharmacokinetics has potentially beneficial biodistribution changes, including avoidance of Reticuloendothelial System (RES) clearance, reduced immunogenicity, and reduced enzymatic and renal filtration loss. These effects can significantly increase the half-life of the peptide in vivo and indirectly improve the bioavailability without adversely affecting the binding and activity of the peptide to the ligand. Compared with the parent drug, PEGylated peptide chain compounds, such as channel calcitonin and epidermal growth factor, have longer half-life and higher biological activity. Especially in the site-directed modification of PEG, peptide compounds are more readily available than proteins. The most common application in PEGylation studies of polypeptide compounds is mPEG.

3. PEGylated small molecule drugs

At present, many small molecules, especially antitumor drugs, can be modified by PEGylation. PEG-loaded small molecules can transfer many of their excellent properties to the conjugates, making polymers with good biocompatibility. Not only can their solubility and biodistribution be improved, but their metabolism and toxicity can be reduced by altering the drug’s exposure to enzymes and vital organs. Many antitumor drugs are modified by high molecular weight PEG to achieve targeted drug delivery to tumor tissue. Small molecule anti-tumor drugs such as irinotecan, camptothecin, doxorubicin, paclitaxel, etc. are prepared into prodrugs by PEG modification, and their solubility, circulation half-life in vivo, adverse reactions, etc. have been greatly improved, and at the same time, they have significantly enhanced Penetration and retention effects, targeting of tumor tissue are also improved.

Despite the remarkable success of PEGylated proteins and peptides, limited progress has been made in the development of PEGylated small-molecule drugs. This may be due to problems such as loss of biological activity of natural medicines, difficulties in chemical coupling and purification, and adverse reactions. For example, PEGylated camptothecin [21], Enzon Pharmaceuticals announced in 2005 to stop further development of this drug based on the data of Phase 2b clinical trial. Clinical trial results showed that the conjugate was highly tolerated with significantly reduced toxicity compared to the commercial formulation. However, the rapid hydrolysis of this conjugate in vivo resulted in toxicity parallel to that of the natural drug, leading to the failure of drug development of this conjugate.

4. PEGylated liposomes

Lipids are amphiphilic molecules with two parts, hydrophilic and hydrophobic. When lipids come into contact with water, the unfavorable interaction of the hydrophobic segment of the molecule with the solvent leads to the self-assembly of the lipids, usually in the form of liposomes. Liposomes are spherical self-enclosed structures formed by one or more concentric lipid bilayers, with an aqueous phase wrapped between the center and the bilayers, and are composed of natural or synthetic lipids. In the 1960s, Alec D Bangham of the Babraham Institute of Cambridge University first discovered liposomes and proposed the idea of ​​using liposomes as drug delivery vehicles. Liposomes are promising drug delivery systems with many advantages due to their size, hydrophobic and hydrophilic properties (in addition to biocompatibility). Liposomes can improve the therapeutic index of new or marketed drugs by changing drug absorption, reducing metabolism, prolonging biological half-life or reducing toxicity. Drug distribution is mainly controlled by the properties of the carrier, not just the physicochemical properties of the drug substance.

Liposomes also have many disadvantages, such as high production cost, easy leakage and fusion when encapsulating drugs/molecules, and phospholipids sometimes undergo oxidation and hydrolysis reactions. The main defect of liposomes is that they are rapidly captured by RES, resulting in short half-life, low solubility, and short stability period. And PEGylated liposomes (PEGylated long-circulating liposomes) can solve these problems. After PEGylation, the PEG chain increases the hydrophilicity of the liposome surface by establishing a hydrophilic protective film on the surface of the liposome, and reduces the affinity with mononuclear phagocytes, thereby escaping the recognition of RES and reducing the liposome’s affinity. Capture and prevent the interaction of liposomes with other molecules, such as various serum components, so they are also called stealth liposomes. A well-known example of the application of this technology is Doxil®, which was developed by the American company Sequus. It is the first liposome drug approved by the US FDA and the first nano drug.

Although PEGylated liposomes have many advantages, with the deepening of research, PEGylated liposomes also bring corresponding problems. The steric hindrance of PEG chains inhibits the uptake of liposomes by target cells, and PEG interferes with the “nuclear escape” of pH-sensitive liposomes (PSLs) carried by gene and protein drugs, resulting in the accumulation of these drugs in lysosomes In addition, repeated injections of PEGylated liposomes in the same animal can cause the phenomenon of “accelerated blood clearance”. This series of negative effects is known as the “PEG dilemma.” The “PEG dilemma” brings severe challenges to the development of PEGylated liposomes.

5. Other applications

PEGylated Affinity Ligands and Cofactors for Purification and Analysis of Biomacromolecules and Cells in Aqueous Two Phase Distribution Systems. PEGylated saccharides can be used as materials and carriers for novel drugs. PEGylated oligonucleotides can improve solubility, resistance to nucleases, and permeability of cell membranes. PEGylated biomaterials can reduce thrombosis and reduce protein and cell adhesion.