Polyethylene glycols (PEGs) are non-toxic, non-immunogenic, non-antigenic, highly soluble in water, and FDA approved. PEGylation is the chemical modification process of attaching a PEG active derivative to a therapeutic protein/peptide drug or drug delivery system (e.g., nanoparticles, nucleic acid drug delivery platforms, etc.).

Figure 1. PEGylation process

PEGylation alters the physical and chemical properties of biomedical molecules, such as conformation, electrostatic binding, and hydrophobicity, thereby improving the pharmacokinetic behavior of drugs. In general, PEGylation improves drug solubility and reduces immunogenicity. PEGylation also increases drug stability and retention time in the bloodstream, reduces proteolysis and renal excretion, thereby allowing a reduced dosing frequency. To benefit from these favorable pharmacokinetic outcomes, a variety of therapeutic proteins, peptides, antibody fragments, and small molecule drugs have been PEGylated.

Figure 2. Advantages of PEGylation

History of PEGylation

In the 1970s, Professor Frank Davis of Rutgers University modified bovine serum albumin with PEG in order to reduce the immunogenicity of recombinant proteins, extend their in vivo metabolism time, and enhance protein activity, and since then, this technology has been widely used in biomedical and other fields.

PEGylated drugs were clinically and commercially available in the 1980s. In 1981, Prof. Davis founded Enzon, Inc. in the USA, and in 1990, the world's first PEGylated drug, Adagen (pegademase bovine) was approved by the FDA for enzyme replacement therapy for adenosine deaminase (ADA) deficiency in patients with severe combined immunodeficiency disease (SCID).

Since then, PEGylation has been frequently used to modify proteins, peptides, oligonucleotides, antibody fragments, organic small molecules and nanoparticles. In the wave of novel coronavirus vaccine development, PEG was first and successfully applied to vaccines. Both BioNTech's and Moderna's mRNA vaccines have an active ingredient structure consisting of lipid nanoparticles encapsulating viral mRNA sequences, which include PEG-2000. PEG-2000 can increase the efficiency of transporting the mRNA to the cell, effectively improving its stability and half-life. By 2023, the FDA has approved more than 40 PEGylated drugs.

Table1. FDA approved PEGylated drugs up to 2023 [1]

Advantages of PEGylated drugs

Significantly extends the half-life of protein peptide drugs in vivo

Long-acting PEGylated protein/peptide drugs can be formed by synthesizing specific PEG derivatives and combining their end groups with specific proteins and peptides. This class of drugs can be released slowly in the body, which stabilizes the blood concentration and reduces drug dosing.

▶ Increases the relative molecular weight of the drug: the drug is less likely to be degraded and excreted by renal filtration, prolonging the effective concentration of the drug in the body.

▶ Forms a barrier on the surface of the drug and delivery system: The long-chained PEG derivatives encapsulate the drug, avoiding phagocytosis by the reticuloendothelial system, inhibiting proteolytic cleavage, and preventing the drug from being rapidly enzymatically cleaved or recognized by the immune system.

Significantly improved solubility of small molecule drugs in vivo

Some small molecule drugs, although highly active, are often difficult to dissolve in water and have high toxicity, making it difficult to be used as needles or injections for the human body, such as camptothecin, paclitaxel, etc. As PEG derivatives have good water solubility, PEGylated small molecule drugs can be quickly dissolved in water and then safely absorbed by the human body. Movantik™ was the first PEGylated small molecular drug approved by the FDA in 2014 as an opioid antagonist, which carrys a PEG moiety with size of less than 1 kDa. 

▶ Increases the hydrophilicity of the drug : Increases the solubility of small molecule drugs and decreases the glomerular filtration rate;

▶ Increases the relative molecular weight of the drug : Small molecule drugs have a small relative molecular weight and are very easily filtered out of the body by the human kidney. Small molecule drugs have a small molecular weight and are easily excreted by the kidneys. Low concentrations of small molecule drugs in the human body result in insignificant drug effects, while high concentrations of small molecule drugs cause strong side effects in the human body. PEGylated small molecule drugs have increased relative molecular weights, and a single injection can maintain the effective drug concentration in the body for a longer period of time, enabling effective drug concentration to be maintained in the lesion continuously between drug administration, and improving the safety of the drug.

Significantly enhance in vivo targeting of biologic drug delivery platforms (LNPs)

PEGylated drug delivery platforms are cutting-edge applications of PEG in the pharmaceutical field, especially in siRNA drug delivery. In 2018, the first PEGylated siRNA therapeutic, Onpattro, was approved by FDA. 

siRNA drugs have relatively large molecular weights and are negatively charged, making them less likely to cross cell membranes to exert their effects. Moreover, they are easily degraded by enzymes and acids, resulting in poor stability. PEGylated polymeric nanoparticles can improve the membrane penetration efficiency of siRNA drugs, thus increasing the concentration of drugs in the cell and efficiently treating diseases.

▶ Passive targeting: PEGylation alters the adsorption of protein crowns on the surface of liposomes, significantly prolongs the blood circulation time of liposomes, improves the biodistribution of drugs, and achieves passive targeting of tumors by exploiting the enhanced permeability and retention (EPR) effect at tumor sites;

▶ Active targeting: PEG can be linked to specific targets to improve drug targeting and realize active targeting.

Figure 3. Passive and active targeting [2]

Challenges

Anti-PEG antibodies

Recent studies challenge the historical perception of PEG as biologically inert, revealing 20%–70% of individuals without known PEG exposure possess anti-PEG antibodies. Daily exposure to PEG in products like cosmetics leads to pre-existing anti-PEG antibodies in many. This phenomenon contributes to reported loss of therapeutic efficacy in PEGylated treatments, inducing immune responses that accelerate blood clearance and reduce half-life. Hypersensitivity reactions, observed in PEGylated drugs like Jivi™ and Doxil®, underscore risks associated with PEG components. PEG-related allergic reactions, noted in Pfizer/BioNTech BNT162b2 and Moderna mRNA-1273 vaccines, involve symptoms such as hives and anaphylaxis.

Heterogeneity of PEGylated drugs

PEGylation has advanced considerably in three decades, progressing from random multi-PEGylation to precise site-specific applications with varied PEG types. Yet, persistent challenges remain. The polydisperse nature of commercial PEGs, spanning broad molecular weights, impacts PEGylated therapies, amplifying heterogeneity if multiple PEGs randomly attach. This diversity leads to batch variability, affecting crucial properties like solubility, clearance rates, posing manufacturing and regulatory hurdles. The pursuit of high molecular weight monodisperse PEGs, crucial for homogenous PEGylated therapeutics, emerges as a pressing goal, albeit limited availability in commercial low-weight variants, marking a pivotal focus in recent PEGylation research.

Conclusion

In the future, PEGylation will remain pivotal for new therapeutic agents, not just extending half-lives but offering broader benefits. Macromolecular drug expansion—proteins, peptides—and emerging LNP encapsulated mRNA therapies will propel the field. PEGylation's role in novel therapies like immunotherapies, combinational therapeutic agents on a single PEG molecule, is crucial. Progress hinges on synthesizing varied monodispersed PEGs and existing clinical-grade PEG products and chemistries. Ultimately, PEGylation promises immense innovation in therapeutic development, backed by advancements in diverse PEG architectures and established clinical practices.

Huateng Pharma, as a leading PEG linker supplier, can provide you with both polydispersed PEGs, monodispersed PEGs and multi-arm PEGs for your drug PEGylation need. We are ISO 9001 and EXCiPACT GMP certified, contact us at sales@huatengusa.com for your PEG inquiries. 

References:
[1] Gao, Y, Joshi, M, Zhao, Z, Mitragotri, S. PEGylated therapeutics in the clinic. Bioeng Transl Med. 2023; 1-28. doi:10.1002/btm2.10600
[2] Prajna Mishra, Bismita Nayak, R.K. Dey, PEGylation in anti-cancer therapy: An overview, Asian Journal of Pharmaceutical Sciences, Volume 11, Issue 3, 2016, Pages 337-348, ISSN 1818-0876, https://doi.org/10.1016/j.ajps.2015.08.011.

Related Articles:

What Are PEG Linkers and Their Applications?

PEG Hydrogels in Medical Devices

Lipid Nanoparticles (LNP) for mRNA Drug Delivery

The Role of Helper Lipids in Lipid Nanoparticles