PEGylated therapeutics in the clinic

Abstract

The covalent attachment of polyethylene glycol (PEG) to therapeutic agents, termed PEGylation, is a well‐established and clinically proven drug delivery approach to improve the pharmacokinetics and pharmacodynamics of drugs. Specifically, PEGylation can improve the parent drug's solubility, extend its circulation time, and reduce its immunogenicity, with minimal undesirable properties. PEGylation technology has been applied to various therapeutic modalities including small molecules, aptamers, peptides, and proteins, leading to over 30 PEGylated drugs currently used in the clinic and many investigational PEGylated agents under clinical trials. Here, we summarize the diverse types of PEGylation strategies, the key advantages of PEGylated therapeutics over their parent drugs, and the broad applications and impacts of PEGylation in clinical settings. A particular focus has been given to the size, topology, and functionalities of PEG molecules utilized in clinically used PEGylated drugs, as well as those under clinical trials. An additional section has been dedicated to analyzing some representative PEGylated drugs that were discontinued at different stages of clinical studies. Finally, we critically discuss the current challenges faced in the development and clinical translation of PEGylated agents.

Mechanisms and Barriers in Nanomedicine: Progress in the Field and Future Directions

“…The predominant strategy for reducing undesirable nanobio interactions and stabilizing particles utilizes a "stealth" polyethylene glycol (PEG) coating. 28 High PEGylation density (typically 5 mol % of total lipid, e.g., Doxil) is required for the long-circulating properties of liposomes. On the other hand, some current products, including mRNA vaccines, include lower mol % of PEG 29,30 or no PEGylation at all, which is dictated by the formulation requirements and the desired pharmacokinetics and pharmacodynamics.…”

“…are sometimes so complex, diverse, and susceptible to degradation that identical nanocarriers loaded with two different cargoes may emerge with varying physicochemical and functional characteristics, thus affecting the nanoformulation toxicity and biodistribution. The predominant strategy for reducing undesirable nanobio interactions and stabilizing particles utilizes a “stealth” polyethylene glycol (PEG) coating . High PEGylation density (typically 5 mol % of total lipid, e.g., Doxil) is required for the long-circulating properties of liposomes.…”

A journey through the history of PEGylated drug delivery nanocarriers

“…For example, Couvreur and his colleagues pioneered work on the performance of PEGylated polycyanoacrylate nanoparticles in crossing the blood-brain barrier (BBB). They hypothesized that passive diffusion across the compromised barrier and macrophage exceptions (refer to Table 1 for a non-exclusive list) [32,33]. Particularly noteworthy is the emergence of PEGylated lipid nanoparticles (LNPs) for RNA delivery, notably in mRNA vaccines, representing a significant milestone.…”

Study of uricase-polynorbornene conjugates derived from grafting-from ring-opening metathesis polymerization

“…7–9 As of October 2023, there are 28 FDA approved PEGylated protein therapeutics used for the treatment of diseases such as cancer, diabetes and hepatitis and many more in various stages of development. 10 However, growing instances show clinical evidence of adverse effects attributed mainly to pre-existing anti-PEG antibodies recognizing either the polymer backbone or the methoxy end group of the polymer. 11,12 Studies indicate that up to 72% of humans who have not been treated with PEGylated therapies still have pre-existing anti-PEG antibodies.…”