PEGylation, successful approach to drug delivery

doi:10.1016/S1359-6446(05)03575-0

Drug Discovery Today

Volume 10, Issue 21, 1 November 2005, Pages 1451-1458

https://doi.org/10.1016/S1359-6446(05)03575-0 Get rights and content

PEGylation defines the modification of a protein, peptide or non-peptide molecule by the linking of one or more polyethylene glycol (PEG) chains. This polymer is non-toxic, non-immunogenic, non-antigenic, highly soluble in water and FDA approved. The PEG-drug conjugates have several advantages: a prolonged residence in body, a decreased degradation by metabolic enzymes and a reduction or elimination of protein immunogenicity. Thanks to these favorable properties, PEGylation now plays an important role in drug delivery, enhancing the potentials of peptides and proteins as therapeutic agents.

Section snippets

Amino group modification

In the early days of PEGylation, researchers directed their attention towards the amino groups as suitable conjugation site, because they are the most represented groups in proteins, generally exposed to the solvent and can be modified with a wide selection of chemical strategies.

Several conjugation strategies are now available, such as alkylation, which maintains the positive charge of the starting amino group because a secondary amine is formed, or acylation, accompanied by loss of charge.

Thiol modification

PEGylation at thiol groups of cysteines not involved in disulphide bridges is one of the most specific methods because cysteines are rarely present in proteins or peptides. Some selective thiol PEGylating agents are reported in Table 3. Unfortunately, as a result of its hydrophobicity, cysteine is often buried inside the protein structure and therefore only partially accessible to reagents.

Thiol modification by PEGylation is expanding its potential, thanks to genetic engineering, which allows

Specific PEGylation by enzymes or by reversible protection

The specific conjugation of PEG to the amide group of glutamines or to the hydroxyl group of serines and threonines is only possible under mild conditions using enzymes. There are several naturally occurring enzymes that recognize glutamine as substrate, namely specific or non-specific transglutaminases. Recently, Sato [20] discovered that glutamine in proteins can be the substrate of the transglutaminase enzymes, if an amino PEG is used as the nucleophilic donor. Through a transglutamination

Limitations in the use of PEG

PEG is obtained by chemical synthesis and, like all synthetic polymers, it is polydisperse, which means that the polymer's batch is composed of molecules having different number of monomers, yielding a Gaussian distribution of the molecular weights. This leads to a population of drug conjugates, which might have different biological properties, mainly in body-residence time and immunogenicity. Nowadays, because of the development of synthetic and purification procedures, PEGs on the market are

Improved protein drugs by PEGylation

Several classes of protein drugs, such as enzymes, cytokines and antibodies, are significantly improved by PEGylation [8]. Table 4 compiles the most important examples of protein conjugates, exploiting the advantages of PEGylation and leading to derivatives that are useful for therapy. In general, the improvements are an increased retention time in the body, a reduction of immunogenicity and increased stability towards metabolic enzymes.

Unfortunately, the PEGylation of proteins is often

Small-drug PEGylation

Common problems encountered in the use of small drugs, especially the antitumor ones, are their low solubility, rapid excretion and untargeted biodistribution. All these factors could be addressed by PEGylation. Generally, the properties of PEG are conveyed to the conjugated drugs and their body fate reflects that of the polymer. Increased solubility, modification of pharmacokinetics and targeting have been described, after PEGylation, for important drugs such as taxol, camptothecin, cis

PEG as a diagnostic carrier

In vivo non invasive diagnosis is done by using tracers detected through magnetic resonance or radioactivity. Usually they are administered in a chelated form using compounds that can give specific biodistribution, stability or targeting. Among the chelators used, the macromolecular ones (e.g. polymers, antibodies and recognition proteins) are receiving increase interest. The properties of PEG have also been exploited in diagnostics. In fact, PEGylation increases the body-residence time of

PEG oligonucleotides

Oligonucleotides, mainly antisense oligonucleotides and aptamers, are now under active investigation as new potential drugs because of their extremely high selectivity in target recognition. All of them, however, share the problems of short half-life in vivo because of either low stability towards the eso- and endo-nucleases (present in plasma and inside the cells) or their rapid excretion caused by their small size. Furthermore, their negative charge prevents an easy penetration into the cells.

Conclusions

Many studies and years of PEGylation development have given important theoretical and commercially useful results (Table 4), but many more applications can still be exploited. The products already approved by the FDA are a clear demonstration of the usefulness of PEGylation in the improvement of therapeutic value of drugs. The most relevant advantages are the prolonged body-residence time, which allows less frequent administrations, the increase in stability towards proteases or nucleases and

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Synthesis, physicochemical characterization, and investigation of anti-inflammatory activity of water-soluble PEGylated 1,2,4-Triazoles
2024, Bioorganic Chemistry
A series of water-soluble PEGylated 1,2,4-triazoles 5–8 were successfully synthesized from methyl 5-(chloromethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates 1. All of the water-soluble PEGylated 1,2,4-triazoles were characterized by FT-IR and ¹H NMR spectroscopy. The solubility, in vitro plasma stability, and anti-inflammatory activity were also determined and compared to original methyl 5-(halomethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates. For SAR study, all PEGylated 1,2,4-triazoles 5–8 performed potential anti-inflammatory activity on LPS-induced RAW 264.7 cells (IC₅₀ = 3.42–7.81 μM). Moreover, the western blot result showed PEGylated 1,2,4-triazole 7d performed 5.43 and 2.37 folds inhibitory activity over iNOS and COX-2 expressions. On the other hand, the cell viability study revealed PEGylated 1,2,4-triazoles 7 and 8 with PEG molecular weight more than 600 presented better cell safety (cell viability > 95 %). Through the solubility and in vitro plasma stability studies, PEGylated 1,2,4-triazoles 7a–d exhibited higher hydrophilicity and prolonged 2.01 folds of half-life in compound 7d. Furthermore, the in vivo anti-inflammatory and gastric safety results indicated PEGylated 1,2,4-triazole 7d more effectively decreased the inflammatory response in edema and COX-2 expression and exhibited higher gastric safety than Indomethacin. Following the in vitro and in vivo study results, PEGylated 1,2,4-triazole 7d possessed favorable solubility, plasma stability features, safety, and significant anti-inflammatory activity to become the potential water-soluble anti-inflammatory candidate.
Sustained zero-order release of dexamethasone after incorporation into crosslinked PEG-dendrons using click reactions
2024, Journal of Drug Delivery Science and Technology
Hydrogel-based localised drug delivery minimises systemic side effects and a linear release profile ensuring a sustained drug release over time, crucial for long-term therapy. The current paper describes the use of the Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAc) to append azidified Dexamethasone (Dex) onto dendrons of first- and second-generation PEGs. Crosslinking with thiolated PEGs using either thiol-acrylate or nucleophilic addition reactions yielded gels containing β-thio-ether ester groups that imparted enhanced hydrolytic susceptibility. In vitro gel degradation was followed gravimetrically and expressed as swelling ratios. Thiol-acrylate crosslinked hydrogels exhibited zero-order Dex release kinetics over 11, 27, and 16 days (G1, G1-star, and G2). Crosslinking the G1-gels by nucleophilic addition also resulted in linear release and the end point was reached in 5 days. Hydrolysis was accounted as the main release mechanism for covalently bound Dex, while physically incorporated Dex showed undefined rapid burst or first-order release, with most of the drug released in the initial 1–3 days. Eluates from covalently bound Dex maintained high activity, whereas Trap-Dex gels lost activity over time, as detected by the upregulation of luciferase expression from a transformed cell line. This novel chemistry combination offers precise drug release control applicable beyond Dex to drugs with suitable nucleophilic groups.
Cutting-edge advancements in anticancer drug delivery and scope for theranostics using biocompatible multifunctional mesoporous silica nanoparticles
2024, Journal of Drug Delivery Science and Technology
With the advancement in nanotechnology, treatment of cancer has improved significantly in the past few decades. However, the hunt for exciting new generation of nanocarriers has no end. Mesoporous silica nanoparticles (MSNs), with their distinct properties such as high surface area and pore volume, high drug loading capacity, easy surface functionalization along with good biocompatibility, have emerged as potential nanocarriers, particularly in cancer therapy. This review focuses on the application of MSNs in cancer treatment, initially unfolding the various methods to synthesize MSNs, while tailoring their surface characteristics via functionalization techniques. The paper also covers cancer targeting methodologies in depth, including passive, active, and stimuli-responsive approaches. Along with this, multimodal application of MSNs in theranosis of cancer is also covered. Additionally, the effect of MSNs' physicochemical characteristics and shape on their biocompatibility and toxicity is outlined. Moreover, the article aims to provide an overview of the various methods available for biocompatibility assessment of MSNs, along with the strategies rendering improvement in MSNs biocompatibility. Overall, this article serves as a valuable resource for researchers working in the field of nanomedicine, facilitating the development of effective and safe MSNs-based drug delivery systems for cancer therapy.
Recent progress on polySarcosine as an alternative to PEGylation: Synthesis and biomedical applications
2024, International Journal of Pharmaceutics
Biotherapeutic PEGylation to prolong action of medications has gained popularity over the last decades. Various hydrophilic natural polymers have been developed to tackle the drawbacks of PEGylation, such as its accelerated blood clearance and non-biodegradability. Polypeptoides, such as polysarcosine (pSar), have been explored as hydrophilic substitutes for PEG. pSar has PEG-like physicochemical characteristics such as water solubility and no reported cytotoxicity and immunogenicity. This review discusses pSar derivatives, synthesis, characterization approaches, biomedical applications, in addition to the challenges and future perspectives of pSar based biomaterials as an alternative to PEG.
Treatment-induced and Pre-existing Anti-peg Antibodies: Prevalence, Clinical Implications, and Future Perspectives
2024, Journal of Pharmaceutical Sciences
Polyethylene glycol (PEG) is a versatile polymer that is used in numerous pharmaceutical applications like the food industry, a wide range of disinfectants, cosmetics, and many commonly used household products. PEGylation is the term used to describe the covalent attachment of PEG molecules to nanocarriers, proteins and peptides, and it is used to prolong the circulation half-life of the PEGylated products. Consequently, PEGylation improves the efficacy of PEGylated therapeutics. However, after four decades of research and more than two decades of clinical applications, an unappealing side of PEGylation has emerged. PEG immunogenicity and antigenicity are remarkable challenges that confound the widespread clinical application of PEGylated therapeutics — even those under clinical trials — as anti-PEG antibodies (Abs) are commonly reported following the systemic administration of PEGylated therapeutics. Furthermore, pre-existing anti-PEG Abs have also been reported in healthy individuals who have never been treated with PEGylated therapeutics. The circulating anti-PEG Abs, both treatment-induced and pre-existing, selectively bind to PEG molecules of the administered PEGylated therapeutics inducing activation of the complement system, which results in remarkable clinical implications with varying severity. These include increased blood clearance of the administered PEGylated therapeutics through what is known as the accelerated blood clearance (ABC) phenomenon and initiation of serious adverse effects through complement activation-related pseudoallergic reactions (CARPA). Therefore, the US FDA industry guidelines have recommended the screening of anti-PEG Abs, in addition to Abs against PEGylated proteins, in the clinical trials of PEGylated protein therapeutics. In addition, strategies revoking the immunogenic response against PEGylated therapeutics without compromising their therapeutic efficacy are important for the further development of advanced PEGylated therapeutics and drug-delivery systems.
Improved pharmacokinetics and enhanced efficacy of the vancomycin derivative FU002 using a liposomal nanocarrier
2024, Nanomedicine: Nanotechnology, Biology, and Medicine
Antibiotic resistance still represents a global health concern which diminishes the pool of effective antibiotics. With the vancomycin derivative FU002, we recently reported a highly potent substance active against Gram-positive bacteria with the potential to overcome vancomycin resistance. However, the translation of its excellent antimicrobial activity into clinical efficiency could be hampered by its rapid elimination from the blood stream. To improve its pharmacokinetics, we encapsulated FU002 in PEGylated liposomes. For PEG-liposomal FU002, no relevant cytotoxicity on liver, kidney and red blood cells was observed. Studies in Wistar rats revealed a significantly prolonged blood circulation of the liposomal antibiotic. In microdilution assays it could be demonstrated that encapsulation does not diminish the antimicrobial activity against staphylococci and enterococci. Highlighting its great potency, liposomal FU002 exhibited a superior therapeutic efficacy when compared to the free form in a Galleria mellonella larvae infection model.

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ReviewPEGylation, successful approach to drug delivery

Section snippets

Amino group modification

Thiol modification

Specific PEGylation by enzymes or by reversible protection

Limitations in the use of PEG

Improved protein drugs by PEGylation

Small-drug PEGylation

PEG as a diagnostic carrier

PEG oligonucleotides

Conclusions

Cell

J. Biol. Chem.

Adv. Protein Chem.

Drug Discov. Today

J. Biol. Chem.

J. Biol. Chem.

J. Pediatr.

Adv. Drug Deliv. Rev.

Adv. Drug Deliv. Rev.

Adv. Drug Deliv. Rev.

J. Control. Release

J. Hepatol.

Bioorg. Med. Chem.

Biochem. Biophys. Res. Commun.

J. Control. Release

J. Control. Release

Tetrahedron Lett.

Blood

Transfus. Clin. Biol.

Protein, peptide and non-peptide drug PEGylation for therapeutic application: a review

Exp. Op. Ther. Patents

PEGASPARAGINASE: a review of clinical studies

Adv. Drug Deliv. Rev.

Rational design of a potent, long lasting form of interferon: a 40kDa branched poly-ethylene glycol-conjugated interferon alpha-2a for the treatment of hepatitis C

Bioconjug. Chem.

Characterization and stability of N-terminally pegylated rhG-CSF

Pharm. Res.

Reactive groups of proteins and their modifying agents

Review
PEGylation, successful approach to drug delivery