Home Drug DeliveryPolyethylene Glycol (PEG) Selection Guide

Polyethylene Glycol (PEG) Selection Guide

What is Polyethylene Glycol?

Poly(ethylene glycol) (PEG) is a synthetic, hydrophilic, biocompatible polymer with widespread use in biomedical and other applications. PEGs are synthesized using a ring-opening polymerization of ethylene oxide to produce a broad range of molecular weights and molecular weight distributions (polydispersity); however, discrete PEGs (dPEG^® reagents) are synthesized with a single, specific molecular weight. PEGs can be synthesized in linear, branched, Y-shaped, or multi-arm geometries. PEGs can be activated by the replacement of the terminal hydroxyl end group with a variety of reactive functional end groups enabling crosslinking and conjugation chemistries.

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How is Polyethylene Glycol used?

PEGs are non-toxic, FDA-approved, generally nonimmunogenic, and are frequently used in many biomedical applications including bioconjugation,¹ drug delivery,^2,3 surface functionalization,⁴ and tissue engineering.⁵ Bioconjugation with PEG (also known as PEGylation) is the covalent conjugation of drug targets such as peptides, proteins, or oligonucleotides with PEG for the optimization of pharmacokinetic properties.⁶ In drug delivery, PEGs can be used as linkers for antibody-drug conjugates (ADCs)⁷ or as a surface coating on nanoparticles to improve systemic drug delivery.⁶ PEG hydrogels are water-swollen, three-dimensional, polymer networks resistant to protein adhesion and biodegradation.⁸ PEG hydrogels are produced by crosslinking reactive PEG end groups and are commonly used in tissue engineering and drug delivery.

Find the right PEG for Your Research Application

Four general characteristics are considered when selecting PEGs for bioconjugation, drug delivery and tissue engineering research applications:


Functionality Monofunctional PEGs contain a single chemically-reactive end and are used for PEGylation, surface conjugation, and nanoparticle coating. PEGs containing two reactive ends, which can either have the same (homobifunctional PEG) or different (heterobifunctional PEG) reactive groups are useful for conjugation and crosslinking for hydrogels	Polymer Architecture Linear PEGs are commonly used for PEGylation, bioconjugation, and crosslinking Multi-arm PEGs (4-,6-,8-arm) can be crosslinked into hydrogels and scaffolds for drug delivery or tissue engineering Y-shaped PEGs are typically used for PEGylation, as the branched structure may improve stability in vivo.
Reactivity Covalent conjugation: PEGs with reactive end groups, such as an N-hydroxysuccinimide ester, thiol, or carboxyl group, can be covalently conjugated to corresponding functional groups. The conjugation chemistry chosen determines site of attachment and number of PEGs per molecule. Click chemistry requires PEGs with azide or alkyne reactive groups. Click chemistry is a rapid, selective, and bioorthogonal method for conjugation or hydrogel formation. Polymerization and photopolymerization can be achieved rapidly using acrylate-terminated PEGs under mild reactive conditions	Molecular Weight Bioconjugation: PEGs with molecular weights ≥5 kDa are typically used for conjugation to small molecules, siRNA, and peptides. Low molecular weight PEGs (≤5 kDa) are often used for PEGylation of proteins. Surface conjugation and crosslinking can be completed with PEGs that are < 40 kDa Hydrogel formation: PEG molecular weight will influence the hydrogel mesh size and mechanical properties. Typically, PEGs ≥5 kDa molecular weight are used.

Functionality

Monofunctional PEGs contain a single chemically-reactive end and are used for PEGylation, surface conjugation, and nanoparticle coating.
PEGs containing two reactive ends, which can either have the same (homobifunctional PEG) or different (heterobifunctional PEG) reactive groups are useful for conjugation and crosslinking for hydrogels

Polymer Architecture

Linear PEGs are commonly used for PEGylation, bioconjugation, and crosslinking
Multi-arm PEGs (4-,6-,8-arm) can be crosslinked into hydrogels and scaffolds for drug delivery or tissue engineering
Y-shaped PEGs are typically used for PEGylation, as the branched structure may improve stability in vivo.

Reactivity

Covalent conjugation: PEGs with reactive end groups, such as an N-hydroxysuccinimide ester, thiol, or carboxyl group, can be covalently conjugated to corresponding functional groups. The conjugation chemistry chosen determines site of attachment and number of PEGs per molecule.
Click chemistry requires PEGs with azide or alkyne reactive groups. Click chemistry is a rapid, selective, and bioorthogonal method for conjugation or hydrogel formation.
Polymerization and photopolymerization can be achieved rapidly using acrylate-terminated PEGs under mild reactive conditions

Molecular Weight

Bioconjugation: PEGs with molecular weights ≥5 kDa are typically used for conjugation to small molecules, siRNA, and peptides. Low molecular weight PEGs (≤5 kDa) are often used for PEGylation of proteins.
Surface conjugation and crosslinking can be completed with PEGs that are < 40 kDa
Hydrogel formation: PEG molecular weight will influence the hydrogel mesh size and mechanical properties. Typically, PEGs ≥5 kDa molecular weight are used.

Common functional groups and their corresponding reactive groups are listed in the table below.

⧧N-Hydroxysuccinimide
⤒1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride)
⤓Dicyclohexylcarbodiimide
Functional Groups	Reactive Groups
Primary Amine (–NH₂)	NHS^⧧Ester Aldehyde Anhydride Epoxide	Isocyanate Sulfonyl Chloride Fluorobenzene Imidoester	Carbodiimide Acyl Azide Carbonate Fluorophenyl Ester
Thiol (–SH)	Maleimide Pyridyl disulfide	Haloacetyl Vinylsulfone	Iodoacetyl
Carboxyl (–COOH)	Amines
Carbonyl (–CHO)	Hydrazides	Alkoxyamines

References

Hermanson GT. 2013. Bioconjugate Techniques,. Burlington, Elsevier Science.

Translating Polymer Science for Drug Delivery; PDDT. 2015. Translating Polymer Science for Drug Delivery; . Aldrich Materials Science: Milwaukee, WI,.

Parveen S, Sahoo SK. 2011. Long circulating chitosan/PEG blended PLGA nanoparticle for tumor drug delivery. European Journal of Pharmacology. 670(2-3):372-383. https://doi.org/10.1016/j.ejphar.2011.09.023

Manson J, Kumar D, Meenan BJ, Dixon D. 2011. Erratum to: Polyethylene glycol functionalized gold nanoparticles: the influence of capping density on stability in various media. Gold Bull. 44(3):195-196. https://doi.org/10.1007/s13404-011-0023-8

Fairbanks BD, Schwartz MP, Bowman CN, Anseth KS. 2009. Photoinitiated polymerization of PEG-diacrylate with lithium phenyl-2,4,6-trimethylbenzoylphosphinate: polymerization rate and cytocompatibility. Biomaterials. 30(35):6702-6707. https://doi.org/10.1016/j.biomaterials.2009.08.055

Suk JS, Xu Q, Kim N, Hanes J, Ensign LM. 2016. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Advanced Drug Delivery Reviews. 9928-51. https://doi.org/10.1016/j.addr.2015.09.012

Jain N, Smith SW, Ghone S, Tomczuk B. 2015. Current ADC Linker Chemistry. Pharm Res. 32(11):3526-3540. https://doi.org/10.1007/s11095-015-1657-7

Hoffman AS. 2002. Adv. Drug Deliv. Rev.. 54(1), 3-12.

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