Multi-Functional Poly(ethylene glycol)

Poly(ethylene glycol) is well-known for its use in pharmaceutical and biomedical applications. Its desirable characteristics like excellent solubility in aqueous and organic media, biocompatibility and flexibility of the main chain have made PEG the "gold standard" over the last decades. The major drawback for many of its applications results from the fact that PEG possesses no functional groups at the polyether chain. However, its functionality can be systematically increased by copolymerization of ethylene oxide with appropriate functional epoxide monomers, resulting in tailored multi-functional PEG (mf-PEG). These functional groups cannot only be used for (reversible) conjugation of therapeutics, but also to systematically manipulate PEG's properties, while preserving its desired characteristics. For example, by incorporating hydrophobic epoxide comonomers, a lower critical solution temperature (LCST) in water below 100 °C can be obtained. The LCST can be tuned by type and ratio of the incorporated comonomer. Especially copolymers with cloud points between 25 °C and 45 °C are of high interest for drug delivery applications and cosmetics. Temperature-responsivity can be combined with pH- or redox-sensitive properties by introducing amino- or ferrocene-groups, respectively, leading to "smart PEG". In summary, mf-PEGs represent a powerful platform for pharmaceutical purposes, catalysis and surface modification.


Figure 1: Overview of selected mf-PEGs

References

Reviews

[1] "Die vielen Gesichter des Poly(ethylenglykol)s" C. Dingels, M. Schömer, H. Frey, Chemie in unserer Zeit 2011, 45, 338–349. DOI: 10.1002/ciuz.201100551.
[2] "Multifunctional Poly(ethylene glycol)s" B. Obermeier, F. Wurm, C. Mangold, H. Frey, Angew. Chem. Int. Ed. 2011, 50, 7988–7997. DOI: 10.1002/anie.201100027.
[3] "Functional PEG-based polymers with reactive groups via anionic ROP of tailor-made epoxides" C. Mangold, F. Wurm, H. Frey, Polym. Chem. 2012, 3, 1714. DOI: 10.1039/c2py00489e.
[4] "Polymerization of Ethylene Oxide, Propylene Oxide, and Other Alkylene Oxides: Synthesis, Novel Polymer Architectures, and Bioconjugation" J. Herzberger, K. Niederer, H. Pohlit, J. Seiwert, M. Worm, F. R. Wurm, H. Frey, Chem. Rev. 2016, 116, 2170–2243. DOI: 10.1021/acs.chemrev.5b00441.

Hydroxyl-functional PEG

[5] "Functional Poly(ethylene glycol)”: PEG-Based Random Copolymers with 1,2-Diol Side Chains and Terminal Amino Functionality" C. Mangold, F. Wurm, B. Obermeier, H. Frey, Macromolecules 2010, 43, 8511–8518. DOI: 10.1021/ma1015352.
[6] "Hetero-Multifunctional Poly(ethylene glycol) Copolymers with Multiple Hydroxyl Groups and a Single Terminal Functionality" C. Mangold, F. Wurm, B. Obermeier, H. Frey, Macromol. Rapid Commun. 2010, 31, 258–264. DOI: 10.1002/marc.200900472.
[7] "From an epoxide monomer toolkit to functional PEG copolymers with adjustable LCST behavior" C. Mangold, B. Obermeier, F. Wurm, H. Frey, Macromol. Rapid Commun. 2011, 32, 1930–1934. DOI: 10.1002/marc.201100489.

Allyl-functional PEG (for Click-chemistry)

[8] "PEG-based Multifunctional Polyethers with Highly Reactive Vinyl-Ether Side Chains for Click-Type Functionalization" C. Mangold, C. Dingels, B. Obermeier, H. Frey, F. Wurm, Macromolecules 2011, 44, 6326–6334. DOI: 10.1021/ma200898n.
[9] "From an epoxide monomer toolkit to functional PEG copolymers with adjustable LCST behavior" C. Mangold, B. Obermeier, F. Wurm, H. Frey, Macromol. Rapid Commun. 2011, 32, 1930–1934. DOI: 10.1002/marc.201100489.
[10] "Poly(ethylene glycol-co-allyl glycidyl ether)s: A PEG-based modular synthetic platform for multiple bioconjugation" B. Obermeier, H. Frey, Bioconjugate Chem. 2011, 22, 436–444. DOI: 10.1021/bc1004747.
[11] "Graft Copolymers with Complex Polyether Structures: Poly(ethylene oxide)- graft -Poly(isobutyl vinyl ether) by Combination of Living Anionic and Photoinduced Cationic Graft Polymerization" M. U. Kahveci, C. Mangold, H. Frey, Y. Yagci, Macromol. Chem. Phys. 2014, 215, 566–571. DOI: 10.1002/macp.201300794.

Amine-functional PEG

[12] "Amino Functional Poly(ethylene glycol) Copolymers via Protected Amino Glycidol" B. Obermeier, F. Wurm, H. Frey, Macromolecules 2010, 43, 2244–2251. DOI: 10.1021/ma902245d.
[13] "From an epoxide monomer toolkit to functional PEG copolymers with adjustable LCST behavior" C. Mangold, B. Obermeier, F. Wurm, H. Frey, Macromol. Rapid Commun. 2011, 32, 1930–1934. DOI: 10.1002/marc.201100489.
[14] "How Structure-Related Collapse Mechanisms Determine Nanoscale Inhomogeneities in Thermoresponsive Polymers" D. Kurzbach, M. Schömer, V. S. Wilms, H. Frey, D. Hinderberger, Macromolecules 2012, 45, 7535–7548. DOI: 10.1021/ma3014299.
[15] "N,N -Diallylglycidylamine: A Key Monomer for Amino-Functional Poly(ethylene glycol) Architectures" V. S. Reuss, B. Obermeier, C. Dingels, H. Frey, Macromolecules 2012, 45, 4581–4589. DOI: 10.1021/ma300292m.
[16] "Thermoresponsive copolymers of ethylene oxide and N,N-diethyl glycidyl amine: Polyether polyelectrolytes and PEGylated gold nanoparticle formation" V. S. Reuss, M. Werre, H. Frey, Macromol. Rapid Commun. 2012, 33, 1556–1561. DOI: 10.1002/marc.201200307.
[17] "Impact of Amino-Functionalization on the Response of Poly(ethylene glycol) (PEG) to External Stimuli" D. Kurzbach, V. S. Wilms, H. Frey, D. Hinderberger, ACS Macro Lett. 2013, 2, 128–131. DOI: 10.1021/mz300596r.
[18] "Aminofunctional polyethers: Smart materials for applications in solution and on surfaces" V. S. Wilms, H. Frey, Polym. Int. 2013, 62, 849–859. DOI: 10.1002/pi.4496.

Ferrocene-functional PEG

[19] "Ferrocenyl Glycidyl Ether: A Versatile Ferrocene Monomer for Copolymerization with Ethylene Oxide to Water-Soluble, Thermoresponsive Copolymers" C. Tonhauser, A. Alkan, M. Schömer, C. Dingels, S. Ritz, V. Mailänder, H. Frey, F. R. Wurm, Macromolecules 2013, 46, 647–655. DOI: 10.1021/ma302241w.