Cleavable Polyethylene Glycol: 3,4-Epoxy-1-butene as a Comonomer to Establish Degradability at Physiologically Relevant pH.

Polyethylene glycol (PEG) has been used for decades to improve the pharmacokinetic properties of protein drugs, and several PEG-protein conjugates are approved by the FDA. However, the nondegradability of PEG restricts its use to a limiting molecular weight to permit renal excretion. In this work, we introduce a simple strategy to overcome the nondegradability of PEG by incorporating multiple pH-sensitive vinyl ether moieties into the polyether backbone. Copolymerization of 3,4-epoxy-1-butene (EPB) with ethylene oxide via anionic ring-opening polymerization (AROP) provides access to allyl moieties that can be isomerized to pH-cleavable propenyl units (isoEPB). Well-defined P(EPB-co-EG) copo…

Polyether-Based Lipids Synthesized with an Epoxide Construction Kit: Multivalent Architectures for Functional Liposomes

N,N-Diallylglycidylamine: A Key Monomer for Amino-Functional Poly(ethylene glycol) Architectures

The first application of N,N-diallylglycidylamine (DAGA) as a monomer for anionic ring-opening polymerization is presented. The monomer is obtained in a one-step procedure using epichlorohydrin and N,N-diallylamine. Both random and block copolymers consisting of poly(ethylene glycol) and poly(N,N-diallylglycidylamine) with adjusted DAGA ratios from 2.5 to 24% have been prepared, yielding well-defined materials with low polydispersities (Mw/Mn) in the range 1.04–1.19. Molecular weights ranged between 2600 and 10 300 g mol–1. Isomerization of allylamine to enamine structures during polymerization depending on time, temperature, and counterion has been realized. The kinetics of the formation o…

PEG-based Multifunctional Polyethers with Highly Reactive Vinyl-Ether Side Chains for Click-Type Functionalization

Introduction of highly reactive vinyl ether moieties along a poly(ethylene-glycol) (PEG) backbone has been realized by copolymerization of the novel epoxide monomer ethoxy vinyl glycidyl ether (EVGE) with ethylene oxide (EO). A series of copolymers with varying structure (block and random) as well as EVGE comonomer content (5-100%) with molecular weights in the range of 3,900-13,200 g/mol and narrow molecular weight distributions (M-w/M-n = 1.06-1.20) has been synthesized and characterized with respect to their microstructure and thermal properties. The facile transformation of the vinyl ether side chains in click type reactions was verified by two different post polymerization modification…

Ferrocenyl Glycidyl Ether: A Versatile Ferrocene Monomer for Copolymerization with Ethylene Oxide to Water-Soluble, Thermoresponsive Copolymers

The first ferrocene-containing epoxide monomer, ferrocenyl glycidyl ether (fcGE), is introduced. The monomer has been copolymerized with ethylene oxide (EO). This leads to electroactive, water-soluble, and thermoresponsive poly(ethylene glycol) (PEG) derived copolyethers. Anionic homo- and copolymerization of fcGE with EO was possible. Molecular weights could be varied from 2000 to 10 000 g mol–1, resulting in polymers with narrow molecular weight distribution (Mw/Mn = 1.07–1.20). The ferrocene (fc) content was varied from 3 to 30 mol %, obtaining water-soluble materials up to 10 mol % incorporation of the apolar ferrocenyl comonomer. Despite the steric bulk of fcGE, random copolymers were …

Acid‐Labile Amphiphilic PEO‐ b ‐PPO‐ b ‐PEO Copolymers: Degradable Poloxamer Analogs

Poly ((ethylene oxide)-b-(propylene oxide)-b-(ethylene oxide)) triblock copolymers commonly known as poloxamers or Pluronics constitute an important class of nonionic, biocompatible surfactants. Here, a method is reported to incorporate two acid-labile acetal moieties in the backbone of poloxamers to generate acid-cleavable nonionic surfactants. Poly(propylene oxide) is functionalized by means of an acetate-protected vinyl ether to introduce acetal units. Three cleavable PEO-PPO-PEO triblock copolymers (Mn,total = 6600, 8000, 9150 g·mol(-1) ; Mn,PEO = 2200, 3600, 4750 g·mol(-1) ) have been synthesized using anionic ring-opening polymerization. The amphiphilic copolymers exhibit narrow molec…

Branched Acid-Degradable, Biocompatible Polyether Copolymers via Anionic Ring-Opening Polymerization Using an Epoxide Inimer

The introduction of acid-degradable acetal moieties into a hyperbranched polyether backbone has been achieved by the design of a novel epoxide-based degradable inimer. This new monomer, namely, 1-(glycidyloxy)ethyl ethylene glycol ether (GEGE), has been copolymerized in the anionic ring-opening polymerization (AROP) with ethylene oxide (EO) or glycidol (G), respectively, yielding branched polyethers, that is, P(EO-co-GEGE) and P(G-co-GEGE), that possess an adjustable amount of acid-cleavable acetal units. In addition, a novel class of multiarm star copolymers P(G-co-GEGE-g-EO) with acid-labile polyether core and PEG side chains was synthesized by using the P(G-co-GEGE) copolymers as multifu…

Squaric acid mediated chemoselective PEGylation of proteins: reactivity of single-step-activated α-amino poly(ethylene glycol)s.

The covalent attachment of poly(ethylene glycol) (PEG) to therapeutically active proteins (PEGylation) has become an important method to deal with the pharmacological difficulties of these polypeptides, such as short body-residence times and immunogenicity. However, the derivatives of PEG used for PEGylation lack further functional groups that would allow the addition of targeting or labeling moieties. Squaric acid diethyl ester was used for the chemoselective single-step activation of poly(ethylene glycol)s into the respective ester amides. The resultant selective protein-reactive poly(ethylene glycol)s were investigated with respect to their selectivity towards amino acid residues in bovi…

From Biocompatible to Biodegradable: Poly(Ethylene Glycol)s with Predetermined Breaking Points

Poly(ethylene glycol) (PEG) is the gold standard polymer for biomedical applications. PEG is known for its biocompatibility and antifouling properties and is widely used for bioconjugation. However, like other synthetic polymers in the field, PEG is not biodegradable, limiting its use for parenteral formulations and protein conjugation to a molecular weight range with a specific upper limit (commonly 40–60 kDa) to avoid polyether accumulation in human tissue. For these biomedical applications, but also for other purposes such as cleavable hydrogels and templates for porous membranes, several routes for the insertion of in-chain biocleavable moieties, such as acetals or disulfides, into PEG …

Universal Concept for the Implementation of a Single Cleavable Unit at Tunable Position in Functional Poly(ethylene glycol)s

Poly(ethylene glycol) (PEG) with acid-sensitive moieties gained attention particularly for various biomedical applications, such as the covalent attachment of PEG (PEGylation) to protein therapeutics, the synthesis of stealth liposomes, and polymeric carriers for low-molecular-weight drugs. Cleavable PEGs are favored over their inert analogues because of superior pharmacodynamic and/or pharmacokinetic properties of their formulations. However, synthetic routes to acetal-containing PEGs published up to date either require enormous efforts or result in ill-defined materials with a lack of control over the molecular weight. Herein, we describe a novel methodology to implement a single acetalde…

Die vielen Gesichter des Poly(ethylenglykol)s

Poly(ethylenglykol) ist in unserem Leben allgegenwartig. Wir begegnen diesem biokompatiblen und hervorragend wasserloslichen Polymer, meist ohne dass uns dies bewusst ist, in fast allen Bereichen des alltaglichen Bedarfs: Von Haut- und Haarpflegeartikeln, uber Kosmetik- und Styling-Produkten bis hin zu Lebensmitteln und Medikamenten. Selbst in der maritimen Militartechnologie und bei der Konservierung geborgener Kulturguter wird es eingesetzt. Dieser Artikel beschaftigt sich mit der Darstellung, den teils uberraschenden Eigenschaften und der Anwendung dieses strukturell simplen, aber faszinierend vielseitigen Polymers.

Squaric Acid Mediated Synthesis and Biological Activity of a Library of Linear and Hyperbranched Poly(Glycerol)-Protein Conjugates

Polymer-protein conjugates generated from side chain functional synthetic polymers are attractive because they can be easily further modified with, for example, labeling groups or targeting ligands. The residue specific modification of proteins with side chain functional synthetic polymers using the traditional coupling strategies may be compromised due to the nonorthogonality of the side-chain and chain-end functional groups of the synthetic polymer, which may lead to side reactions. This study explores the feasibility of the squaric acid diethyl ester mediated coupling as an amine selective, hydroxyl tolerant, and hydrolysis insensitive route for the preparation of side-chain functional, …

α ,ω n -Heterotelechelic Hyperbranched Polyethers Solubilize Carbon Nanotubes

The synthesis of novel linear-hyperbranched (linhb) polyether block copolymers based on poly(ethylene oxide) and branched poly(glycerol), bearing a single pyrene or myristyl moiety at the α-position of the linear chain is described. The polymers exhibit low polydispersity (M w /M n < 1.3) and controlled molecular weights (M n = 5 000 g·mol -1 ). The mainly hydrophilic block copolymers with multiple hydroxyl end groups readily dissolve multiwalled carbon nanotubes (MWCNTs) in water by mixing and subsequent sonification, resulting in noncovalent attachment of the linhb hybrid structure to the carbon nanotubes (CNTs). Transmission electron microscopy (TEM) was employed to visualize the solubil…