In the rapidly evolving multidisciplinary field of polymer therapeutics, tailored polymer structures represent the key constituent to explore and harvest the potential of bioactive macromolecular hybrid structures. In light of the recent developments for anticancer drug conjugates, multifunctional polymers are becoming ever more relevant as drug carriers. However, the potentially best suited polymer, poly(ethylene glycol) (PEG), is unfavorable owing to its limited functionality. Therefore, multifunctional linear copolymers (mf-PEGs) based on ethylene oxide (EO) and appropriate epoxide comonomers are attracting increased attention. Precisely engineered via living anionic polymerization and defined with state-of-the-art characterization techniques-for example real-time (1)H NMR spectroscopy monitoring of the EO polymerization kinetics-this emerging class of polymers embodies a powerful platform for bio- and drug conjugation.

The synthesis of poly(ethylene glycol) (PEG) copolymers with multiple amino functionalities within the chain is described, relying on an epoxide comonomer bearing a protected amino group. N,Ndibenzyl amino glycidol (DBAG) and ethylene oxide (EO) were copolymerized via anionic polymerization, leading to well-defined polymers with varied comonomer content and low polydispersities (M w /M n in the range of 1.1 to 1.2). Subsequent hydrogenolysis with Pearlman's catalyst afforded poly(ethylene glycol-coamino glycerol)s (PEG-co-PAG) with a precisely adjusted number of randomly incorporated amino groups in the range of 2-15%. For the first time, the kinetics of an EO copolymerizations have has been directly monitored by 1 H NMR spectroscopy in real time. Monomer consumption and compositional drift in monomer feed have been studied for various reaction temperatures, revealing a slightly tapered yet random DBAG distribution in the copolymers. The random structure of the copolymers was confirmed by detailed 13 C NMR characterization of EO-and DBAG-centered triad sequence distribution and DSC measurements.

A series of random copolymers comprising ethylene oxide (EO) and 0-100% allyl glycidyl ether (AGE) has been prepared by anionic ring-opening polymerization with molecular weights between 5000 and 13,600 g/mol and polydispersity indices in the range of 1.04-1.19. As key for the homogeneity of the PEG conjugates, real-time ¹H NMR polymerization kinetics, ¹³C NMR analysis of triad sequence distribution, and analysis of the thermal behavior by differential scanning calorimetry (DSC) revealed a distinctive random copolymer structure. Via thiol-ene coupling (TEC), showing mainly "click" characteristics and nearly quantitative yields, PEG derivatives with multiple amino, carboxy, or hydroxy functionalities have been prepared, providing suitable reactivities for further attachment. Without further modification, P(EO-co-AGE)s were conjugated with cysteine or the tripeptide glutathione (GSH) via TEC, resulting in well-defined hybrid materials with multiple peptide units conjugated to the PEG backbone. The results demonstrate superior loading capacity of the copolymers in comparison to the PEG homopolymer.

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 (5À100%) with molecular weights in the range of 3,900À13,200 g/mol and narrow molecular weight distributions (M w /M n = 1.06À1.20) 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 reactions: (i) thiolÀene addition and (ii) acetal formation, employing various model compounds. Both strategies are very efficient, resulting in quantitative conversion. The rapid and complete acetal formation with alcohols results in an acid-labile bond and is thus highly interesting with respect to biomedical applications that require slow or controlled release of a drug, while the thiolÀene addition to a vinyl ether prevents cross-linking efficiently compared to other double bonds.

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 (M w/M n) 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 of the copolymer structure obtained by random copolymerization was investigated, using time-resolved 1H NMR measurements and 13C NMR triad sequence analysis. A tapered character of the monomer incorporation was revealed in the course of the concurrent copolymerization of EO and DAGA. The thermal behavior of the copolymers in both bulk and aqueous solution has been studied, revealing LCSTs in the range 29–94 °C. Quantitative removal of protective groups via double-bond isomerization mediated by Wilkinson’s catalyst and subsequent acidic hydrolysis yielded multiamino-functional PEG copolymers with tapered or block structure. Accessibility of liberated primary amines for further transformation was demonstrated in a model reaction by derivatization with acetic anhydride. In contrast to previous approaches, the DAGA monomer permits the synthesis of block copolymers with PEG block combined with multiamino-functional polyether block.