No abstract

Methods to stabilize and retain enzyme activity in the gastrointestinal tract are investigated rarely because of the difficulty of protecting proteins from an environment that has evolved to promote their digestion. Preventing the degradation of enzymes under these conditions, however, is critical for the development of new protein-based oral therapies. Here we show that covalent conjugation to polymers can stabilize orally administered therapeutic enzymes at different locations in the gastrointestinal tract. Architecturally and functionally diverse polymers are used to protect enzymes sterically from inactivation and to promote interactions with mucin on the stomach wall. Using this approach the in vivo activity of enzymes can be sustained for several hours in the stomach and/or in the small intestine. These findings provide new insight and a firm basis for the development of new therapeutic and imaging strategies based on orally administered proteins using a simple and accessible technology.

We investigate the linear rheology of welldefined dendronized polymers (DPs). They consist of polymethacrylate backbones with tree-like branches (dendrons) of different generations, from zeroth to fourth, grafted at each monomer and a methyleneoxycarbonyl spacer between the polymerizable group and the dendritic substituent. The degrees of polymerization for the different generation polymers are almost constant, allowing for systematic studies as a function of generation. Because of the synthetic approach, these macromolecules possess tert-butoxycarbonyl (Boc) groups which promote hydrogen bonding, whereas the benzene groups allow for weaker bonding (π-stacking) as well. The master curves of frequency-dependent storage and loss moduli of these macromolecular structures were obtained via time− temperature superposition of dynamic frequency sweeps at various temperatures. To access slow relaxations, creep measurements were performed at long times and converted to frequency-dependent moduli. For the first generation, it was possible to detect relaxation processes suggesting an approach to the terminal regime (flow). On the other hand, the zeroth and second to fourth generation polymers exhibited a solid-like behavior throughout a wide range of frequencies. The fast relaxations reflect the coupling of segmental friction and hydrogen bonding and render the WLF-type analysis nontrivial. On the basis of the molecular structure of these unique materials as revealed by molecular dynamics simulations and complementary studies with their linear analogues poly(methyl methacrylate) and poly(tert-butyl)methacrylate, we propose that DPs resemble weakly interpenetrating elongated core−shell systems. As generation increases, their enhanced rigidity and intermolecular hydrogen bonding, which occurs primarily toward the outer surface of the DPs, appear to dominate the dynamics. PG0 is not a DP and has an open structure that promotes intermolecular bonding. These results provide design guidelines for ultrahigh-molecular-weight responsive polymers with possibilities for multifunctional substitution and tailoring Frheological response from liquid-like to solid-like.

Classical theory predicts that branching defects are unavoidable in large dendritic molecules when steric congestion is important. Here we report first experimental evidence of this effect via labelling measurements of an extended homologous series of generations g ¼ 1y6 of dendronized polymers. This system exhibits a single type of defect interrogated specifically by the Sanger reagent thus permitting to identify the predicted upturn in the number of branching defects when g approaches g max and the polymer density approaches close packing. The average number of junctions and defects for each member of the series is recursively obtained from the measured molar concentrations of bound labels and the mass concentrations of the dendritic molecules. The number of defects increases at g ¼ 5 and becomes significant at g ¼ 6 for dendronized polymers where the g max was estimated to occur at 6.1 rg max r 7.1. The combination of labelling measurements with the novel theoretical analysis affords a method for characterizing high g dendritic systems.

Despite a growing interest in two-dimensional polymers, their rational synthesis remains a challenge. The solution-phase synthesis of a two-dimensional polymer is reported. A DNA-based monomer self-assembles into a supramolecular network, which is further converted into the covalently linked two-dimensional polymer by anthracene dimerization. The polymers appear as uniform monolayers, as shown by AFM and TEM imaging. Furthermore, they exhibit a pronounced solvent responsivity. The results demonstrate the value of DNA-controlled self-assembly for the formation of two-dimensional polymers in solution.

Several applications require strong noncovalent adhesion of polymers to substrates. Graft and branched polymers have proven superior to linear polymers, but the molecular mechanism is still unclear. Here, this question is addressed on the single molecule level with an atomic force microscopy (AFM) based method. It is determined how the presence of side chains and their molecular architecture influence the adhesion and the mobility of polymers on solid substrates. Surprisingly, the adhesion of mobile polymers cannot significantly be improved by side chains or their architecture. Only for immobile polymers a significantly higher maximum rupture force for graft, bottle-brush, and branched polymers compared to linear chains is measured. Our results suggest that a combination of polymer architecture and strong molecular bonds is necessary to increase the polymer-surface contact area. An increased contact area together with intrachain cohesion (e.g., by entanglements) leads to improved polymer adhesion. These findings may prove useful for the design of stable polymer coatings.

The sixth generation (g = 6) dendronized polymer (DP) PG6 was synthesized on a 2 g scale with P n ∼ 500 in 60% chemical yield and with a coverage degree of 87−90% using a recently developed "n + 2" approach from its structurally virtually perfect, deprotected g = 4 congener dePG4. This synthesis represents the first fully reliable access to a g = 6 representative of this DP series and was therefore used for the synthesis of two higher generation representatives, the g = 7 and g = 8 DPs, PG7 and PG8, which are the highest g DPs ever reported. The structure perfection of the obtained DPs was analyzed by the conventional UV-labeling method and compared with the results from TGA, with which the amount of cleaved-off Boc-protecting groups was quantified. The accuracy of the TGA method was assessed as ±3% by using a Boc-containing dendron and well-characterized low generation DPs as reference. For the high generation DPs obtained by "n + 2" approach the TGA results confirmed the UV-determined coverages. For PG7, the TGA result slightly exceeds the error range (3.3%), which may suggest a possible overestimation of the coverage determined by UV quantification. AFM imaging shows a so far uncommon inhomogeneous appearance for PG7 and PG8, which may be a result of structural defects in both DPs.

The synthesis of one-dimensional tubular polymers via a preorganization-polymerization approach is presented. Prior to polymerization, photo-reactive monomers self-assemble into one-dimensional tubular structures in aqueous medium. The supramolecular polymers are subsequently converted into covalent polymers by light-induced anthracene dimerization.