Polymers Interfacing with Biology

The development of various controlled radical polymerization techniques as well as site- and residue specific strategies to modify peptides/proteins with synthetic polymers have made polymer chemistry a powerful tool to address materials problems at the biology interface. This article will present recent examples for bioactive surface modification and polymer therapeutics; it will highlight the use of controlled radical polymerization techniques and bioconjugation strategies to develop surface coatings for regenerative medicine and diagnostics, respectively, polymer-based nanomedicines

Structural transformations in poly(di-n-alkylsiloxane)s with alkyl side groups containing 7 to 10 carbon atoms

Temperature dependent X-ray diffraction studies of poly(di-n-alkylsiloxane)s substituted with side chains containing 7 to 10 carbon atoms have been carried out in order to elucidate the crystalline structure of these materials. In contrast to their lower substituted homologues, no evidence for the presence of a hexagonal columnar mesophase could be found for the investigated materials. At low temperatures, far below the melting temperature, the polysiloxane backbones are assumed to pack in an orthorhombic lattice, with the n-alkyl side chains in a planar all-trans conformation and oriented perpendicularly to the backbone. The paraffinic n-alkyl side chains were found to crystallize in an orthorhombic lattice. The thermal behaviour of the investigated materials has been observed to show an odd-even effect. Whereas poly(di-n-heptylsiloxane) and poly(di-n-nonylsiloxane) were found to melt in a single step, an intermediate state of order was observed for poly(di-n-octylsiloxane) and poly(di-n-decylsiloxane) upon heating from the crystalline to the isotropic state. For this intermediate state, a pseudohexagonal packing of the n-alkyl side chains is proposed

Hydrosilylation of 1-alkenes with dichlorosilane

Symmetrically and unsymmetrically substituted diorganodichlorosilanes have been prepared by hydrosilylation with dichlorosilane using two different platinum catalysts, i.e., hexachloroplatinic acid (Speier's catalyst) and a platinum cyclovinylmethylsiloxane complex. Hydrosilylation of unsubstituted 1-alkenes proved to be very efficient, yielding anti-Markonikov substituted di-n-alkyldichlorosilanes. However, no reaction was observed when electron-deficient 1-alkenes were used. Octacarbonyldicobalt enabled formation of the monoadduct of 1H,1H,2H-perfluoro-1-hexene with dichlorosilane, which was employed in a second hydrosilylation of the olefin. Thus, the anti-Markovnikov diadduct was obtained in 40% overall yield. The two-step synthesis has also been applied successfully to obtain unsymmetrically substituted diorganodichlorosilanes containing nitrile and ether groups

Synthesis and Optical Properties of Water-Soluble NIR Absorbing Star Polypeptides based on Functional Rylene Dyes

Summary : In this contribution, the synthesis of two novel amino-functionalized terrylene and quaterrylene diimide derivatives is described. These chromophores have been used as initiators for the ring-opening polymerization of Nɛ-benzyloxycarbonyl-L-lysine N-carboxyanhydride. 4-Arm star polypeptides were obtained with number average chain lengths of 50 and 100 units. Removal of the Nɛ-benzyloxycarbonyl side-chain protective groups afforded unprecedented water-soluble terrylene and quaterrylene based star polypeptides that combined high extinction coefficients in the NIR range with very good chemical and photostabilit

Assessment of transferrin recycling by Triplet Lifetime Imaging in living cells

An optical method is presented that allows the measurement of the triplet lifetime of a fluorescent molecule. This is a characteristic specific to each fluorophore. Based on differences in triplet lifetimes of two fluorescent species (autofluorescence versus label), this novel approach measures relative quantities of a transmembrane receptor and associated fluorescently labeled ligand during its recycling in living cells. Similarly to fluorescence-lifetime based methods, our approach is almost insensitive to photobleaching. A simple theory for unmixing two known triplet lifetimes is presented along with validation of the method by measurements of transferrin recycling in a model system based on chinese hamster ovarian cells (CHO). Transferrin is the delivery carrier for Fe3+ to the cell

Synthesis and Postpolymerization Modification of Fluorine-End-Labeled Poly(Pentafluorophenyl Methacrylate) Obtained via RAFT Polymerization

Chain-end-labeled polymers are interesting for a range of applications. In polymer nanomedicine, chain-end-labeled polymers are useful to study and help understand cellular internalization and intracellular trafficking processes. The recent advent of fluorescent label-free techniques, such as nanoscale secondary ion mass spectrometry (NanoSIMS), provides access to high-resolution intracellular mapping that can complement information obtained using fluorescent-labeled materials and confocal microscopy and flow cytometry. Using poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA) as a prototypical polymer nanomedicine, this paper presents a synthetic strategy to polymers that contain trace element labels, such as fluorine, which can be used for NanoSIMS analysis. The strategy presented in this paper is based on reversible addition fragmentation chain transfer (RAFT) polymerization of pentafluorophenyl methacrylate (PFMA) mediated by two novel chain-transfer agents (CTAs), which contain either one (alpha) or two (alpha,omega) fluorine labels. In the first part of this study, via a number of polymerization experiments, the polymerization properties of the fluorinated RAFT CTAs were established. F-19 NMR spectroscopy revealed that these fluorinated RAFT agents possess unique spectral signatures, which allow to directly monitor RAFT agent conversion and measure end-group fidelity. Comparison with 4-cyanopentanoic acid dithiobenzoate, which is a standard CTA for the RAFT polymerization of PFMA, revealed that the introduction of one or two fluorine labels does not significantly affect the polymerization properties of the CTA. In the last part of this paper, a proof-of-concept study is presented that demonstrates the feasibility of the fluorine-labeled poly(pentafluorophenyl methacrylate) polymers as platforms for the postpolymerization modification to generate PHPMA-based polymer nanomedicines

Controlled release from a mechanically-stimulated thermosensitive self-heating composite hydrogel

Temperature has been extensively explored as a trigger to control the delivery of a payload from environment-sensitive polymers. The need for an external heat source only allows limited spatiotem- poral control over the delivery process. We propose a new approach by using the dissipative properties of a hydrogel matrix as an internal heat source when the material is mechanically loaded. The system is comprised of a highly dissipative hydrogel matrix and thermo-sensitive nanoparticles that shrink upon an increase in temperature. Exposing the hydrogel to a cyclic mechanical loading for a period of 5 min leads to an increase of temperature of the nanoparticles. The concomitant decrease in the volume of the nanoparticles increases the permeability of the hydrogel network facilitating the release of its payload. As a proof-of-concept, we showed that the payload of the hydrogel is released after 5e8 min following the initiation of the mechanical loading. This delivery method would be particularly suited for the release of growth factor as it has been shown that cell receptor to growth factor is activated 5e20 min following a mechanical loading

Site-Specific Polymer Attachment to HR2 Peptide Fusion Inhibitors against HIV-1 Decreases Binding Association Rates and Dissociation Rates Rather Than Binding Affinity

A popular strategy for overcoming the limited plasma half-life of peptide heptad repeat 2 (HR2) fusion inhibitors against HIV-1 is conjugation with biocompatible polymers such as poly(ethylene glycol) (PEG). However, despite improved resistance to proteolysis and reduced renal elimination, covalent attachment of polymers often causes a loss in therapeutic potency. In this study, we investigated the molecular origins of the loss in potency upon conjugation of linear, midfunctional, and hyperbranched PEG-like polymers to peptides that inhibit HIV-1 host cell membrane fusion. Fluorescence binding assays revealed that polymer conjugation imparted mass transport limitations that manifested as coexistent slower association and dissociation rates from the gp41 target on HIV-1. Furthermore, reduced association kinetics rather than affinity disruption was responsible for the loss in antiviral potency. Finally, the binding assays indicated that the unmodified HR2-derived peptide demonstrated diffusion-limited binding. The observed high potency of the unmodified peptide in HIV-1 inhibition assays was therefore attributed to rapid peptide conformational changes upon binding to the gp41 prehairpin structure. This study emphasizes that the view in which polymer ligation to therapeutic peptides inadvertently leads to loss in potency due to a loss in binding affinity requires scientific verification on a case-by-case basis and that high peptide potency may be due to rapid target binding events

Influence of Block versus Random Monomer Distribution on the Cellular Uptake of Hydrophilic Copolymers

The use of polymers has revolutionized the field of drug delivery in the past two decades. Properties such as polymer size, charge, hydrophilicity, or branching have all been shown to play an important role in the cellular internalization of polymeric systems. In contrast, the fundamental impact of monomer distribution on the resulting biological properties of copolymers remains poorly studied and is always only investigated for biologically active self-assembling polymeric systems. Here, we explore the fundamental influence of monomer distribution on the cellular uptake of nonaggregating and biologically passive copolymers. Reversible addition-fragmentation chain-transfer (RAFT) polymerization was used to prepare precisely defined copolymers of three hydrophilic acrylamide monomers. The cellular internalization of block copolymers was compared with the uptake of a random copolymer where monomers are statistically distributed along the chain. The results demonstrate that monomer distribution in itself has a negligible impact on copolymer uptake