A multistimuli-responsive transient supramolecular polymerization of β-sheet-encoded dendritic peptide monomers in water is presented. The amphiphiles, which contain glutamic acid and methionine, undergo a glucose oxidase catalyzed, glucose-fueled transient hydrogelation in response to an interplay of pH and oxidation stimuli, promoted by the production of reactive oxygen species (ROS). Adjusting the enzyme and glucose concentration allows tuning of the assembly and the disassembly rates of the supramolecular polymers, which dictate the stiffness and transient stability of the hydrogels. The incorporation of triethylene glycol chains introduces thermoresponsive properties to the materials. We further show that repair enzymes are able to reverse the oxidative damage in the methionine-based thioether side chains. Since ROS play an important role in signal transduction cascades, our strategy offers great potential for applications of these dynamic biomaterials in redox microenvironments.
A modular route to prepare functional self-assembling dendritic peptide amphiphiles decorated with mannosides, to effectively target antigen-presenting cells, such as macrophages, is reported. The monomeric building blocks were equipped with tetra(ethylene glycol)s (TEGs) or labeled with a Cy3 fluorescent probe. Experiments on the uptake of the multifunctional supramolecular particles into murine macrophages (Mφs) were monitored by confocal microscopy and fluorescence-activated cell sorting. Mannose-decorated supramolecular polymers trigger a significantly higher cellular uptake and distribution, relative to TEG carrying bare polymers. No cytotoxicity or negative impact on cytokine production of the treated Mφs was observed, which emphasized their biocompatibility. The modular nature of the multicomponent supramolecular polymer coassembly protocol is a promising platform to develop fully synthetic multifunctional vaccines, for example, in cancer immunotherapy.
Tumor-associated macrophages (TAMs) promote the immune suppressive microenvironment inside tumors and are, therefore, considered as a promising target for the next generation of cancer immunotherapies. To repolarize their phenotype into a tumoricidal state, the Toll-like receptor 7/8 agonist imidazoquinoline IMDQ is site-specifically and quantitatively coupled to single chain antibody fragments, so-called nanobodies, targeting the macrophage mannose receptor (MMR) on TAMs. Intravenous injection of these conjugates result in a tumor-and cell-specific delivery of IMDQ into MMR high TAMs, causing a significant decline in tumor growth. This is accompanied by a repolarization of TAMs towards a pro-inflammatory phenotype and an increase in anti-tumor T cell responses. Therefore, the therapeutic benefit of such nanobody-drug conjugates may pave the road towards effective macrophage re-educating cancer immunotherapies.
Enhancing the immunogenicity of an antitumour vaccine still poses a major challenge. It depends upon the selected antigen and the mode of its presentation. We here describe a fully synthetic antitumour vaccine, which addresses both aspects. For the antigen, a tumour-associated MUC1 glycopeptide as B-cell epitope was synthesised and linked to the immunostimulating T-cell epitope P2 derived from tetanus toxoid. The MUC1-P2 conjugate is presented multivalently on a hyperbranched polyglycerol to the immune system. In comparison to a related vaccine of lower multivalency, this vaccine exposing more antigen structures on the hyperbranched polymer induced significantly stronger immune responses in mice and elicited IgG antibodies of distinctly higher affinity to epithelial tumour cells.
The endothelial glycoprotein MUC1 is known to underlie alterations in cancer by means of aberrant glycosylation accompanied by changes in morphology. The heavily shortened glycans induce a collapse of the peptide backbone and enable accessibility of the latter to immune cells, rendering it a tumor-associated antigen. Synthetic vaccines based on MUC1 tandem repeat motifs, comprising tumor-associated 2,3-sialyl-T antigen, conjugated to the immunostimulating tetanus toxoid, are reported herein. Immunization with these vaccines in a simple water/oil emulsion produced a strong immune response in mice to which stimulation with complete Freund's adjuvant (CFA) was not superior. In both cases, high levels of IgG1 and IgG2a/b were induced in C57BL/6 mice. Additional glycosylation in the immunodominant PDTRP domain led to improved binding of the induced antisera to MCF-7 breast tumor cells, compared with that of the monoglycosylated peptide vaccine.
We report the sequential growth of supramolecular copolymers on gold surfaces, using oppositely charged dendritic peptide amphiphiles. By including water-solubilising thermoresponsive chains in the monomer design, we observed non-linear effects in the temperature-dependent sequential growth. The step-wise copolymerisation process is characterised using temperature dependent SPR and QCM-D measurements. At higher temperatures, dehydration of peripheral oligoethylene glycol chains supports copolymer growth due to more favourable comonomer interactions. Both monomers incorporate methionine amino acids but remarkably, desorption of the copolymers via competing sulphur gold interactions with the initial monomer layer is not observed. The surface-confined supramolecular copolymers remain kinetically trapped on the metal surface at near neutral pH and form viscoelastic films with a tuneable thickness.
Glycopeptide supramolecular polymers displaying multivalent carbohydrates are particularly suitable for immune-relevant biomaterials, due to the important functions of carbohydrates in mediating cell-cell communication and modulating immune responses. However, the diversity and complexity of carbohydrates limited the generation of glycopeptide supramolecular monomers. Thereby, a modular platform of presenting various carbohydrates, especially more complex oligosaccharides, is highly desirable but remains underexplored. Here, we first prepared the linear amphiphilic glycopeptides that self-assembled into spherical nanoparticles and worm-like nanoparticles. Furthermore, the dendritic glycopeptides that self-assembled into uniform nanorods were designed to generate modular supramolecular polymers with variable functionality, via redesigning the molecular backbone. With various functional oligosaccharide-modified supramolecular polymers, the in vitro studies further indicated that these polymers were not cytotoxic to macrophages, and significantly modulated the production of proinflammatory cytokines. These findings provide a promising platform to develop supramolecular glycopeptide biomaterials with potential applications in immunomodulation and immunotherapy.
Wirs tellen eine durchm ehrfache Stimuli ansprechbare transiente supramolekulare Polymerisation von b-Faltblatt-kodierten dendritischen Peptidmonomeren in Wasser vor. Die Glutaminsäure-und Methionin-tragenden Amphiphile gehen eine durch Glucose-Oxidase katalysierte und Glucosegetriebene transiente Hydrogelierung ein. Diese basiert auf einem Zusammenspiel eines pH-und oxidativen Stimulus,der durch die Produktion reaktiver Sauerstoffspezies (ROS)g efçrdert wird. Mit Veränderung der Enzym-und Glucosekonzentration wird eine Feineinstellung der Assemblierungs-sowie Disassemblierungsgeschwindigkeit vorgenommen, wodurch die Steifigkeit und Stabilitätd es transienten Hydrogels bestimmt wird. Die Verwendung von Triethylenglycolketten führt zu thermoresponsiven Eigenschaften der Materialien. Weiterhin zeigen wir,dass Reparaturenzyme den oxidativen Schaden in den Methionin-basierten Thioetherseitenketten beheben kçnnen. Da reaktive Sauerstoffspezies eine wichtige Rolle in Signaltransduktionskaskadens pielen, bietet unsere Strategie großes Potential zur Anwendung dieser dynamischen Biomaterialien in redoxaktiven Mikroumgebungen.
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