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Antibody–drug conjugates (ADCs) are promising alternatives to naked antibodies for selective drug‐delivery applications and treatment of diseases such as cancer. Construction of ADCs relies upon site‐selective, efficient and mild conjugation technologies. The choice of a chemical linker is especially important, as it affects the overall properties of the ADC. We envisioned that hydrophilic bifunctional chemical linkers based on carbohydrates would be a useful class of derivatization agents for the construction of linker–drug conjugates and ADCs. Herein we describe the synthesis of carbohydrate‐based derivatization agents, glycolinker–drug conjugates featuring the tubulin inhibitor monomethyl auristatin E and an ADC based on an anti‐EGFR antibody. In addition, an initial in vitro cytotoxicity evaluation of the individual components and the ADC is provided against EGFR‐positive cancer cells.  相似文献   
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DNA is considered to be a promising biomolecule as a template and scaffold for arranging and organizing functional molecules on the nanoscale. The construction and evaluation of DNAs containing multiple functional molecules that are useful for optoelectronic devices and sensors has been studied. In this paper we report the efficient incorporation of perylenediimide (PDI) units into DNA by using abasic sites both as binding sites and as reactive sites and the construction of PDI stacks within the DNA structure, accomplished through the preorganization of the PDI units in the hydrophobic pocket within the DNA. Our approach could become a valuable method for construction of DNA/chromophore hybrid structures potentially useful for the design of DNA‐based devices and biosensors.  相似文献   
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Microbial transglutaminase (MTG) was stably solid‐phase immobilized on glass microbeads by using a second‐generation dendronized polymer. Immobilized MTG enabled the efficient generation of site‐specifically conjugated proteins, including antibody fragments, as well as whole antibodies through distinct glutamines and, unprecedentedly, also through lysines with various bifunctional substrates with defined stoichiometries. With this method, we generated dual, site‐specifically modified antibodies comprising a fluorescent probe and a metal chelator for radiolabeling—a strategy anticipated to design antibodies for imaging and simultaneous therapy. Furthermore, we provide evidence that immobilized MTG features higher siteselectivity than soluble MTG.  相似文献   
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Nanotechnology seeks to mimic what nature has achieved: self‐assembly at the nanometer scale. Viral nanoparticles (VNPs) provide natural examples of self‐assembled architectures with unique structural and chemical properties. Here, the utilization of an archaeal virus, Sulfolobus islandicus rod‐shaped virus 2 (SIRV2), as a template for site‐selective and spatially controlled bioconjugation is described. SIRV2 is a virus of a hyperthermophilic and acidophilic host, the archaeon S. islandicus growing optimally at 80 °C and pH 3, and is thus, by its nature, an extremely stable VNP. The stability of SIRV2 in different solvent/water mixtures is monitored, and it is found that in other, non‐natural harsh conditions the VNPs also remained intact. Further, the question of whether the particles offer attachment sites allowing for selective chemical modification and decoration with functional ligands using biotin as a probe is addressed. It is found that carboxylate‐, carbohydrate‐ and amine‐selective chemistries are applicable and various biotinylated SIRV2 formulations can be fabricated. Depending on the chemistry and hence attachment site used, the display of the biotin labels can be spatially controlled at the virus body and at the ends. Labeling studies also provide novel insights into the structural properties of SIRV2, indicating that the major coat protein (CP) forms the virus body while the minor CP is located in the tail fibers at the end of the particles. Overall, SIRV2 represents an extremely stable and structurally interesting VNP with the potential for novel nanobiotechnological applications.  相似文献   
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Covalently bound azide on a (small) organic molecule or a (large) biomolecular structure has proven an important handle for bioconjugation. Azides are readily introduced, small, and stable, yet undergo smooth ligation with a range of reactive probes under mild conditions. In particular, the potential of azides to undergo metal‐free reactions with strained unsaturated systems has inspired the development of an increasing number of reactive probes, which are comprehensively summarized here. For each individual probe, the synthetic preparation is described, together with reaction kinetics and the full range of applications, from materials science to glycoprofiling. Finally, a qualitative and quantitative comparison of azido‐reactive probes is provided.  相似文献   
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Systematic characterisation of the reactivity of the lysine moieties in CRM197 towards N‐hydroxysuccinimide linkers bearing alkynes or azides is described. This involves two‐step conjugation of various glycans to CRM197 by click chemistry in a well‐defined manner. By semiquantitative LC‐MS/MS analysis of proteolytic digests of the conjugates formed, the reactivity of lysine residues in the protein was mapped and ranked. Computational analysis of the solvent accessibility of each lysine residue (based on the CRM197 crystal structure) established a correlation between reactivity and surface exposure. By this approach, conjugation involving lysine residues (normally a random process) can be controlled. It enables the preparation of lysine‐mediated glycoconjugates with improved batch‐to‐batch reproducibility, thereby producing neo‐glycoconjugates with more‐consistent biological activity.  相似文献   
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Fluorogenic oligonucleotide probes allow mRNA imaging in living cells. A key challenge is the cellular delivery of probes. Most delivery agents, such as cell-penetrating peptides (CPPs) and pore-forming proteins, require interactions with the membrane. Charges play an important role. To explore the influence of charge on fluorogenic properties and delivery efficiency, we compared peptide nucleic acid (PNA)- with DNA-based forced intercalation (FIT) probes. Perhaps counterintuitively, fluorescence signaling by charged DNA FIT probes proved tolerant to CPP conjugation, whereas CPP–FIT PNA conjugates were affected. Live-cell imaging was performed with a genetically engineered HEK293 cell line to allow the inducible expression of a specific mRNA target. Blob-like features and high background were recurring nuisances of the tested CPP and lipid conjugates. By contrast, delivery by streptolysin-O provided high enhancements of the fluorescence of the FIT probe upon target induction. Notably, DNA-based FIT probes were brighter and more responsive than PNA-based FIT probes. Optimized conditions enabled live-cell multicolor imaging of three different mRNA target sequences.  相似文献   
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Fluorescent nanodiamonds (FNDs) are promising bioimaging probes compared with other fluorescent nanomaterials such as quantum dots, dye‐doped nanoparticles, and metallic nanoclusters, due to their remarkable optical properties and excellent biocompatibility. Nevertheless, they are prone to aggregation in physiological salt solutions, and modifying their surface to conjugate biologically active agents remains challenging. Here, inspired by the adhesive protein of marine mussels, encapsulation of FNDs within a polydopamine (PDA) shell is demonstrated. These PDA surfaces are readily modified via Michael addition or Schiff base reactions with molecules presenting thiol or nitrogen derivatives. Modification of PDA shells by thiol terminated poly(ethylene glycol) (PEG‐SH) molecules to enhance colloidal stability and biocompatibility of FNDs is described. Their use as fluorescent probes for cell imaging is demonstrated; it is found that PEGylated FNDs are taken up by HeLa cells and mouse bone marrow‐derived dendritic cells and exhibit reduced nonspecific membrane adhesion. Furthermore, functionalization with biotin‐PEG‐SH is demonstrated and long‐term high‐resolution single‐molecule fluorescence based tracking measurements of FNDs tethered via streptavidin to individual biotinylated DNA molecules are performed. This robust polydopamine encapsulation and functionalization strategy presents a facile route to develop FNDs as multifunctional labels, drug delivery vehicles, and targeting agents for biomedical applications.  相似文献   
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