共查询到20条相似文献,搜索用时 15 毫秒
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Peiyan Yuan Xin Mao Xiaofeng Wu Si Si Liew Lin Li Shao Q. Yao 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(23):7739-7743
Mitochondria are key organelles in mammalian cells whose dysfunction is linked to various diseases. Drugs targeting mitochondrial proteins provide a highly promising strategy for potential therapeutics. Methods for the delivery of small‐molecule drugs to the mitochondria are available, but these are not suitable for macromolecules, such as proteins. Herein, we report the delivery of native proteins and antibodies to the mitochondria using biodegradable silica nanoparticles (BS–NPs). The modification of the nanoparticle surface with triphenylphosphonium (TPP) and cell‐penetrating poly(disulfide)s (CPD) facilitated their rapid intracellular uptake with minimal endolysosomal trapping, providing sufficient time for effective mitochondrial localization followed by glutathione‐triggered biodegradation and of native, functional proteins into the mitochondria. 相似文献
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《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(41):12655-12659
Antibodies are important biopharmaceuticals, but almost all existing antibody‐based drugs are limited to targeting antigens located at the cell exterior because of the inability of antibodies to enter the cell interior. Available methods for intracellular delivery of antibodies have major shortcomings. Herein, we report an approach to encapsulate native antibodies in a biodegradable silica nanoquencher (BS‐qNP), which could undergo efficient cellular uptake and intracellular degradation to release antibodies only under hypoxic conditions. By coating the surface of BS‐qNP with cell‐penetrating poly(disulfide)s (CPD), the delivered antibodies (or other proteins) avoided endolysosomal trapping. Doping of the silica coating with a fluorescent dye and a dark hole quencher further endowed BS‐qNP with hypoxia‐responsive fluorescence turn‐on property. Our antibody delivery system thus provides the first platform capable of stable encapsulation, efficient uptake, on‐demand antibody release, and imaging of release/cell state. 相似文献
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《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(47):15159-15163
A four‐membered oxygen ring (oxetane) can be readily grafted into native peptides and proteins through site‐selective bis‐alkylation of cysteine residues present as disulfides under mild and biocompatible conditions. The selective installation of the oxetane graft enhances stability and activity, as demonstrated for a range of biologically relevant cyclic peptides, including somatostatin, proteins, and antibodies, such as a Fab arm of the antibody Herceptin and a designed antibody DesAb‐Aβ against the human Amyloid‐β peptide. Oxetane grafting of the genetically detoxified diphtheria toxin CRM197 improves significantly the immunogenicity of this protein in mice, which illustrates the general utility of this strategy to modulate the stability and biological activity of therapeutic proteins containing disulfides in their structures. 相似文献
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《Helvetica chimica acta》2017,100(3)
Cell‐penetrating poly(disulfide)s (CPD s) have been introduced recently to explore new ways to enter into cells. In this report, we disclose a general method to covalently modify the sidechains of CPD s. Compatibility of copper‐catalyzed alkyne‐azide cycloaddition (CuAAC ) with the addition of either strained cyclic disulfides of varied ring tension or increasing numbers of guanidinium and phosphonium cations is demonstrated. Reloading CPD s with disulfide ring tension results in an at least 20‐fold increase in activity with preserved sensitivity toward inhibition with the Ellman 's reagent. The cumulation of permanent positive charges by sidechain engineering affords Ellman‐insensitive CPD s with similarly increased activity. Co‐localization experiments indicate that the CPD s reach endosomes, cytosol and nucleus, depending on their nature and their concentration. Supported by pertinent controls, these trends confirm that CPD s operate with combination of counterion‐ and thiol‐mediated uptake, and that the balance between the two can be rationally controlled. For the most active CPD s, uptake can be observed at substrate (fluorophore) concentrations as low as 5 nm . 相似文献
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Annemiek Uvyn Ruben DeCoen Mandy Gruijs Cees W. Tuk Jana DeVrieze Marjolein vanEgmond Bruno G. DeGeest 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(37):13122-13127
Binding of monoclonal antibodies (mAbs) onto a cell surface triggers antibody‐mediated effector killing by innate immune cells through complement activation. As an alternative to mAbs, synthetic systems that can recruit endogenous antibodies from the blood stream to a cancer cell surface could be of great relevance. Herein, we explore antibody‐recruiting polymers (ARPs) as a novel class of immunotherapy. ARPs consist of a cell‐binding motif linked to a polymer that contains multiple small molecule antibody‐binding motifs along its backbone. As a proof of concept, we employ a lipid anchor that inserts into the phospholipid cell membrane and make use of a polymeric activated ester scaffold onto which we substitute dinitrophenol as an antibody‐binding motif. We demonstrate that ARPs allow for high avidity antibody binding and drive antibody recruitment to treated cells for several days. Furthermore, we show that ARP‐treated cancer cells are prone to antibody‐mediated killing through phagocytosis by macrophages. 相似文献
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Marc‐Andr Kasper Andreas Stengl Philipp Ochtrop Marcus Gerlach Tina Stoschek Dominik Schumacher Jonas Helma Martin Penkert Eberhard Krause Heinrich Leonhardt Christian P. R. Hackenberger 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(34):11757-11762
Requirements for novel bioconjugation reactions for the synthesis of antibody–drug conjugates (ADCs) are exceptionally high, since conjugation selectivity as well as the stability and hydrophobicity of linkers and payloads drastically influence the performance and safety profile of the final product. We report Cys‐selective ethynylphosphonamidates as new reagents for the rapid generation of efficacious ADCs from native non‐engineered monoclonal antibodies through a simple one‐pot reduction and alkylation. Ethynylphosphonamidates can be easily substituted with hydrophilic residues, giving rise to electrophilic labeling reagents with tunable solubility properties. We demonstrate that ethynylphosphonamidate‐linked ADCs have excellent properties for next‐generation antibody therapeutics in terms of serum stability and in vivo antitumor activity. 相似文献
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Justin T. Huckaby Christina L. Parker Tim M. Jacobs Alison Schaefer Daniel Wadsworth Alexander Nguyen Anting Wang Jay Newby Samuel K. Lai 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(17):5660-5664
Mucus represents a major barrier to sustained and targeted drug delivery to mucosal epithelium. Ideal drug carriers should not only rapidly diffuse across mucus, but also bind the epithelium. Unfortunately, ligand‐conjugated particles often exhibit poor penetration across mucus. In this work, we explored a two‐step “pretargeting” approach through engineering a bispecific antibody that binds both cell‐surface ICAM‐1 and polyethylene glycol (PEG) on the surface of nanoparticles, thereby effectively decoupling cell targeting from particle design and formulation. When tested in a mucus‐coated Caco‐2 culture model that mimics the physiological process of mucus clearance, pretargeting increased the amount of PEGylated particles binding to cells by around 2‐fold or more compared to either non‐targeted or actively targeted PEGylated particles. Pretargeting also markedly enhanced particle retention in mouse intestinal tissues. Our work underscores pretargeting as a promising strategy to improve the delivery of therapeutics to mucosal surfaces. 相似文献