Boronate cross-linked ATP- and pH-responsive nanogels for intracellular delivery of anticancer drugs.
A novel adenosine-5'-triphosphate (ATP) and pH dual-responsive degradable nanogel (NG) system are developed based on the complexation of 1,2-diols in dendritic polyglycerol (dPG), and boronic acids, which are conjugated with dPG as the macromolecular cross-linker. The NG is formed by a mild and surfactant-free inverse nanoprecipitation method. An anticancer drug, methotrexate (MTX), is coprecipitated with the macromolecular precursors and cross-linkers to form MTX-loaded NG (NG-MTX) with a loading capacity of 13 wt%. The size of NG is controllable from 100 to 300 nm, which is suitable for the enhanced permeation and retention (EPR) effect and can be degraded into small fragments that are within the clearance limitation in the presence of 5 × 10(-3) m ATP or at pH 4 after 24 h. Increasing ATP concentrations and decreasing pH values of the release medium accelerate the release of MTX. Both the real-time cell analysis (RTCA) and MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) results show no cytotoxic effect of NG and a dose-dependent effect of NG-MTX on HeLa cells as well as MCF-7 cells. The fluorescein isothiocyanate (FITC)-labeled NG (FITC-NG) exhibits a time-dependent intracellular uptake tendency and cell organelle permeability as determined by confocal laser scanning microscopy (CLSM) or flow cytometry.
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 3, 14195, Berlin, Germany.
Xuejiao
X
Zhang
Katharina
K
Achazi
Rainer
R
Haag
D000255:Adenosine Triphosphate / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000737:chemistry*; D016923:Cell Death / Q000187:drug effects; D011232:Chemical Precipitation; D003432:Cross-Linking Reagents / Q000737:chemistry*; D016503:Drug Delivery Systems; D000067493:Dynamic Light Scattering; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D061986:MCF-7 Cells; D008727:Methotrexate / Q000494:pharmacology; D000080385:Nanogels; D010316:Particle Size; D010539:Permeability / Q000187:drug effects; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000633:toxicity; D011094:Polyethyleneimine / Q000737:chemistry* / Q000633:toxicity
D000970:Antineoplastic Agents; D001897:Boronic Acids; D003432:Cross-Linking Reagents; D000080385:Nanogels; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D000255:Adenosine Triphosphate; D011094:Polyethyleneimine; D008727:Methotrexate
ATP-responsiveness; organelle permeation; pH degradation; polyglycerol nanogels