ABSTRACT
Multivalent glycodendrimers make promising tools to tackle the basic and translational research in the field of carbohydrate-mediated interactions. Despite advances in glycodendrimers and glycopolymers, the multivalent probes available to date are still far from being ideal biological mimics. This work demonstrates the inherent chirality of glycodendrimers to be one of the promising factors to generate different spatial carbohydrate micro-environments to modulate specific carbohydrate-protein interactions. By exploiting the host-guest strategy, chiral Ru(ii) complexes (Δ and Λ) and mannose capped ß-cyclodextrin (ß-CD), we generated a library of homologous metallo-glycodendrimers (MGDs) with sizes of 50-70 nm. These nanoclusters can enantioselectively bind to specific C-type lectins and displayed selectivity in cellular uptake. We also discovered their potential clathrin-mediated endocytotic pathway in DC-SIGN and SIGNR3-transfected cell lines. Finally, in vivo biodistribution and sequestration of MGDs was determined to understand the role of chirality mediated spatial arrangement in carbohydrate-mediated interactions.
Subject(s)
Carbohydrates/chemistry , Lectins, C-Type/chemistry , Nanostructures , Ruthenium , Animals , Cell Line , Dendrimers/chemistry , HeLa Cells , Humans , Mannose/chemistry , Mice , Molecular Structure , Tissue Distribution , beta-Cyclodextrins/chemistryABSTRACT
A host-guest interaction between Ru(ii)-complexes and sugar-capped ß-cyclodextrin was employed to synthesize metalloglycodendrimers. These glycodendrimers demonstrated selective carbohydrate-protein interactions and controlled the delivery of the Ru(ii) complexes into cancer cells, which may facilitate cell-specific apoptosis. Lectin binding assay revealed micromolar range IC50 values with different plant lectins. Cell viability assay and confocal imaging studies of Ru(ii) complexes exhibited cytotoxic activities in cancer cells compared to normal cells with IC50 values close to other literature Ru(ii) complexes. The cell death inducer was found to accumulate favorably to the endoplasmic reticulum (ER) and induced ER stress in cells. The upregulation of CHOP, caspase-3 and caspase-12 disturbed the ER morphology initiating the apoptosis pathway.
Subject(s)
Dendrimers/chemistry , Drug Carriers/chemistry , Lectins/metabolism , Organometallic Compounds/chemistry , Organometallic Compounds/metabolism , Ruthenium/chemistry , beta-Cyclodextrins/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum Stress/drug effects , HeLa Cells , Hep G2 Cells , Humans , Mice , Models, Molecular , Molecular Conformation , NIH 3T3 Cells , Organometallic Compounds/pharmacologyABSTRACT
Advances in shape-dependent nanoparticle (NP) research have prompted a close scrutiny of the behaviour of nanostructures in vitro and in vivo. Data pertaining to cellular uptake and site specific sequestration of different shapes of NPs will undoubtedly assist researchers to design better nano-probes for therapeutic and imaging purposes. Herein, we investigated the shape dependent uptake of glyco-gold nanoparticles (G-AuNPs) in different cancer cell lines. Specifically, we have compared the behaviour of spherical, rod and star AuNPs with mannose and galactose conjugations. In vitro experiments showed that the rod-AuNPs exhibited the highest uptake over that of the star and spherical counterparts. Further, an investigation of the mechanism of the uptake clearly demonstrated clathrin mediated endocytosis of the specific G-AuNPs. These results reveal the benefits of different G-AuNP shapes in carbohydrate-mediated interactions.
Subject(s)
Endocytosis , Gold , Metal Nanoparticles , Animals , Galactose/chemistry , HeLa Cells , Humans , Lectins/chemistry , Mannose/chemistry , Mice , NIH 3T3 Cells , Proteins/chemistryABSTRACT
Perfluoro undecanoyl chain conjugated peptide nucleic acids (PNAs) show 2.5 to 3 fold higher cellular uptake efficiency in NIH 3T3 and HeLa cells compared to simple undecanoyl PNAs. Fluorination of PNAs leads to the formation of lower size (â¼100-250 nm) nanoparticles compared to larger size (â¼500 nm) nanoparticles from non-fluorinated PNAs, thereby improving the efficiency of cell penetration.
