ABSTRACT
The design of novel chelators for therapeutic applications has been the subject of extensive research to address various diseases. Many chelators can manipulate the levels of metal ions within cells and effectively modulate the metal excess. In some cases, chelators show significant toxicity to cells. We investigated polyimidazole ligands by potentiometry and UV-Vis spectroscopy for their ability to form copper(II) complexes. We also compared the antiproliferative activity of the polyimidazole ligands and their copper(II) complexes with polypyridine ligands in CaCo-2 (colorectal adenocarcinoma), SH-SY5Y (neuroblastoma) and K562 (chronic myelogenous leukemia) cells and normal HaCaT (keratinocyte) cells. Polyimidazole ligands are less cytotoxic than their analogous polypyridine ligands. All polyimidazole ligands, except the tetraimidazole ligand for K562 cells, did not show any significant effect on the viability of cancer and normal cells. In contrast, the cytotoxic activity of polypiridine ligands was also observed in normal cells with IC50 values similar to those of cancer cells. Tetraimidazole ligand, the only ligand active on the leukemic K562 cell line, induced caspase-dependent apoptosis and increased intracellular reactive oxygen species production with mitochondrial damage. The low cytotoxicity of the polyimidazole ligands, even if it limits their use as anticancer agents, could make them useful in other medical applications, such as in the treatment of metal overload, microbial infections, inflammation or neurodegenerative disorders.
ABSTRACT
In recent years, nanoparticles based on cyclodextrins have been widely investigated, mainly for drug delivery. In this work, we synthesized nanoparticles with a hyaluronic acid backbone (11â kDa and 45â kDa) functionalized with γ-cyclodextrins. We tested sorafenib in the presence of the new hyaluronan-cyclodextrin conjugates in A2780 (ovarian cancer), SK-HeP-1 (adenocarcinoma) and MDA-MB-453 (breast cancer) cell lines. We found that hyaluronan-cyclodextrin conjugates improve the antiproliferative activity of sorafenib. Remarkably, the system based on the 11â kDa hyaluronan conjugate was the most effective and, in the MDA-MB-453â cell line, significantly reduced the IC50 value of sorafenib cells by about 75 %.
ABSTRACT
In recent years, cyclodextrin polymeric nanoparticles have been designed to introduce new properties and extend their medical applications. Based on the features of cyclodextrins, we derivatized cross-linked cyclodextrin polymers with histidine or carcinine moieties. We found that amylases do not hydrolyze cyclodextrin polymers. The new polymers can form copper(II) complexes and may act as nanochelators to counteract copper(II) dyshomeostasis-related diseases. Furthermore, the copper(II) complexes show superoxide dismutase activity, similar to free carcinine and histidine complexes. The antioxidant biological activity of the copper(II) complex formed inâ situ may protect cells from oxidative damage related to copper dyshomeostasis.
Subject(s)
Carnosine , Cyclodextrins , Copper , Histidine , Antioxidants , Cyclodextrins/pharmacology , Chelating Agents/pharmacologyABSTRACT
Core-shell superparamagnetic iron oxide nanoparticles hold great promise as a theranostic platform in biological systems. Herein, we report the biological effect of multifunctional cyclodextrin-appended SPIONs (CySPION) in mutant Npc1-deficient CHO cells compared to their wild type counterparts. CySPIONs show negligible cytotoxicity while they are strongly endocytosed and localized in the lysosomal compartment. Through their bespoke pH-sensitive chemistry, these nanoparticles release appended monomeric cyclodextrins to mobilize over-accumulated cholesterol and eject it outside the cells. CySPIONs show a high rate of transport across blood-brain barrier models, indicating their promise as a therapeutic approach for cholesterol-impaired diseases affecting the brain.
Subject(s)
Cyclodextrins , Nanoparticles , Cricetinae , Animals , Cricetulus , Precision Medicine , Blood-Brain Barrier , Nanoparticles/therapeutic use , CholesterolABSTRACT
In the last years, nanoparticles based on cyclodextrins have been widely investigated for the delivery of anticancer drugs. In this work, we synthesized nanoparticles with a hyaluronic acid backbone functionalized with cyclodextrins under green conditions. We functionalized hyaluronic acid with two different molecular weights (about 11 kDa and 45 kDa) to compare their behavior as doxorubicin delivery systems. We found that the new hyaluronan-cyclodextrin conjugates increased the water solubility of doxorubicin. Moreover, we tested the antiproliferative activity of doxorubicin in the presence of the new cyclodextrin polymers in SK-N-SH and SK-N-SH-PMA (over-expressing CD44 receptor) cancer cells. We found that hyaluronan-cyclodextrin conjugates improved the uptake and antiproliferative activity of doxorubicin in the SK-N-SH-PMA compared to the SK-N-SH cell line at the ratio 8/1 doxorubicin/polymer. Notably, the system based on hyaluronan (45 kDa) was more effective as a drug carrier and significantly reduced the IC50 value of doxorubicin by about 56%. We also found that hyaluronic acid polymers determined an improved antiproliferative activity of doxorubicin (IC50 values are on average reduced by about 70% of free DOXO) in both cell lines at the ratio 16/1 doxorubicin/polymer.
ABSTRACT
Beta-lactam antibiotics are one of the most commonly used drug classes in managing bacterial infections. However, their use is threatened by the alarming phenomenon of antimicrobial resistance, which represents a worldwide health concern. Given the continuous spread of metallo-ß-lactamases (MBLs) producing pathogens, the need to discover broad-spectrum ß-lactamase inhibitors is increasingly growing. A series of zinc chelators have been synthesized and investigated for their ability to hamper the Zn-ion network of interactions in the active site of MBLs. We assessed the inhibitory activity of new polyimidazole ligands N,N'-bis((imidazol-4-yl)methyl)-ethylenediamine, N,N,N'-tris((imidazol-4-yl)methyl)-ethylenediamine, N,N,N,N'-tetra((imidazol-4-yl-methyl)-ethylenediamine toward three different subclasses B1 MBLs: VIM-1, NDM-1 and IMP-1 by in vitro assays. The activity of known zinc chelators such as 1,4,7,10,13-Pentaazacyclopentadecane, 1,4,8,11-Tetraazacyclotetradecane and 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid was also assessed. Moreover, a molecular docking study was carried to gain insight into the interaction mode of the most active ligands.
Subject(s)
beta-Lactamase Inhibitors , beta-Lactamases , beta-Lactamases/chemistry , Molecular Docking Simulation , beta-Lactamase Inhibitors/pharmacology , beta-Lactamase Inhibitors/chemistry , Ligands , Zinc , Chelating Agents , Anti-Bacterial Agents/pharmacology , Microbial Sensitivity TestsABSTRACT
In the few last years, nanosystems have emerged as a potential therapeutic approach to improve the efficacy and selectivity of many drugs. Cyclodextrins (CyDs) and their nanoparticles have been widely investigated as drug delivery systems. The covalent functionalization of CyD polymer nanoparticles with targeting molecules can improve the therapeutic potential of this family of nanosystems. In this study, we investigated cross-linked γ- and ß-cyclodextrin polymers as carriers for doxorubicin (ox) and oxaliplatin (Oxa). We also functionalized γ-CyD polymer bearing COOH functionalities with arginine-glycine-aspartic or arginine moieties for targeting the integrin receptors of cancer cells. We tested the Dox and Oxa anti-proliferative activity in the presence of the precursor polymer with COOH functionalities and its derivatives in A549 (lung, carcinoma) and HepG2 (liver, carcinoma) cell lines. We found that CyD polymers can significantly improve the antiproliferative activity of Dox in HepG2 cell lines only, whereas the cytotoxic activity of Oxa resulted as enhanced in both cell lines. The peptide or amino acid functionalized CyD polymers, loaded with Dox, did not show any additional effect compared to the precursor polymer. Finally, studies of Dox uptake showed that the higher antiproliferative activity of complexes correlates with the higher accumulation of Dox inside the cells. The results show that CyD polymers could be used as carriers for repositioning classical anticancer drugs such as Dox or Oxa to increase their antitumor activity.
Subject(s)
Antineoplastic Agents/therapeutic use , Cellulose/therapeutic use , Cyclodextrins/therapeutic use , Doxorubicin/therapeutic use , Drug Delivery Systems/methods , Nanoparticles/therapeutic use , Oxaliplatin/therapeutic use , A549 Cells , Amino Acid Motifs , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cellulose/chemistry , Cyclodextrins/chemistry , Doxorubicin/chemistry , Drug Carriers/chemistry , Hep G2 Cells , Humans , Nanoparticles/chemistry , Oxaliplatin/chemistry , beta-Cyclodextrins/chemistry , beta-Cyclodextrins/therapeutic use , gamma-Cyclodextrins/chemistry , gamma-Cyclodextrins/therapeutic useABSTRACT
Over the years, cyclodextrin uses have been widely reviewed and their proprieties provide a very attractive approach in different biomedical applications. Cyclodextrins, due to their characteristics, are used to transport drugs and have also been studied as molecular chaperones with potential application in protein misfolding diseases. In this study, we designed cyclodextrin polymers containing different contents of ß- or γ-cyclodextrin, and a different number of guanidinium positive charges. This allowed exploration of the influence of the charge in delivering a drug and the effect in the protein anti-aggregant ability. The polymers inhibit Amiloid ß peptide aggregation; such an ability is modulated by both the type of CyD cavity and the number of charges. We also explored the effect of the new polymers as drug carriers. We tested the Doxorubicin toxicity in different cell lines, A2780, A549, MDA-MB-231 in the presence of the polymers. Data show that the polymers based on γ-cyclodextrin modified the cytotoxicity of doxorubicin in the A2780 cell line.