Structural and biological characterization of anticancer nickel(II) bis(benzimidazole) complex

In the present study, nickel(II) complex with 2-[2-[2-(1H-benzimidazol-2-yl)ethylsulfanyl]ethyl]-1H-benzimidazole (tebb) of formula [Ni(tebb)](ClO) has been prepared and its structure was proved by X-ray crystallography. The central nickel atom is in deformed octahedral vicinity. Four nitrogen atoms of two ligands form plane of octahedral and sulfur atoms are in apical positions. Perchlorate anions are outside the coordination sphere. The coordination compound was tested for its biological activities in an array of in vitro assays. It was found that the synthesized complex possesses interesting biological activity, which is most likely related to its cell-type related uptake kinetics. The synthesized complex is readily uptaken by malignant MDA-MB-231 and CACO-2 cells with the lowest uptake by healthy Hs27 fibroblasts. The lowest IC values were obtained for MDA-MB-231 cells (5.2–12.7 μM), highlighting exceptional differential cytotoxicity (IC values for healthy fibroblasts were 38.6–51.5 μM). Furthermore, it was found the complex is capable to cause hydrolytic DNA cleavage, promotes an efficient DNA fragmentation and to trigger an extensive formation of intracellular reactive oxygen species. Overall, current work presents a synthesis of Ni(II) coordination compound with interesting biological behavior and with a promising potential to be further tested in pre-clinical models.Financial support from CEITEC 2020 (LQ1601), ERDF “Multidisciplinary research to increase application potential of nanomaterials in agricultural practice” (No. CZ.02.1.01/0.0/0.0/16_025/0007314) and Palacky University Olomouc project IGA_PrF_2020_016 is gratefully acknowledged

Komplexní mechanismus cytotoxicity svazků anodických samo-organizovaných TiO2 nanotrubic

The present study reports on a comprehensive investigation of mechanisms of in vitro cytotoxicity of high aspect ratio (HAR) bundles formed from anodic TiO2 nanotube (TNT) layers. Comparative cytotoxicity studies were performed using two types of HAR TNTs (diameter of similar to 110 nm), differing in initial thickness of the nanotubular layer (similar to 35 mu m for TNTs-1 vs. similar to 10 mu m for TNTs-2). Using two types of epithelial cell lines (MDA-MB-231, HEK-293), it was found that nanotoxicity is highly cell-type dependent and plausibly associates with higher membrane fluidity and decreased rigidity of cancer cells enabling penetration of TNTs to the cell membrane towards disruption of membrane integrity and reorganization of cytoskeletal network. Upon penetration, TNTs dysregulated redox homeostasis followed by DNA fragmentation and apoptotic/necrotic cell death. Both TNTs exhibited haemolytic activity and rapidly activated polarization of RAW 264.7 macrophages. Throughout the whole study, TNTs-2 possessing a lower aspect ratio manifested significantly higher cytotoxic effects. Taken together, this is the first report comprehensively investigating the mechanisms underlying the nanotoxicity of bundles formed from self-organised 1-D anodic TNT layers. Except for description of nanotoxicity of industrially-interesting nanomaterials, the delineation of the nanotoxicity paradigm in cancer cells could serve as solid basis for future efforts in rational engineering of TNTs towards selective anticancer nanomedicine.Tato studie představuje komplexní výzkum mechanizmu in vitro cytotoxicity svazků anodických vrstev TiO2 nanotrubic (TNT). Komparativní studie byly realizována s dvěma typy svazků se stejným nominálním průreme trubic (cca 110 nm), ale rozdílnou tloušťkou původních vrstev trubic: 35 mikrometrů pro TNTs-1 a 10 mikrometrů pro TNTs-2. S využitím dvou buněčných linií (MDA-MB-231, HEK-293) bylo zjištěno, že nanotoxicita je velmi závislá na použité bunečné linii a je pravděpodobně závislá od difuzních vlastností rakovinových buněčných membrán. Svazkům TNT je umožněno penetrovat tyto membrány směrem k porušení jejich celistvosti a reorganizaci cytoskeletálních sítí. Oba typy TNT svazků vykazují hemolytickou aktivitu a rapidně aktivují polarizaci RAW 264.7 makrofágů. V celé studii vykazovali svazky TNTs-2, které mají nižší poměr délky trubic vůči jejich průměru, o něco vyšší cytotoxický efekt. Toto je první report, který se uceleně zabývá mechanismem nanotoxicity svazků nanotrubic TiO2. Kromě popisu toxicity těchto aplikačně velmi zajímavých nanomateriálů, náčrt paradigmat toxicity rakovinových buněk by mohl sloužit jako pevná základna pro další optimalizaci využití TNT vrstev pro selektivní protirakovinovou nanomedicínu

Surface-PASylation of ferritin to form stealth nanovehicles enhances in vivo therapeutic performance of encapsulated ellipticine

Surface functionalisations substantially influence the performance of drug delivery vehicles by improving their biocompatibility, selectivity and circulation in bloodstream. Herein, we present the study of in vitro and in vivo behaviour of a highly potent cytostatic alkaloid ellipticine (Elli) encapsulated in internal cavity of ferritin (FRT)-based nanocarrier (hereinafter referred to as FRTElli). In addition, FRTElli surface was functionalised with three different molecular coatings: two types of protective PAS peptides (10- or 20-residues lengths) with sequences comprising amino acids proline (P), alanine (A) and serine (S) (to form PAS-10-FRTElli or PAS-20-FRTElli, respectively), or polyethylene glycol (PEG-FRTElli). All three surface modifications of FRT disposed sufficient encapsulation efficiency of Elli with no premature cumulative release of cargo. Noteworthy, all tested surface modifications displayed beneficial effects on the in vitro biocompatibility. PAS-10-FRTElli exhibited markedly reduced uptake by macrophages compared to PAS-20-FRTElli, PEG-FRTElli or unmodified FRTElli. The exceptional properties of PAS-10-FRTElli were validated by an array of in vitro analyses including formation of protein corona, uptake efficiency or screenings of selectivity of cytotoxicity. In murine preclinical model bearing triple-negative breast cancer (MDA-MB-231) xenograft, compared to free Elli or FRTElli, PAS-10-FRTElli displayed enhanced accumulation of Elli within tumour tissue, while hampering the uptake of Elli into off-target tissues. Noteworthy, PAS-10-FRTElli led to decreased in vivo complement (C3) activation and protein corona formation. Taken together, presented in vivo results indicate that PAS-10-FRTElli represents a promising stealth platform for translation into clinical settings.info:eu-repo/semantics/publishedVersio