Zwitterion-Coated Iron Oxide Nanoparticles: Surface Chemistry and Intracellular Uptake by Hepatocarcinoma (HepG2) Cells

Nanoparticles (NPs) have received much attention in recent years for their diverse potential biomedical applications. However, the synthesis of NPs with desired biodistribution and pharmacokinetics is still a major challenge, with NP size and surface chemistry being the main factors determining the behavior of NPs in vivo. Here we report on the surface chemistry and in vitro cellular uptake of magnetic iron oxide NPs coated with zwitterionic dopamine sulfonate (ZDS). ZDS-coated NPs were compared to similar iron oxide NPs coated with PEG-like 2-[2-(2-methoxyethoxy)­ethoxy]­acetic acid (MEEA) to investigate how surface chemistry affects their in vitro behavior. ZDS-coated NPs had a very dense coating, guaranteeing high colloidal stability in several aqueous media and negligible interaction with proteins. Treatment of HepG2 cells with increasing doses (2.5–100 μg Fe/mL) of ZDS-coated iron oxide NPs had no effect on cell viability and resulted in a low, dose-dependent NP uptake, inferior than most reported data for the internalization of iron oxide NPs by HepG2 cells. MEEA-coated NPs were scarcely stable and formed micrometer-sized aggregates in aqueous media. They decreased cell viability for dose ≥50 μg Fe/mL, and were more efficiently internalized than ZDS-coated NPs. In conclusion, our data indicate that the ZDS layer prevented both aggregation and sedimentation of iron oxide NPs and formed a biocompatible coating that did not display any biocorona effect. The very low cellular uptake of ZDS-coated iron NPs can be useful to achieve highly selective targeting upon specific functionalization

Design, Synthesis, and Anti-Breast Cancer Potential of Imidazole–Pyridine Hybrid Molecules <i>In Vitro</i> and Ehrlich Ascites Carcinoma Growth Inhibitory Activity Assessment <i>In Vivo</i>

Breast cancer remains a challenging medical issue and is a high priority for biomedical research despite significant advancements in cancer research and therapy. The current study aims to determine the anticancer activity of a group of imidazole–pyridine-based scaffolds against a variety of breast cancer cell lines differing in their receptor expression (estrogen receptor (ER), progesterone receptor (PR), and HER-2). A series of 10 molecules (coded 5a–5j) were synthesized through multicomponent and alkylation reactions. FTIR, MS, 1H, and 13C NMR spectral analyses confirmed the structures and purity of the synthesized molecules. Subsequently, these molecules were tested for their ability to inhibit the viability of cell lines representing carcinoma of the breast, viz., MDA-MB-468 (ER–, PR–, and HER−), BT-474 (ER+, PR+, and HER+), T-47D (ER+, PR+, and HER−), and MCF-7 (ER+, PR+, and HER−) in vitro. Among these 10 molecules, 5a, 5c, 5d, and 5e exhibited better potency, as evidenced by IC50 < 50 μM at 24 h of treatment against BT-474 and MDA-MB-468 cell lines. However, except for 5d, the IC50 value is much higher than 50 μM when tested against T47D and MCF-7 cell lines at 24h. Extended treatment for 48 h reduced the effect of these molecules, as an increase in IC50 was observed. In mice, intraperitoneal administration of 5e retarded the Ehrlich ascites carcinoma (EAC) growth without causing any organ toxicity at the doses tested. In summary, we report the synthesis scheme and key structural requirements for a new series of imidazole–pyridine molecules for in vitro inhibition of the feasibility of breast cancer cells and in vivo inhibition of EAC tumors

Polyphenol contents (mg/g of fresh vegetable material) of pomegranate matrices.

Polyphenols were divided into chemical subclasses. BR-PA, BR-B, BG-PA, BG-B, M-PA and M-B correspond to extract labels as indicated in Fig 3. See also S1 Table for individual and collective quantitative data.</p

Statistical comparisons of antiproliferative activity of pomegranate immature and mature fruits treatments in cancer cells H1299 and HCT116^a.

Statistical comparisons of antiproliferative activity of pomegranate immature and mature fruits treatments in cancer cells H1299 and HCT116a.</p

Metabolite contents (mg/g of fresh material) in the pomegranate matrices investigated.

(DOCX)</p

Structural Insight into Inhibitor of Apoptosis Proteins Recognition by a Potent Divalent Smac-Mimetic

<div><p>Genetic alterations enhancing cell survival and suppressing apoptosis are hallmarks of cancer that significantly reduce the efficacy of chemotherapy or radiotherapy. The Inhibitor of Apoptosis Protein (IAP) family hosts conserved proteins in the apoptotic pathway whose over-expression, frequently found in tumours, potentiates survival and resistance to anticancer agents. In humans, IAPs comprise eight members hosting one or more structural Baculoviral IAP Repeat (BIR) domains. Cellular IAPs (cIAP1 and 2) indirectly inhibit caspase-8 activation, and regulate both the canonical and the non-canonical NF-κB signaling pathways. In contrast to cIAPs, XIAP (X chromosome-linked Inhibitor of Apoptosis Protein) inhibits directly the effector caspases-3 and -7 through its BIR2 domain, and initiator caspase-9 through its BIR3 domain; molecular docking studies suggested that Smac/DIABLO antagonizes XIAP by simultaneously targeting both BIR2 and BIR3 domains. Here we report analytical gel filtration, crystallographic and SAXS experiments on cIAP1-BIR3, XIAP-BIR3 and XIAP-BIR2BIR3 domains, alone and in the presence of compound 9a, a divalent homodimeric Smac mimetic. 9a is shown to bind two BIR domains inter- (in the case of two BIR3) and intra-molecularly (in the case of XIAP-BIR2BIR3), with higher affinity for cIAP1-BIR3, relative to XIAP-BIR3. Despite the different crystal lattice packing, 9a maintains a right handed helical conformation in both cIAP1-BIR3 and XIAP-BIR3 crystals, that is likely conserved in solution as shown by SAXS data. Our structural results demonstrate that the 9a linker length, its conformational degrees of freedom and its hydrophobicity, warrant an overall compact structure with optimal solvent exposure of its two active moieties for IAPs binding. Our results show that 9a is a good candidate for pre-clinical and clinical studies, worth of further investigations in the field of cancer therapy.</p> </div

Anticancer effects of different extracts from pomegranate immature and ripe fruits.

A) Heatmap of proliferation in H1299 and HCT116 cells exposed for 48 h to 100 μg/mL of the indicated pomegranate fruit extracts. Data (left) and color scale (right) reflects % of respective controls treated with the vehicle DMSO. A1) Trend analysis of anticancer effects by pomegranate peel extracts shown in A. **, p ≤ 0.01. A2) Trend analysis of anticancer effects by pomegranate mesocarp/arils extracts shown in A.</p

Peak list and diagnostics of selected metabolites from pomegranate matrices object of this study.

Peak list and diagnostics of selected metabolites from pomegranate matrices object of this study.</p

Dimeric assemblies of cIAP1- and XIAP1-BIR3 bound to 9a.

<p>A) X-Ray structure of cIAP1-BIR3 dimer (cartoon in blue and pale blue) in complex with 9a (green sticks). B) X-Ray structure of XIAP-BIR3 dimer in complex with 9a: the A and F molecules are in orange and pale yellow, respectively, 9a is represented as green sticks (drawn with Pymol).</p

Chemical structures of the pomegranate metabolites cited in this study.

Please see Results & discussion for further details. (DOCX)</p