Modified magnetic core-shell mesoporous silica nano-formulations with encapsulated quercetin exhibit anti-amyloid and antioxidant activity

Targeted tissue drug delivery is a challenge in contemporary nanotechnologically driven therapeutic approaches, with the interplay interactions between nanohost and encapsulated drug shaping the ultimate properties of transport, release and efficacy of the drug at its destination. Prompted by the need to pursue the synthesis of such hybrid systems, a family of modified magnetic core-shell mesoporous silica nano-formulations was synthesized with encapsulated quercetin, a natural flavonoid with proven bioactivity. The new nanocarriers were produced via the sol-gel process, using tetraethoxysilane as a precursor and bearing a magnetic core of surface-modified monodispersed magnetite colloidal superparamagnetic nanoparticles, subsequently surface-modified with polyethylene glycol 3000 (PEG3k). The arising nano-formulations were evaluated for their textural and structural properties, exhibiting enhanced solubility and stability in physiological media, as evidenced by the loading capacity, entrapment efficiency results and in vitro release studies of their load. Guided by the increased bioavailability of quercetin in its encapsulated form, further evaluation of the biological activity of the magnetic as well as non-magnetic core-shell nanoparticles, pertaining to their anti-amyloid and antioxidant potential, revealed interference with the aggregation of β-amyloid peptide (Aβ) in Alzheimer’s disease, reduction of Aβ cellular toxicity and minimization of Aβ-induced Reactive Oxygen Species (ROS) generation. The data indicate that the biological properties of released quercetin are maintained in the presence of the host nanocarriers. Collectively, the findings suggest that the emerging hybrid nano-formulations can function as efficient nanocarriers of hydrophobic natural flavonoids in the development of multifunctional nanomaterials toward therapeutic applications

In-depth synthetic, physicochemical and in vitro biological investigation of a new ternary V(IV) antioxidant material based on curcumin.

Curcumin is a natural product with a broad spectrum of beneficial properties relating to pharmaceutical applications, extending from traditional remedies to modern cosmetics. The biological activity of such pigments, however, is limited by their solubility and bioavailability, thereby necessitating new ways of achieving optimal tissue cellular response and efficacy as drugs. Metal ion complexation provides a significant route toward improvement of curcumin stability and biological activity, with vanadium being a representative such metal ion, amply encountered in biological systems and exhibiting exogenous bioactivity through potential pharmaceuticals. Driven by the need to optimally increase curcumin bioavailability and bioactivity through complexation, synthetic efforts were launched to seek out stable species, ultimately leading to the synthesis and isolation of a new ternary V(IV)-curcumin-(2,2’-bipyridine) complex. Physicochemical characterization (elemental analysis, FT-IR, Thermogravimetry (TGA), UV-Visible, NMR, ESI-MS, Fluorescence, X-rays) portrayed the solid-state and solution properties of the ternary complex. Pulsed-EPR spectroscopy, in frozen solutions, suggested the presence of two species, cis- and trans-conformers. Density Functional Theory (DFT) calculations revealed the salient features and energetics of the two conformers, thereby complementing EPR spectroscopy. The well-described profile of the vanadium species led to its in vitro biological investigation involving toxicity, cell metabolism inhibition in S. cerevisiae cultures, Reactive Oxygen Species (ROS)-suppressing capacity, lipid peroxidation, and plasmid DNA degradation. A multitude of bio-assays and methodologies, in comparison to free curcumin, showed that it exhibits its antioxidant potential in a concentration-dependent fashion, thereby formulating a bioreactivity profile supporting development of new efficient vanado-pharmaceuticals, targeting (extra)intra-cellular processes under (patho)physiological conditions

Magnetic cationic liposomal nanocarriers for the efficient drug delivery of a curcumin-based vanadium complex with anticancer potential

In this work novel magnetic cationic liposomal nanoformulations were synthesized for the encapsulation of a crystallographically defined ternary V(IV)-curcumin-bipyridine (VCur) complex with proven bioactivity, as potential anticancer agents. The liposomal vesicles were produced via the thin film hydration method employing N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium (DOTAP) and egg phosphatidylcholine lipids and were magnetized through the addition of citric acid surface-modified monodispersed magnetite colloidal magnetic nanoparticles. The obtained nanoformulations were evaluated for their structural and textural properties and shown to have exceptional stability and enhanced solubility in physiological media, demonstrated by the entrapment efficiency and loading capacity results and the in vitro release studies of their cargo. Furthermore, the generated liposomal formulations preserved the superparamagnetic behavior of the employed magnetic core maintaining the physicochemical and morphological requirements for targeted drug delivery applications. The novel nanomaterials were further biologically evaluated for their DNA interaction potential and were found to act as intercalators. The findings suggest that the positively charged magnetic liposomal nanoformulations can generate increased concentration of their cargo at the DNA site, offering a further dimension in the importance of cationic liposomes as nanocarriers of hydrophobic anticancer metal ion complexes for the development of new multifunctional pharmaceutical nanomaterials with enhanced bioavailability and targeted antitumor activity

Nitrogen-Containing Molecules: Natural and Synthetic Products including Coordination Compounds

Nitrogen constitutes one of the most crucial elements in synthetic compounds, both in organic and in coordination chemistry [...

Study of metal-organic materials with anti-diabetic properties and molecular carriers for the encapsulation and delivery of metal-drugs and other micro- and macro-molecular substrates to cellular tissues

The goal of the present research is the synthesis, study, physicochemical characterization and determination of the effectiveness of a) (Zn(II)) insulin-mimetic and insulin-active complexes with biocompatible organic substrates, such as Schiff bases, b) inorganic polymeric carriers of natural antioxidant flavonoids, such as quercetin, and c) inorganic polymeric carriers of antimicrobial formulations of coordinated zinc (Zn(II)). The reasons of this research were the study of the interactions of metal-ion Zn(II), well-known for its insulin-mimetic and antibacterial activity, with low molecular mass physiological and biomimetic substrates that lead to specific complexes of potential biological activity, the investigation of their toxicity, insulin-mimetic and antibacterial effectiveness, and the generation of new knowledge on the morphological properties, permeability, pharmacokinetics and thermodynamic behavior of inorganic polymeric carriers of flavonoids and antimicrobial zinc complexes, as tools to treat diseases (infections, Alzheimer’s disease). The inorganic polymeric carriers were synthesized through sol–gel methods using tetraethoxysilane (TEOS) as a precursor. The antioxidant flavonoid quercetin and antimicrobial Zn(II) complexes were embedded in the inorganic polymeric carriers in three ratios. The methods for the characterization of the new, free or encapsulated, materials included elemental analysis, X-ray crystallography, infrared spectroscopy FT-IR, nuclear magnetic resonance NMR, thermogravimetric analysis TGA, and scanning electron microscopy SEM. Dynamic light scattering measurements and the time-dependent release of quercetin and zinc metal-ion from the inorganic polymeric carriers were made using ultraviolet-visible spectroscopy UV-Visible and flame atomic absorption spectroscopy, respectively.Αντικείμενο της παρούσας διδακτορικής διατριβής είναι η σύνθεση, η μελέτη, ο φυσικοχημικός χαρακτηρισμός και ο καθορισμός της αποτελεσματικότητας α) ινσουλινομιμητικών συμπλόκων ενώσεων του ψευδαργύρου (Zn(II)) με βιοσυμβατά οργανικά υποστρώματα, όπως οι βάσεις Schiff, β) ανόργανων πολυμερικών φορέων αντιοξειδωτικών φυσικών φλαβονοειδών, όπως η κερσετίνη, και γ) ανόργανων πολυμερικών φορέων αντιμικροβιακών σκευασμάτων συμπλοκοποιημένου ψευδαργύρου (Zn(II)). Οι λόγοι της έρευνας αυτής ήταν η δυνατότητα μελέτης των αλληλεπιδράσεων του μεταλλοϊόντος ψευδαργύρου, γνωστού για την ινσουλινομιμητική και αντιβακτηριδιακή του δράση, με μικρής μοριακής μάζας φυσιολογικά και βιομιμητικά υποστρώματα, που οδηγούν σε συγκεκριμένα σύμπλοκα υλικά εν δυνάμει βιολογικής δραστικότητας, η διερεύνηση της τοξικότητας, της ινσουλινομιμητικής και αντιβακτηριδιακής δράσης τους και η προσφορά νέας γνώσης για τις μορφολογικές ιδιότητες, τη διαπερατότητα, τη φαρμακοκινητική και θερμοδυναμική συμπεριφορά των ανόργανων πολυμερικών φορέων του φλαβονοειδούς κερσετίνη και αντιμικροβιακών συμπλόκων του ψευδαργύρου, ως μέσων αντιμετώπισης ασθενειών (μολύνσεις, νόσος του Alzheimer). Οι ανόργανοι πολυμερικοί φορείς συντέθηκαν σύμφωνα με τη μέθοδο sol–gel, χρησιμοποιώντας τετρααιθοξυ σιλάνιο (TEOS) ως πρόδρομη ένωση. Το αντιοξειδωτικό φλαβονοειδές κερσετίνη και τα αντιμικροβιακά σύμπλοκα του ψευδαργύρου εγκλείστηκαν στους πολυμερικούς φορείς σε τρεις αναλογίες. Ο χαρακτηρισμός των νέων υλικών, εγκλεισμένων και μη, έγινε με τις εξής μεθόδους χαρακτηρισμού: στοιχειακή ανάλυση, κρυσταλλογραφία ακτίνων Χ, φασματοσκοπία υπερύθρου, φασματοσκοπία πυρηνικού μαγνητικού συντονισμού, θερμοσταθμική ανάλυση, ηλεκτρονική μικροσκοπία σάρωσης, και δυναμική σκέδαση φωτός. Ο ποσοτικός προσδιορισμός της χρονοεξαρτώμενης αποδέσμευσης τoυ φλαβονοειδούς κερσετίνη και του μεταλλοϊόντος του ψευδαργύρου από τους ανόργανους πολυμερικούς φορείς έγιναν με φασματοσκοπία υπεριώδους-ορατού και φασματοσκοπία ατομικής απορρόφησης φλόγας, αντίστοιχα

Nitrogen-Containing Molecules: Natural and Synthetic Products including Coordination Compounds

Nitrogen constitutes one of the most crucial elements in synthetic compounds, both in organic and in coordination chemistry [...

Unraveling the binding mechanism of an Oxovanadium(IV) – Curcumin complex on albumin, DNA and DNA gyrase by in vitro and in silico studies and evaluation of its hemocompatibility

An oxovanadium(IV) – curcumin based complex, viz. [VO(cur)(2,2´-bipy)(H2O)] where cur is curcumin and bipy is bipyridine, previously synthesized, has been studied for interaction with albumin and DNA. Fluorescence emission spectroscopy was used to evaluate the interaction of the complex with bovine serum albumin (BSA) and the BSA-binding constant (Kb) was calculated to be 2.56 x 105 M-1, whereas a single great-affinity binding site was revealed. Moreover, the hemocompatibility test demonstrated that the complex presented low hemolytic fraction (mostly below 1%), in all concentrations tested (0-250 μΜ of complex, 5% DMSO) assuring a safe application in interaction with blood. The binding of the complex to DNA was also investigated using absorption, fluorescence, and viscometry methods indicating a binding through a minor groove mode. From competitive studies with ethidium bromide the apparent binding constant value to DNA was estimated to be 4.82 x 106 M-1. Stern-Volmer quenching phenomenon gave a ΚSV constant [1.92 (± 0.05) x 104 M-1] and kq constant [8.33 (± 0.2) x 1011 M-1s-1]. Molecular docking simulations on the crystal structure of BSA, calf thymus DNA, and DNA gyrase, as well as pharmacophore analysis for BSA target, were also employed to study in silico the ability of [VO(cur)(2,2´-bipy)(H2O)] to bind to these target bio-macromolecules and explain the observed in vitro activity. © 2021 Elsevier Inc

In vitro and in silico evaluation of the inhibitory effect of a curcumin-based oxovanadium (IV) complex on alkaline phosphatase activity and bacterial biofilm formation

Abstract: The scientific interest in the development of novel metal-based compounds as inhibitors of bacterial biofilm-related infections and alkaline phosphatase (ALP) deregulating effects is continuous and rising. In the current study, a novel crystallographically defined heteroleptic V(IV)-curcumin-bipyridine (V-Cur) complex with proven bio-activity was studied as a potential inhibitor of ALP activity and bacterial biofilm. The inhibitory effect of V-Cur was evaluated on bovine ALP, with two different substrates: para-nitrophenyl phosphate (pNPP) and adenosine triphosphate (ATP). The obtained results suggested that V-Cur inhibited the ALP activity in a dose-dependent manner (IC50 = 26.91 ± 1.61 μM for ATP, IC50 = 2.42 ± 0.12 μM for pNPP) exhibiting a mixed/competitive type of inhibition with both substrates tested. The evaluation of the potential V-Cur inhibitory effect on bacterial biofilm formation was performed on Gram (+) bacteria Staphylococcus aureus (S. aureus) and Gram (−) Escherichia coli (E. coli) cultures, and it positively correlated with inhibition of bacterial ALP activity. In silico study proved the binding of V-Cur at eukaryotic and bacterial ALP, and its interaction with crucial amino acids of the active sites, verifying complex’s inhibitory potential. The findings suggested a specific anti-biofilm activity of V-Cur, offering a further dimension in the importance of metal complexes, with naturally derived products as biological ligands, as therapeutic agents against bacterial infections and ALP-associated diseases. Key points: • V-Cur inhibits bovine and bacterial alkaline phosphatases and bacterial biofilm formation. • Alkaline phosphatase activity correlates with biofilm formation. • In silico studies prove binding of the complex on alkaline phosphatase. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature