Remdesivir-loaded bis-MPA hyperbranched dendritic nanocarriers for pulmonary delivery.

Remdesivir is the only clinically available antiviral drug for the treatment of COVID-19. However, its very limited aqueous solubility confines its therapeutic activity and the development of novel inhaled nano-based drug delivery systems of remdesivir for enhanced lung tissue targeting and efficacy is internationally pursued. In this work 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) hyperbranched dendritic nano-scaffolds were employed as nanocarriers of remdesivir. The produced nano-formulations, empty and loaded, consisted of monodisperse nanoparticles with spherical morphology and neutral surface charge and sizes ranging between 80 and 230 nm. The entrapment efficiency and loading capacity of the loaded samples were 82.0% and 14.1%, respectively, whereas the release of the encapsulated drug was complete after 48 h. The toxicity assays in healthy MRC-5 lung diploid fibroblasts and NR8383 alveolar macrophages indicated their suitability as potential remdesivir carriers in the respiratory system. The novel nano-formulations are non-toxic in both tested cell lines, with IC50 values higher than 400 µΜ after 72 h treatment. Moreover, both free and encapsulated remdesivir exhibited very similar IC50 values, at the range of 80-90 µM, while its aqueous solubility was increased, overall presenting a suitable profile for application in inhaled delivery of therapeutics.

Hydrophilic bis-MPA hyperbranched dendritic scaffolds as nanocarriers of a fully characterized flavonoid morin-Zn(II) complex for anticancer applications.

In this work the first crystallographically characterized complex of the bioactive flavonoid morin with the Zn(II) ion is presented along with its complete physico-chemical characterization. In view of the antioxidant activity of morin and its toxicity against respiratory tract cancers, the encapsulation of the complex in the hydrophilic bis(methylol)propionic acid hyperbranched dendritic scaffolds (bis-MPA HDSs) was effected. The produced nano-formulations were characterized with physico-chemical and electron microscopy techniques, and biologically evaluated for their antioxidant and anticancer activity against human A549 and H520 lung cancer cells, as well as healthy human MRC-5 lung fibroblasts. The obtained results demonstrate that encapsulation increases the solubility, and thus bioavailability, of the complex in physiological media and enhances anticancer action. They also highlight the importance of the non-toxic bis-MPA HDSs as nanocarriers of bioactive flavonoid metal complexes for anticancer therapeutic applications.

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 ß-amyloid peptide (Aß) in Alzheimer's disease, reduction of Aß cellular toxicity and minimization of Aß-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.

Synthesis, physicochemical characterization and biological properties of two novel Cu(II) complexes based on natural products curcumin and quercetin.

Curcumin and quercetin are two of the most prominent natural polyphenols with a diverse spectrum of beneficial properties, including antioxidant, anti-inflammatory, chemopreventive and chemotherapeutic activity. The complexation of these natural products with bioactive transition metal ions can lead to the generation of novel metallodrugs with enhanced biochemical and pharmacological activities. Within this framework, the synthesis and detailed structural and physicochemical characterization of two novel complex assemblies of Cu(II) with curcumin and quercetin and the ancillary aromatic chelator 2,2'-bipyridine is presented. The two complexes represent the only crystallographically characterized structures with Cu(II) as the central metal ion and curcumin or quercetin as the ligands. The new complexes were biologically evaluated in vitro for their antioxidant potential, both exhibiting strong scavenging activity in the 2,2-diphenyl-1-picrylhydrazyl assay, and their plasmid DNA binding/cleavage properties. Both complexes appear to be non-toxic in the eukaryotic experimental model Saccharomyces cerevisiae and merit further investigation of their pharmacological profile.

Structurally characterized gallium-chrysin complexes with anticancer potential.

Chemotherapeutic metal-based compounds are effective anticancer agents; however, their cytotoxic profile and significant side effects limit their wide application. Natural products, especially flavonoids, are a prominent alternative source of anticancer agents that can be used as ligands for the generation of new bioactive complexes with metal ions of known biochemical and pharmacological activities. Herein, we present the synthesis and detailed structural and physicochemical characterizations of three novel complex assemblies of Ga(iii) with the flavonoid chrysin and the ancillary aromatic chelators 1,10-phenanthroline, 2,2'-bipyridine and imidazole. The complexes constitute the only crystallographically characterized structures having a metal core from the boron group elements and a flavonoid as the ligand. The in vitro biological evaluation of the three complexes in a series of cancer cell lines of different origin established their cytotoxicity and ROS generating potential. In particular, the Ga(iii)-chrysin-imidazole complex displayed the highest anticancer efficacy against all cancer cell lines with IC50 values in the low micromolar range (<1.18 µM), a result worth further investigation.

Structure Differentiation of Hydrophilic Brass Nanoparticles Using a Polyol Toolbox.

Nano-brasses are emerging as a new class of composition-dependent applicable materials. It remains a challenge to synthesize hydrophilic brass nanoparticles (NPs) and further exploit them for promising bio-applications. Based on red/ox potential of polyol and nitrate salts precursors, a series of hydrophilic brass formulations of different nanoarchitectures was prepared and characterized. Self-assembly synthesis was performed in the presence of triethylene glycol (TrEG) and nitrate precursors Cu(NO3)2·3H2O and Zn(NO3)2·6H2O in an autoclave system, at different temperatures, conventional or microwave-assisted heating, while a range of precursor ratios was investigated. NPs were thoroughly characterized via X-ray diffraction (XRD), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), transmition electron microscopy (TEM), Fourier-transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), and ζ-potential to determine the crystal structure, composition, morphology, size, state of polyol coating, and aqueous colloidal stability. Distinct bimetallic α-brasses and γ-brasses, α-Cu40Zn25/γ-Cu11Zn24, α-Cu63Zn37, α-Cu47Zn10/γ-Cu19Zn24, and hierarchical core/shell structures, α-Cu59Zn30@(ZnO)11, Cu35Zn16@(ZnO)49, α-Cu37Zn18@(ZnO)45, Cu@Zinc oxalate, were produced by each synthetic protocol as stoichiometric, copper-rich, and/or zinc-rich nanomaterials. TEM sizes were estimated at 20-40 nm for pure bimetallic particles and at 45-70 nm for hierarchical core/shell structures. Crystallite sizes for the bimetallic nanocrystals were found ca. 30-45 nm, while in the case of the core-shell structures, smaller values around 15-20 nm were calculated for the ZnO shells. Oxidation and/or fragmentation of TrEG was unveiled and attributed to the different fabrication routes and formation mechanisms. All NPs were hydrophilic with 20-30% w/w of polyol coating, non-ionic colloidal stabilization (-5 mV < ζ-potential < -13 mV) and relatively small hydrodynamic sizes (<250 nm). The polyol toolbox proved effective in tailoring the structure and composition of hydrophilic brass NPs while keeping the crystallite and hydrodynamic sizes fixed.

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.