Concomitant Effect of Quercetin and Its Copper Complex in the Development of Sustained-Release Nanoparticles of Polycaprolactone, Used for the Treatment of Skin Infection.

The study aimed to improve the treatment of impetigo with naturally occurring quercetin and its copper-quercetin (Cu-Q) complex by preparing sustained-release (SR) nanoparticles of polycaprolactone (PCL). The solvent evaporation method was used for the copper-quercetin (Cu-Q) complex formation, and their PCL nanoparticles (PCL-NPs, Q-PCL-NPs, and Cu-Q-PCL-NPs) were prepared by the high-pressure homogenization method. Synthesis of nanoparticles was confirmed by their physicochemical and antibacterial properties of quercetin against Gram-positive as well as Gram-negative bacteria. The percentage loading efficiency of quercetin and release in 100 mM of phosphate buffer pH 7.4 and 5.5 at 37 °C was found to be more than 90% after 24 h with the zero-order release pattern. Minimum inhibitory concentration of nanoparticles was found to increase threefold in the case of Cu-Q-PCL-NPs may be due to the synergistic antibacterial behavior. Scanning electron microscopy showed spherical nanoparticles, and surface roughness was confirmed by atomic force microscopy analysis. Fortunately, no sign of irritation on rat skin even at 3%, was seen. In vitro antioxidant assay by 2,2-diphenyl-1-picrylhydrazyl reduction was found to be ≤80 ± 0.02% which confirmed their scavenging activity. Interestingly, for the ex vivo study, the tape-stripping model was applied against Staphylococcus aureus containing rats and showed the formation of the epidermal layer within 4-5 days. Confirmation of antibacterial activity of pure quercetin, from Cu-Q complex, and their SR release from Q-PCL-NPs and Cu-Q-PCL-NPs was considered an effective tool for the treatment of skin diseases and can be used as an alternative of already resistant ciprofloxacin in impetigo.

Cellular and Non-cellular Antioxidant Properties of Vitamin E-Loaded Metallic-Quercetin/Polycaprolactone Nanoparticles for the Treatment of Melanogenesis.

Inhibition of melanogenesis by quercetin and vitamin E is extensively reported in the literature, independently, with limitations in antioxidant potential owing to less permeation, solubility, decreased bioavailability, and reduced stability. Thus, the aim of the present study was to synthesize a novel complex of metal ions (copper and zinc) with quercetin to enhance antioxidant properties which were confirmed by docking studies. Polycaprolactone-based nanoparticles of the synthesized complex (PCL-NPs, Q-PCL-NPs, Zn-Q-PCL-NPs, Cu-Q-PCL-NPs) were made later loaded with vitamin E which made the study more interesting in enhancing antioxidant profile. Nanoparticles were characterized for zeta size, charge, and polydispersity index, while physiochemical analysis of nanoparticles was strengthened by FTIR. Cu-Q-PCL-NPs-E showed maximum in vitro release of vitamin E, i.e., 80 ± 0.54%. Non-cellular antioxidant effect by 2,2-diphenyl-1-picrylhydrazyl was observed at 93 ± 0.23% in Cu-Q-PCL-NPs-E which was twofold as compared to Zn-Q-PCL-NPs-E. Michigan Cancer Foundation-7 (MCF-7) cancer cell lines were used to investigate the anticancer and cellular antioxidant profile of loaded and unloaded nanoparticles. Results revealed reactive oxygen species activity of 90 ± 0.32% with the addition of 89 ± 0.64% of its anticancer behavior shown by Cu-Q-PCL-NPs-E after 6 and 24h. Similarly, 80 ± 0.53% inhibition of melanocyte cells and 95 ± 0.54% increase of keratinocyte cells were also shown by Cu-Q-PCL-NPs-E that confirmed the tyrosinase enzyme inhibitory effect. Conclusively, the use of zinc and copper complex in unloaded and vitamin E-loaded nanoparticles can provide enhanced antioxidant properties with inhibition of melanin, which can be used for treating diseases of melanogenesis.

Fabrication, Evaluation, In Vivo Pharmacokinetic and Toxicological Analysis of pH-Sensitive Eudragit S-100-Coated Hydrogel Beads: a Promising Strategy for Colon Targeting.

The aim of present research aims to fabricate a system of enteric coating of hydrogel beads with pH-sensitive polymer, which shows solubility at pH > 7, and explore their potential to target the colon for drug delivery. Hydrogel beads were fabricated through the extrusion-dripping technique followed by ion gelation crosslinking. Moreover, freeze-thaw cycle was implemented for crosslinking of polyvinyl alcohol (PVA)/Ca-alginate blend beads. The oil-in-oil solvent evaporation method was adopted for the Eudragit coating of hydrogel beads using different coat: core ratios (4:1 or 8:1). Coated and uncoated hydrogel beads were evaluated by in vitro physicochemical properties, swelling and drug release behaviours, and in vivo pharmacokinetics, swelling, and toxicity evaluation. Diclofenac sodium was loaded as an experimental drug. Drug entrapment efficiency for the PVA/Ca-alginate beads was calculated as 98%, and for Ca-alginate beads, it came out to a maximum of 74%. Drug release study at various pH suggested that, unlike uncoated hydrogel beads, the coated beads delay the release of diclofenac sodium in low pH of the gastric and intestinal environment, thus targeting the colon for the drug release. It was concluded that Eudragit S-100-coated hydrogel beads could serve as a more promising and reliable way to target the colon for drug delivery.Graphical abstract.

Design, synthesis, spectroscopic characterization, in-vitro antibacterial evaluation and in-silico analysis of polycaprolactone containing chitosan-quercetin microspheres.

Aim of present study was to synthesize a novel chitosan-quercetin (CTS-QT) complex by making a carbodiimide linkage using maleic anhydride as cross-linker and to investigate its enhanced antibacterial and antioxidant activities as compare to pure CTS and QT. Equimolar concentration of QT and maleic anhydride were used to react with 100 mg CTS to form CTS-QT complex. For this purpose, three bacterial strains namely E. Coli, S. Aureus and P. Aeruginosa were used for in-vitro antibacterial analysis (ZOI, MIC, MBC, checker board and time kill assay). Later molecular docking studies were performed on protein structure of E. Coli to assess binding affinity of pure QT and CTS-QT complex. MD simulations with accelerated settings were used to explore the protein-ligand complex's binding interactions and stability. Antioxidant profile was determined by performing DPPH• radical scavenging assay, total antioxidant capacity (TAC) and total reducing power (TRP) assays. Delivery mechanism to CTS-QT complex was improved by synthesizing polycaprolactone containing microspheres (CTS-QT-PCL-Levo-Ms) using Levofloxacin as model drug to enhance their antibacterial profile. Resulted microspheres were evaluated by particle size, charge, surface morphology, in-vitro drug release and hemolytic profile and are all were found within limits. Antibacterial assay revealed that CTS-QT-PCL-Levo-Ms showed more than two folds increased bactericidal activity against E. Coli and P. Aeruginosa, while 1.5 folds against S. Aureus. Green colored formation of phosphate molybdate complexes with highest 85 ± 1.32% TAC confirmed its antioxidant properties. Furthermore, molecular docking and dynamics studies revealed that CTS-QT was embedded nicely within the active pocket of UPPS with binding energy greater than QT with RSMD value of below 1.5. Conclusively, use of maleic acid, in-vitro and in-silico antimicrobial studies confirm the emergence of CTS-QT complex containing microspheres as novel treatment strategy for all types of bacterial infections.Communicated by Ramaswamy H. Sarma.

Chitosan/halloysite nanotubes microcomposites: A double header approach for sustained release of ciprofloxacin and its hemostatic effects.

Clotting time of lower gastro intestinal bleeding (LGIB) can be reduced by using simple, cost-effective, and naturally occurring halloysite nanotubes (HNTs). The present study aimed to decrease the clotting time by the application of chitosan (CHT) and its microcomposites (MCs) prepared by suspension emulsification technique with HNTs (CHT/HNTs MC). Physicochemical properties, X-Ray diffraction (XRD), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and percentage release of ciprofloxacin from CHT/HNTs MCs was evaluated. In-vitro procoagulant activity of CHT, HNTs and their complexes CHT/HNTs MCs was performed on rabbit blood which was confirmed by a rat tail amputation. Direct relation of HNTs was observed for the whole-blood clotting kinetics i.e., 2% HNTs showed a maximum 66.0% increase in the clotting ability as compared with pure CHT. Interestingly, rat-tail amputation studies showed comparative results of CHT, HNTs, and CHT/HNTs MCs. A total of 75% permeation of ciprofloxacin of CHT/HNTs MCs on rat intestinal membrane was observed within 3 h, confirming their SR behavior. Furthermore, improved hemostatic and clotting properties were CHT/HNTs MC1 > CHT/HNTs MC2 > CHT/HNTs MC3 > CHT > HNTs, respectively. Thus, it provided the control of bleeding disorders in LGIB with any antibacterial agents, particularly ciprofloxacin.

Improved solubility and corneal permeation of PEGylated curcumin complex used for the treatment of ophthalmic bacterial infections.

Naturally occurring curcumin can be used for the treatment of corneal bacterial infections with its limitation of poor solubility. Aim of the present study was to enhance solubility and permeation of curcumin for the treatment of corneal bacterial infections. For increasing solubility, curcumin and polyethylene glycol (PEG 6000) complex (1:3) was prepared by fusion melting method. Phase solubility studies were used for the calculation of Gibbs free energy of curcumin. Central composite rotatable design (CCRD) was applied for optimization of Curcumin (CUR), PEGylated Curcumin (PEG-CUR), penetration enhancer cremophore (CR). Optimized ointments were further evaluated by mucous permeation, membrane permeability and cell toxicity studies by Transwell cell, ussing chamber and Caco-2 cells respectively. Antibacterial test was also performed by agar well diffusion method. Solubility of PEG-CUR was increased up to 93±3.2% as compared to pure curcumin and content uniformity was in the range of 95-110%. Curcumin permeation from PEG-CUR ointment was increased up to 12 folds. No toxicity of Caco-2 cells for PEG-CUR even after 24h was observed. Activity index of pure CUR, PEG-CUR ointment with or without CR against S. aureus and P. aeruginosa was 97±2.3, 96±1.6, 95±2.5% respectively. Ointment with solubility enhanced PEG-CUR and cremophore can be used as a promising tool for the treatment of corneal bacterial infections.