Embelin-loaded chitosan gold nanoparticles interact synergistically with ciprofloxacin by inhibiting efflux pumps in multidrug-resistant Pseudomonas aeruginosa and Escherichia coli.

A global upsurge in emergence and spread of antibiotic resistance (ABR) in bacterial populations is a serious threat for human health. Unfortunately, ABR is no longer confined to nosocomial environments and is frequently reported from community microbes as well. The ABR is resulting in shrinking potent antibiotics pool and thus necessitating novel and alternative therapies and therapeutics. Current investigation was aimed to assess the synergistic potential of a synthesized, phytomolecule-loaded, polysaccharide-stabilized metallic nanoparticles (NPs) against Pseudomonas aeruginosa (PA) and Escherichia coli (EC) isolated from river waters. ABR profiling of these strains characterized them as multidrug resistant (MDR). Synthesized embelin (Emb, isolated from Embelia tsjeriam-cottam)-loaded, chitosan-gold (Emb-Chi-Au) NPs were assessed for their potential synergistic activity with ciprofloxacin (CIP) via checker-board assay and time-kill curve analysis. The NPs reduced the minimal inhibitory concentration (MIC) of CIP by 16- and 4-fold against MDR PA (PA-r) and EC (EC-r) strains, respectively. Fractional inhibitory concentration (FIC) indices with ≤0.5 values confirmed the synergy between the Emb-Chi-Au NPs and CIP, which was further confirmed at ½ MICs in both PA-r and EC-r via time-kill curve analysis. In order to decipher the mode of action, efflux pump inhibitory effects of Emb-Chi-Au NPs were evaluated in terms of the increase in the EtBr mediated fluorescence in control versus NP-treated MDR strains. Molecular docking based in silico simulations were used to predict the interactions between Emb and the active sites of the efflux pump related proteins in PA-r (MexA, MexB and OprM) and EC-r (AcrA, AcrB and TolC), which revealed the probable bond formation between Emb and respective amino acid residues.

Functional design of pH-responsive folate-targeted polymer-coated gold nanoparticles for drug delivery and in vivo therapy in breast cancer.

BACKGROUND: Curcumin has been widely used owing to its various medicinal properties including antitumor effects. However, its clinical application is limited by its instability, poor solubility and low bioavailability. Folic acid (FA)-functionalized nanoformulations may enhance the sustained release of an anticancer drug (curcumin) by tumor-specific targeting to improve therapeutic benefit. This study aims to design a nanoconjugate (NC) comprised of folate-curcumin-loaded gold-polyvinylpyrrolidone nanoparticles (FA-CurAu-PVP NPs) for targeted delivery in breast cancer model systems. METHODS: We developed curcumin-loaded FA-functionalized Au-PVP NCs by layer-by-layer assembly. The folic acid-curcumin Au-PVP NCs (FA-CurAu-PVP NCs) were characterized by ultraviolet-visible spectra, Fourier transform infrared spectroscopy, X-ray powder diffraction and thermogravimetric analysis. In vitro anticancer and antimigratory effects of NCs were examined by performing MTT and wound migration assays. The in vivo antitumor efficacy of NCs was investigated using a preclinical breast cancer orthotopic mouse model. RESULTS: Curcumin (40 µg/mL) was loaded along with conjugation of folate onto Au-PVP NPs to form FA-CurAu-PVP NCs. The size and charge of the NCs were increased gradually through layer-by-layer assembly and showed 80% release of curcumin at acidic pH. The NC did not show aggregation when incubated with human serum and mimicked an intrinsic peroxidase-like property in the presence of 3,3',5,5'-tetramethylbenzidine substrate. The MTT data using these NCs showed efficient anticancer activity at lower doses in estrogen/progesterone receptor (ER/PR)-negative cells compared with ER/PR-positive cells. Furthermore, the NCs did not show cytotoxicity at the investigated concentration in human breast epithelial and mouse fibroblast cell lines. They showed inhibitory effects on cell migration and high antitumor efficacy in in vivo analysis. CONCLUSION: These results suggest that folate-based tumor targeting using CurAu-PVP NCs is a promising approach for tumor-specific therapy of breast cancer without harming normal cells.