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Purpose: To improve curcumin's pharmacokinetic, in vitro cytotoxicity and release property. Methods: A novel linear-dendrimer methoxy-poly (ethylene glycol)-b-poly (ϵ-caprolactone) copolymer was synthesized through O-alkylation, basic hydrolysis and ring-opening polymerization reaction with methoxy-poly (ethylene glycol), epichlorohydrin and ϵ-caprolactone as raw materials. Its structure was characterized by 1H-NMR and GPC. The copolymer's hemolysis and micellar encapsulation for curcumin by thin-film hydration were studied. Curcumin-loaded micelles were evaluated by use of in vitro release, FT-IR and X-ray diffraction. Curcumin-loaded micelles' in vitro cytotoxic activities against Hela and HT-29 cells were done, and its pharmacokinetic parameters were also carried out. Results: Curcumin was encapsulated into the micelles with 92.54% of entrapment efficiency and 12.84% of drug loading in amorphous forms. The dissolubility of nanoparticulate curcumin was 1.70 × 105 times higher than that of curcumin in water. The obtained copolymer showed no hemolysis. In vitro drug release study indicated that, in all cases, the kinetics was adjusted well to the Makoid-Banakar model ( = 0.9984). In addition, data were analyzed by the Korsmeyer-Peppas model, n values were 0.43, indicating that the drug release was accomplished by the combination diffusion and polymer chain relaxation. The cytotoxicity experiment indicated that the nanoparticulate curcumin kept up its potent anti-cancer activities. The pharmacokinetic results showed that the MRT0-∞, t1/2z and AUC0-∞ of Curcumin-loaded micelles were 1.64, 6.54 and 4.67 times higher than that of CUR control solution. Conclusions: The copolymeric micelles loading curcumin might act as a delivery vehicle for CUR. [ABSTRACT FROM AUTHOR]

Abstract The ubiquity of methicillin-resistant Staphylococcus aureus (MRSA) and the mounting prevalence of antibiotic resistance necessitate the identification of novel therapeutic approaches to reduce the selective pressure of antibiotics. Targeting bacterial virulence factors is a wise option, as it can mitigate the pathogenicity of bacteria without eradicating them. Sortase A (SrtA), which is critical for bacterial adhesion, invasion, and immune evasion, is a promising target for virulence inhibition in S. aureus. α-Hemolysin (Hla), a toxin secreted by S. aureus, is closely linked to virulence and has been identified as a key target against MRSA. Herein, we report the discovery of a flavonoid, isosakuranetin, which inhibits the activity of S. aureus SrtA. A fluorescence resonance energy transfer assay revealed that isosakuranetin exhibited a low IC50 of 21.20 μg/mL. Furthermore, isosakuranetin significantly inhibited SrtA-related virulence properties, such as bacterial adhesion to fibrinogen, biofilm formation, and invasion of A549 cells. We employed fluorescence quenching and molecular docking to determine the interactions between isosakuranetin and SrtA, revealing the key amino acid sites for binding. Importantly, isosakuranetin inhibited the hemolytic activity of S. aureus in vitro at a concentration of 32 μg/mL. Moreover, isosakuranetin effectively suppressed the transcription and expression of Hla in a dose-dependent manner and regulated the transcription of RNAIII, the upstream operator of Hla. Notably, isosakuranetin demonstrated in vivo efficacy in a mouse model of S. aureus-induced pneumonia by significantly improving survival rates and reducing lung damage. This is a valuable finding, as isosakuranetin’s dual inhibitory effects on SrtA and hemolytic activity, as well as its anti-virulence activity against MRSA, make it an excellent candidate for therapeutic development. [ABSTRACT FROM AUTHOR]