Acid-responsive Co-delivery Of Curcumin And Chrysin In Polymeric Micelles

The aim of this project was to achieve the co-delivery of curcumin and chrysin in polymeric micelles in an acid-responsive manner.Both agents were loaded via chemical and physical means,respectively.Curcumin was conjugated to amphiphilic polymer backbone via p H-sensitive hydrazone bonds.The obtained polymer-curcumin conjugates could self-assemble into micellar nanocarriers.Chrysin was first complexed with Fe²⁺to form a dimer that was then physically encapsulated within the hydrophobic core of micelles.Upon the trigger of acidic environment,curcuim was released by hydrozone hydrolysis,while chrysin was liberated by de-complexation.The complexation behavior of chrysin with Fe²⁺was assessed via a series of techniques including proton nuclear magnetic resonance,ultraviolet specoscopy,and mass spectroscopy.The Chrysin and the chrysin ion chelation can self-assemble into micelle in 0.5%Poloxamer aqueous solution.The hydrodynamic sizes of Poloxamer-Chrysin and Poloxamer-Chrysin-Fe²⁺were 1450.7±269.1 nm and 420.1±56.0 nm.Poloxamer-Chrysin-Fe²⁺diluted with water by 5 times,sizes increase to664.2±79.4 nm.The forming micelle ability and stability of dimer was stronger.The effect of complexation on drug loading was investigated using vitamin E polyethylene glycol succinate?TPGS?as a model carrier.It was found that the chelation significantly enhanced the chrysin loading from 0.1±0.0%to 0.6±0.0%?w/w?.The two samples prepared by solvent evaporation method has higher drug loading:0.2±0.1%and 0.9±0.0%.The backbone of polymer-curcumin conjugate was synthesized via the polymerization of aspartic acid initiated by amine-ended poly?ethylene glycol?.The polymer was decorated by hydrazine;curcumin was modified by levulinic acid to bring in a carbonyl group.Then the conjugation of curcumin derivative and backbone result in amphiphilic polymer-curcumin conjugate,i.e.m PEG-PAsp-NHN=Cur.The curcumin loading was 30.2%and the grafting ratio was 39.6%?w/w?.The drug loading of chrysin and dimer realized by solvent evaporation approach were 0.8±0.4%and 1.2±0.5%?w/w?.The dynamic light scattering analysis revealedthatthehydrodynamicsizesofm PEG-PAsp-NHN=Cur,m PEG-PAsp-NHN=Cur/Chrysin and m PEG-PAsp-NHN=Cur/Chrysin-Fe²⁺were106.0±0.90 nm,113.1±1.32 nm and 163.2±4.10 nm.The transmission electron microscopy imaging showed that all micellar samples exhibited a spherical shape.The Curcumin Cumulative drug release of m PEG-PAsp-NHN=Cur was 29.8±3.0%at p H=5.0 and 9.2±0.7%at p H=7.4,the Chrysin Cumulative drug release of m PEG-PAsp-NHN=Cur/Chrysin-Fe²⁺was 74.5±5.1%at p H=5.0 and 48.5±2.5%at p H=7.4.The drug release study showed the increased release of curcumin and chrysin at acidic condition compared with neutral condition.The cellular uptake study employed He La cells.Due to the short excitation wavelength of chrysin,only curcumin was visualized via confocal laser scanning imaging.The distribution of curcumin concentrated on cytomembrane and cytoplasm.The cytotoxicity study employed the same cell line and the IC₅₀ of the co-loaded micelles was 15.1±2.9?M.Compared to Cur?M?(IC₅₀=38.6±2.2?M),micelle has stronger ability of tumor destruction.The current work generated a p H-responsive nanoscale delivery system for combinational delivery of curcumin and chrysin.There was broad prospects at hydrophobic drugs'co-delivery,increasing tumor-targeting and drug controlled release.