Oral colon-targeted mucoadhesive micelles with enzyme-responsive controlled release of curcumin for ulcerative colitis therapy

摘要

Although multitudinous nanoscale drug-delivery systems(DDSs)have been recommended to improve anti-ulcerative colitis(UC)outcomes,to enhance the mucoadhesion of nanosystems on the colon and specifically release the loaded drugs in response to the colon micro-environment would be critical factors.The application of curcumin(Cur),an acknowledged anti-UC phytochemical compound,for UC therapy requires more efficient nano-carriers to improve its therapeutic outcome.Herein,we developed the colon-targeted nano-micelles with mucoadhesive effect and Azo reductase-triggered drug release profiles for Cur delivery in UC treatment.Specifically,the amphiphilic block polymer containing the Azo-reductase sensitive linkage(PEG-Azo-PLGA),and catechol-modified TPGS(Cat-TPGS)were synthesized respectively.Based on the self-assembly of the mixed polymers,Cur-micelles(142.7±1.7 nm of average size,72.36%±1.54%of DEE)were obtained.Interestingly,the Cur-micelles exhibited the Azo-reductase sensitive particle dissociation and drug release,the enhanced cellular uptake and the prolonged retention on colonic mucosa,mediated by the strong mucoadhesion of catechol structure.Ultimately,Cur-micelles significantly mitigated colitis symptoms and accelerated colitis repair in DSS-treated mice by regulating the intestinal flora and the levels of pro-inflammatory factors(MPO,IL-6,IL-1β,and TNF-α)related to TLR4/MyD88/NF-κB signaling pathway.This work provides an effective drug delivery strategy for anti-UC drugs by oral administration.