Delivery Of Curcumin By Reversible Disulfide Core Cross-Linked Polymeric Micelles

Curcumin was reported to possess anti-tumor,anti-inflammatory,anti-bacterial,and anti-oxidant bioactivities.However,its low water-solubility,rapid systemic elimination,and poor bioavailability had extremely limited its application.Polymeric micelles could overcome these difficulities but easily lost their drug content after systemic administration.The study prepared curcumin-loaded micelles with a novel polymer and finally determinted a series of characteristics.The main results are as follows:1)We firest synthesized a novel polymer methoxy-poly(ethylene glycol)-block-poly(D,L-lactic acid)grafted with four 6,8-dithio-n-octanoin acids(mPEG-PLA-(LA)4),and then determined its characteristics.Gel permeation chromatography showed that the polydispersity index was 1.0287,meaning narrow molecular weight distribution.The critical micelle concentration was 0.012 mg/ml,suggesting great thermodynamic stability.2)We exproled and optimized the conditions of curcumin-loaded core cross-linked micelles(curcumin-loaded CCM)and determined its physicochemical properties.Nitrogen and alkalescent buffer(pH 8.5)were beneficial for cross-linking.Drug loading capacity(DLC)of 5%and drug concentration of 3 mg/ml with ethyl acetate as organic solvent and glucose as cryoprotector contributed to robust micelles.The cross-linking density was 72.6%.Particle size was 17.65 nm.Actual DLC and encapsulation efficiency were 4.44%and 89.93%,respectively.The curcumin-loaded CCM possessed great stability in sodium dodecyl sulfate solution and the mixture remained clear even after 24 h.3)The biological performances of curcumin-loaded CCM were investigated.The drug release showed that curcumin-loaded CCM was much stable but weak in reductive conditions with 81.8%of curcumin released.Curcumin-loaded CCM showed weak cytotoxicity against MCF-7 celles,while when intracellular glutathione concentration improved,the IC50 was 24.8?g/ml.The pharmacokinetics in Sprague-Dawley reflected that curcumin-loaded CCM could significantly improve micellar stability and curcumin concentration in blood could still retain 5.8%after 24 h.The tumor growth inhibition of combination of curcumin-loaded CCM and anti-PD1 antibody was 98.5%after 16 days,higher then both single,which suggested that curcumin-loaded CCM could enhance anti-tumor effect of anti-PD1 antibody.