Co-delivery System Of Redox-sensitive Mixed Micelles Based On MPEG-SS-PTX

Cancer is a leading cause of death in the world.The conventional cancer treatments include surgery,radiotherapy,chemotherapy,hormone therapy and immunotherapy.Among them,chemotherapy plays an irreplaceable role in the treatment of cancer.Paclitaxel(PTX)and doxorubicin(DOX)are excellent anticancer drugs that are widely used to treat solid tumors in clinic.However,the application of chemotherapy is restricted as a result of many disadvantages.For example,the solubility of PTX is poor and DOX has severe cardiotoxicity.Besides,there is systematic toxicity because of the non-specificity of drug distribution.More importantly,multidrug resistance(MDR)appears with the wide use of a single drug and becomes one of the major causes of chemotherapy failure for cancers.In order to improve the above drawbacks,we have constructed two kinds of mixed micelles based on polymer-drug conjugates.In order to improve the antitumor effect of PTX and reverse MDR caused by the treatment of a single drug,we proposed a new drug delivery system(mPEG-SS-PTX/TPGS mixed micelles),which was constructed by redox-sensitive mPEG-SS-PTX conjugate and TPGS,in the present study.The mPEG-SS-PTXwas an amphiphilic block synthesized by conjugating hydrophilic mPEG with hydrophobic drug PTX via redox-sensitive disulfide bond.And TPGS was used as a P-gp inhibitor to reverse the P-gp-mediated MDR.mPEG-SS-PTX and TPGS could self-assemble into mixed micelles in water because they are both amphiphilic.The mPEG-SS-PTX/TPGS mixed micelles had a low critical micelle concentration(CMC,?1.05 x 10-3mg/mL)and a high drug loading content(?19.6%).The average size of the micelles was 78.0 nm which was suitable for passive targeting to tumor cells by the EPR effect.The cellular uptake results showed that mPEG-SS-PTX/TPGS mixed micelles could increase the concentration of drugs in MCF-7/A cells by inhibiting the drug-efflux.Besides,the cytotoxicity test indicated that the mPEG-SS-PTX/TPGS mixed micelles showed stronger cytotoxicity compared to free PTX.Therefore,the mixed micelles could enhance the anti-tumor effect in vitro.Single drug treatments are often prone to multidrug resistance.In order to make up for deficiencies caused by the single drug treatment,combination of anticancer drugs has attracted much attention.Both doxorubicin(DOX)and paclitaxel(PTX)are anti-neoplastic agents that possess different mechanisms of action.It has been reported that the combination of PTX and DOX could synergically enhance their anticancer effect,but simultaneously accompanied by severe side effects,such as cardiotoxicity and allergic reactions.In order to relieve the side effects caused by combination of free drugs and to realize the controlled release of PTX and DOX,we have constructed a redox-sensitive co-delivery micelle system.Two kinds of redox-sensitive polymer-drug conjugates,mPEG-SS-PTX and mPEG-SS-DOX,have been synthesized by linking mPEG and PTX(or DOX)through disulfide bond.The two polymer-drug conjugates,mPEG-SS-PTX and mPEG-SS-DOX conjugates,were amphiphic and could self-assemble in water.The mPEG-SS-PTX/mPEG-SS-DOX mixed micelles had an average size of 93.3 nm,which was suitable for passive targeting to tumor tissues by the EPR effect.In addition,the ratio of PTX and DOX in the new drug delivery system was fixed and the drug delivery system could realize redox-triggered release of PTX and DOX.In vitro release profile showed both PTX and DOX released faster in reducing environment provided by DTT.Importantly,in vivo anticancer study showed the mixed micelles had better anticancer effect and lower system toxicity compared to free PTX/DOX solution during the treatment.In summary,the constructed redox-sensitive mixed micelles have good anti-tumor effect in vitro and in vivo.They are promising drug delivery systems for cancer therapy.