A Multiple Environment-sensitive Prodrug Nanomicelle Strategy For Enhancing Anti-tumor Therapy Of Chemo-immune Synergy

Tumor was a serious threat to human health.Chemotherapy was one of the main ways of tumor treatment,and cytotoxic compounds were used to kill tumor cells.But it had great toxic and side effects on normal tissues.In addition,in the process of tumor treatment,the immunosuppressive state of tumor microenvironment was easy to evolve resistance to chemotherapy drugs,and resulted in treatment failure.Improving the immunosuppressive state of tumor microenvironment was an effective strategy to increase the therapeutic effect of chemotherapy drugs.Furthermore,abnormal proliferation of tumor cells could lead to acidic microenvironment and high intracellular concentration of GSH,which can be used as environmentally controlled conditions for accurate delivery of anti-tumor drugs by nanoccarriers.According to the acid tumor microenvironment and high concentration of GSH within the tumor cells,Dextran with good biocompatibility was used as the skeleton,which was connected with CPT by way of the reduction-responsive disulfide bond,and was grafted with PTD through the acid-base sensitive ester bond.The synthetic compounds had good drug loading ability and environmental response for controlled release.The prepared amphiphilic prodrug CPT-SS-DEX-PTD could be selfassembled into micelles.The prepared micelles were spherical profile under TEM,with diameter of about 180 nm and Zeta potential of about-12 m V.The polymer micelles had good stability in storage at 4 °C,25 °C and 37 °C and lyophilization reconstitution.The results of hemolysis test showed that the micelles hemolysis rate was less than 5 %,and indicated its application safety.In vitro drug release experiments showed that the cumulative release of CPT in micelles was 96 % in the10 mmol/L concentration of GSH,and the cumulative release of PTD in micelles was91 % in p H 6.5 PBS.These results indicated that the release of CPT in micelles was GSH responsive,and the release of PTD in micelles was p H responsive.Pharmacokinetic results showed that CPT-SS-DEX-PTD group compared with free CPT group and free PTD group,had higher peak concentration and larger area under drug time curve.The prepared micelles could increase plasma drug concentration of CPT and PTD and increase drug bioavailability.Pharmacodynamics results showed that CPT-SS-DEX-PTD micelles group had better antitumor effect in 4T1 cytotoxicity test.Compared with free CPT+PTD group,the CPT-SS-DEX-PTD micelles group had significant anti-tumor effect in 4T1 tumor-bearing mice and reduced the toxic and side effects of CPT.In conclusion,the prepared polymer micelles(CPT-SS-DEX-PTD)could release PTD into the tumor microenvironment to improve the immunosuppressive state,deliver CPT to tumor cells and kill tumor cells,and display synergistic anti-tumor effect.The prepared micelles could effectively reduce the toxicity and side effects of CPT,increase bioavailability,and achieve to chemo-immunotherapy synergistic anti-tumor.These results indicated that micellar had good chemo-immunotherapy antitumor effect,and provided a new treatment option for cancer patients.