Preparation And Anticancer Study Of Novel Tumor-Microenvironment-Modulating Nanomedicines

Nanomedicines have enhanced the anticancer efficacy and reduced the side effects of the drugs by improving the pharmacokinetic parameters and promoting tumor targeting,etc.At the same time,abnormal tumor microenvironment,including low pH,high reactive oxygen species(ROS),high glutathione(GSH),etc.have been widely used to trigger tumor-specific drugs release.However,the efficiency and selectivity are hampered because of the tumor heterogeneity.Also,the detoxification mechanism in the tumor tissue limits the efficacy.This work aims to change the tumor microenvironment to improve tumor selectivity and overcome the detoxification mechanism,and enhancing the therapeutic effect of nanomedicine.Tyrosinase is specifically overexpressed in melanoma and it can catalyze the oxidization of substances,containing phenolic hydroxyl groups,to increase ROS and reduce GSH within the cells.Thus,in the first part,a tyrosinase-responsive cascadeamplification drug release nanoparticle(TR-CARN)was designed to achieve melanoma-specific therapy.Acetaminophen(APAP),which could be oxidized by tyrosinase,was linked to amphiphilic polymer PEG-PAPAP through thioether bonds,and prodrug BDOX was loaded into the polymer to obtain TR-CARN.Once TR-CARN entered the tumor,endogenous ROS triggered initial APAP and BDOX release and the release rate were slow.Tyr-mediated ROS synthesis by APAP then accelerated APAP and BDOX release and activation.This process could not happen in normal tissues and other tumors thus is highly melanoma selectivity.TR-CARN had a high drug loading efficiency(22.5%)with a suitable size(65 nm)and surface Zeta potential(-13.8 mV)for in vivo application.The particle was stable after 7 days of incubation in FBS.TRCARN remarkably increased the ROS level in B16F10,which accelerate the release and activation of BDOX into DOX.In mouse tumor models,it showed a significantly enhanced efficacy than DOX with reduced side effects.In the second part,PDA/Tyr/Pt was designed and prepared to reduce the GSH level and enhanced the antitumor efficacy of cisplatin.PDA/Tyr/Pt consisted of PDA,hyaluronic acid(HA),cisplatin,and tyrosinase,among them tyrosinase could catalyze the oxidization of substances,containing phenolic hydroxyl groups,to delete GSH and avoid the detoxification mechanism towards cisplatin.The particle size was 86 nm with the surface potential of-32 mV,and it was stable in FBS.The Cisplatin was complexed with hyaluronic acid(HA),and the release rate was accelerated under acidic conditions.At the same time,HA could target CD44 to promote cancer uptake and tumor accumulation.PDA/Tyr/Pt exhibited an excellent ability to reduce GSH level,so it showed low IC50 than PDA/Pt,which did not contain tyrosinase,and it efficiently hampered the tumor growth in mouse tumor models.Finally,we invented PMT/BSN38 to solve the problems that indoleamine 2,3dioxygenase inhibitor idoximod(1-MT)were met in clinical:excessive toxicity when combined with chemotherapy and the low intestinal absorption efficiency.PEG-PMT was decorated with 1-MT,which acts as the hydrophobic part,and prodrug BSN38 was loaded into PMT/BSN38.Because of the strong crystallization ability of SN38,it can hardly be loaded in the nanoparticle.However,BSN38 could be easily packaged into PMT/BSN38 with a loading content of 12.6%.Esterase could trigger 1-MT release and ROS could mediate SN38 release from PMT/BSN38,efficiently.PMT/BSN38 could kill cancer through immunogenic cell death and synergize chemotherapy and immunotherapy to achieve superior anticancer efficacy.Also,PMT/BSN38 improved the immune microenvironment in tumor and lymph nodes and the cytokine in serum.