Application Of Tumor Micro-environment-responsive Nanodrug Delivery System In The Treatment Of Breast Cancer

The nano drug delivery system can control the release of the drug,so as to effectively deliver the effective amount of drug to the disease site,which greatly improving the stability and bioavailability of the drug.In the treatment of diseases,the toxic and side effects of the nano drug delivery system will be greatly reduced,and the therapeutic effect of the drugs on the disease will be significantly improved.Therefore,the nano drug delivery system has become a new clinical strategy for treating diseases due to its unique advantages.Today,cancer-related deaths account for 13%of global deaths and have been recognized as one of the most challenging and devastating diseases in the world.For women,breast cancer is still the most frequent malignant tumor.Generally,most breast cancer patients have corresponding metastatic symptoms at the time of consultation,especially the continuous loss of skeletal muscle tissue caused by bone metastasis of breast cancer cells,which can cause persistent pain,pathological fractures,and limited joint movement.Patients with advanced breast cancer usually lose self-care ability,then companied with a poor quality of life and have a high mortality rate.Therefore,it is urgent to find a safer and more effective method to treat breast cancer of patient clinically.Therefore,we construct the drug-loaded delivery system based on synthetic high molecular polymers or natural high molecular polymers for breast cancer.The research mainly conclude following two parts:1.The application of ROS-responsive polymer nanoparticles loaded with chemotherapeutics in the treatment of breast cancer:In this part of the work,a polymer with reactive oxygen response（ROS）activity was synthesized:poly（vanillyl alcohol-co-oxalate）（PVAX）.Then,PVAX was used as a drug delivery carrier to load the anti-tumor drug curcumin（CUR）,and CUR-loaded nanoparticles（PVAX-NPs）based on PVAX were prepared by the solvent evaporation method.At the same time,polylactic-co-glycolic acid（PLGA）copolymer was used as a control drug delivery carrier to load CUR to obtain PLGA-NPs.We characterized the physical and chemical characteristics of the nanoparticles（the hydrated particle size,surface charge,surface morphology,and encapsulation efficiency）.The obtained PVAX-NPs had uniform particle size（about 242 nm）and stable surface negative charge（about-17.3 mV）,which allows the nanoparticles to be effectively can phagocytosied by cells,and chemotherapeutic drugs can play an anti-cancer effect inside MCF 7 tumor cells.In addition,we simulated the drug release of PVAX-NPs in an environment rich in hydrogen peroxide（H₂O₂）,and the results showed that PVAX-NPs can react with H₂O₂ and accelerate drug release.More importantly,we validated the anti-cancer activity and pro-apoptotic capacity of the ROS-responsive nano drug-loading system in vitro and in vivo.Compared with PLGA-NPs,PVAX-NPs showed a stronger ability to inhibit breast cancer cell proliferation.In summary,this PVAX-based ROS-responsive nano-delivery system can effectively inhibit the proliferation of breast cancer cells.2.Application of chemotherapeutic drug-loaded functionalized silk fibroin nanoparticles in targeted combination chemotherapy for breast cancer:In this part of the work,silk fibroin（SF）was extracted from natural silkworm cocoons,and used regenerated silk fibroin（RSF）as a drug delivery carrier for the antitumor drugs curcumin（CUR）and 5-fluorouracil（5-FU）.Hyaluronic acid（HA）modified drug-loaded nanoparticles based on regenerated silk fibroin（RSF）modified by desolvation method were used,using carboxymethyl cellulose（carboxymethyl cellulose）cellulose,CUL)modified drug-loaded nanoparticles as its control.We characterized the physical and chemical characteristics of the hydration particle size,surface charge,surface morphology,and encapsulation efficiency about various nanoparticles（HA-NPs and CUL-NPs）.Most importantly,we simulated the multiple-responsive release of HA-NPs in different pH,different concentrations of reactive oxygen species（ROS）,glutathione（GSH）,and hyaluronidase（HAase）.The results show that HA-NPs NPs can respond to multiple responsive environments in the body and accelerate drug release.Cell experiments further showed that after 48 h of culture,the combination index（CI）of HA-CUR/5-FU-NPs（1:4）was lower than0.06,indicating that the two drugs had a synergistic effect and HA-CUR/5-FU-NPs（1:4）has a strong ability to inhibit the proliferation of 4 T1 cells and the ability to induce apoptosis of cancer cells.The results of in vivo anti-breast cancer experiments clearly show that HA-NPs have higher anti-breast cancer activity than CUL-NPs.Moreover,the dual-drug combination therapy has a better anti-cancer effect.Therefore,the nano-drug delivery system with pH/ROS/GSH/HAase multiple response based on silk fibroin carrier can effectively inhibit the proliferation and metastasis of breast cancer cells.In summary,the two parts of this paper are both closely related and different.The nanocarrier used in the project has changed from a synthetic polymer PVAX to a natural polymer silk fibroin.The breast cancer microenvironment response type has changed from ROS response type to become a pH/ROS/GSH/HAase multiple response type.The nanoparticle delivery method has also changed from passive targeting to active targeting.Both in vivo and in vitro experiments have proved that the nano-delivery system based on synthetic polymers or natural polymers as the carrier used in this study has a good stimulus responsiveness to the microenvironment of breast tumors,which can realize the controlled release of drugs.The breast tumors cell proliferation and metastasis were effectively inhibited.So the nano-delivery system have broad application prospects in breast cancer chemotherapy.