The Primary Research On The Growth Inhibition And Reverse Function Of Drug Resistance In Breast Cancer Based On The Novel Mesoporous Silica Nanocomposite Construction

Breast cancer is a malignant tumor that occurs in the mammary epithelial tissue.It is a serious threat to women's health and even life.The incidence of breast cancer stays at the top rate among all the female malignant tumors in the United States.In recent years,the incidence of breast cancer in China is 1² percentage higher than that in high incidence countries which has a young trend nowdays.Breast cancer has become a major public health problem in the current society.Tumor drug resistance is the main cause of chemotherapy failure in breast cancer,and it is an important factor affecting the prognosis of the cancer patients.Therefore,the study of new methods to overcome or reverse the chemotherapeutic drug resistance of breast cancer has become a key exploration direction.In this study,we used magnetic mesoporous silica nanomaterials to construct nanocomposites with tumor double targeting and pH response release.The nanocomposites combined with autophagy inhibitor can achieve tumor-targeted chemotherapy/photodynamic therapy,control the release of drugs and reduce the side effects.The study mainly includes the following three parts:In the first part of this study,the mesoporous silica nanoparticles with core-shell structure was synthesized by improved St?ber method.The diameter of MSN was about 100nm with uniform particle size,regular spherical morphology and good dispersion.Next,magnetic mesoporous silica nanoparticles were constructed on the surface of aminated MSN by nucleophilic substitution of superparamagnetic iron oxide nanoparticles.DCC was used as a condensation agent to combine the photosensitizer Ce6,the BCRP inhibitor Ko143 and DOX were loaded,the polymer FA-PEG-b-PAsp was crosslinked.Thus,we successfully designed and synthesized nanocomposites Ce6@MMSN/DOX/Ko143@PAsp-b-PEG-FA.The DOX drug loading of the nanocomposites was 21.76%,and the study of pH corresponding drug release showed that the nanocomposites had pH sensitive control release performance,and the cumulative release rate of DOX was up to 80.53%at 60 h under the acidic condition.The nanocomposites had a good superparamagnetic,which was potential for magnetic targeting.In the second part of this study,the proliferation inhibition and reversal effect of nanocomposites on MCF-7/ADR cells were evaluated at the cellular level.The results of fluorescence microscopy,transmission electron microscopy and flow cytometry showed that the nanocomposite possessed good magnetic targeting,folic acid targeting and cellular uptake ability.CCK-8 results showed that the IC₅₀ value of nanocomposites on MCF-7/ADR cells was 4.23?g/ml,and free DOX was 363.2?g/ml.Thus,nanocomposites could significantly reverse the resistance of MCF-7/ADR cells and effectively induce apoptosis or death of MCF-7/ADR cells.Transwell experiments results showed that nanocomposites could effectively inhibit the transfer and migration of MCF-7/ADR cells.In the third part of this study,the therapeutic effect of nanocomposite on DOX resistant breast cancer was evaluated by observing tumor volume,tumor weight,nude body weight and life cycle in vivo.A model of drug-resistant breast cancer was established by injection MCF-7/ADR cells on the fourth breast fat pad of BABL/c nude mice.The results of Prussian blue staining showed that the nanocomposites had good magnetic targeting in vivo.The blood biochemical parameters and HE staining showed that the toxicity of the nanocomposites was less in vivo.The tumor volume and tumor weight of nude mice showed that the nanocomposite significantly inhibited the growth of tumor.The survival curve showed that the nanocomposite could prolong the survival time of nude mice.The volume and weight of the tumor were least in the magnetic nanocomposite group,and the survival period was the longest.The results of animal experiments showed that nanocomposites have good therapeutic effect and small side effects in DOX resistant breast cancer in vivo.In conclusion,we successfully synthesized nanocomposites with double targeting and pH responsive drug release.These nanocomposites had well superparamagnetic and can be effectively uptaken by MCF-7/ADR cells.The nanocomposites with good folate targeted,magnetic targeting and pH responsive drug release properties had good effect of inhibiting the growth and metastasis of drug-resistant tumor both in vivo and in vitro.Furthermore,the nanocomposites could overcome the drug resistance of tumor cells and reduce the side effects of chemotherapeutic drugs.This study was expected to provide a new idea for the design of tumor targeting delivery system and open up a new way for the treatment of drug-resistant breast cancer,which has great scientific and research significance.