Preparation Of Near Infrared Light Responsive Upconversion Nanocarrier For Reversing Tumor Multidrug-Resistance

At present,the main methods of treating cancer are radiotherapy,chemotherapy and surgical resection.Although chemotherapy is the most widely used treatment strategy,there are still some problems in clinical application.For example,broad-spectrum antitumor drug doxorubicin（DOX）is one small molecular drug,which can penetrate the blood vessel wall during the blood circulation and enter into the normal area by free diffusion,resulting in serious side effects to normal tissues.In addition,prolonged use of a chemotherapy drug can easily lead to multidrug resistance（MDR）in tumor cells,which results in the failure of chemotherapy.It is generally accepted that ATP binding cassette transporter（ABC）,which is highly expressed on the surface of tumor cell membrane,is the main cause of drug resistance.Among these ABC transporters,P-glycoprotein（P-gp）plays the most important role.When the drug enters the cells,P-gp will eliminate the drug through the cell membrane with the support of ATP,therefore the amount of intracellular drug will be insufficient kill the cancer cells.With the development of molecular biology and the intensive study of the mechanism of tumor drug resistance,more attention has been paid to gene therapy for MDR.At present,RNA interference technique has attracted much attention as a highly efficient and specific new technique for inhibiting gene expression to reverse tumor drug resistance.P-gp targeting small interfering RNA（siRNA）is employed to,develop siRNA and chemotherapy drug codelivery system by inhibiting the expression of P-gp,improving the therapeutic effect of chemotherapy drug against tumor.In recent years,upconversion nanoparticles（UCNPs）have attracted widespread attention in biomedical field due to their own advantages.UCNPs have stable physical and chemical properties,optical properties,low background fluorescence and strong antiphotobleaching ability.Meanwhile,the near infrared light can increase the penetration depth of the tissue.However,there are few reports on near infrared light triggered chemotherapeutic and genetic drugs release system based on upconversion nanocarriers to reverse tumor mulitdrug-resistance.In this project,by combining chemotherapy with gene therapy,we construct a multifunctional nanoplatform to reverse tumor mulitdrug-resistance-using mesoporous silica（mSiO₂）coated UCNP.A functional photosensitive group was employed as the sensitive"gate"to encapsulate an anticancer drug DOX in the mesopore.Upon 980 nm laser irradiation,UCNPs can convert NIR light into UV light to break the bond of photosensitive group and release the siRNA and encapsulated DOX.In the present study,in vivo and in vitro results indicate that the multifunctional nanoplatform realized efficient delivery of chemotherapy and gene drugs,and effectively inhibited the proliferation of mulitdrug-resistance cancer cells by inhibiting the expression of P-gp.These results provide new idea for the construction of drug and gene delivery system to reverse mulitdrug-resistance,and have great significance for providing basic research data for the clinical application of small nucleic acid and combined cancer therapy in the future.