Drug Nanocarriers For Tumor Immunotherapy Combined With Chemotherapy For Thyroid Cancer

Background and objective:Thyroid cancer is the most common endocrine malignancy,accounting for 1.7%of all cancers.In the past 30 years,its incidence has increased year by year.By 2017,the number of patients with thyroid cancer worldwide has reached 3.2 million.Among them,the number of female thyroid cancer patients is about three times that of male patients,and thyroid cancer has become the fifth most common malignant tumor in women.Differentiated thyroid cancer has a better prognosis than undifferentiated carcinoma and medullary carcinoma,but for patients with distant metastasis and radioactive iodine resistance,treatment options are very limited.Patients with undifferentiated carcinoma and medullary carcinoma are mostly diagnosed at the advanced stage of the tumor and have obvious distant metastasis of the tumor.They lose the best time for surgery,and the patient's own state is poor,and can not tolerate radiotherapy and chemotherapy,which brings difficulty to the treatment.Therefore,we urgently need to find a more effective treatment to treat refractory thyroid cancer.Tumor immunotherapy is a treatment method for controlling and clearing tumors by changing the tumor immune microenvironment and restoring the normal anti-tumor immune response of the body.This study firstly explored the expression of PD-L1 and CD47 in tumor cells treated with JQ1,and designed and synthesized a nano drug carrier combining BRD4 small molecule inhibitor JQ1 and CD47 siRNA molecules for the treatment of tumor-bearing mouse tumor models.The drug-loaded nanoparticles can not only exert anti-tumor effects in cell lines in vitro,but also can be enriched in tumor tissues in tumor-bearing mice.It enters tumor cells and rapidly disintegrates in tumor cells,releasing anti-tumor drugs,thereby enhancing anti-tumor effects,reducing the dosage of chemotherapeutic drugs,saving costs and reducing its side effects.Method:1.The effect of JQ1 on the expression of PD-L1 and CD47 in tumor cells was detected by flow cytometry.2.The surface potential and particle size of the synthesized drug-loaded nanoparticles were determined by a particle size analyzer.3.Real-time quantitative PCR was used to detect the effect of nanoparticles on the expression of PD-L1 and CD47 in tumor cells.4.Flow cytometry and laser confocal microscopy were used to observe the distribution of drug-loaded nanoparticles in tumor cells.5.The distribution of drug-loaded nanoparticles in tumor-bearing mice was detected by small animal living imager.The distribution of drug-loaded nanoparticles in tumor tissues was detected by laser confocal microscopy.6.The tumor growth curve was observed by injecting different drug-loaded nanoparticles into the tumor-bearing mice by tail vein injection.Result:1.JQ1 can down-regulate the expression of PD-L1 in tumor cells.2.Nanoparticles containing both JQ1 and CD47 siRNA molecules were successfully prepared.The particle size of _JQ1NPs^CD47siRNAD47siRNA was about 123.8±1.1 nm,and the potential was about 10.05±0.66 mV.3._JQ1NPs^CD47siRNAD47siRNA can down-regulate the expression of PD-L1 and CD47 in tumor cells in vitro.4._JQ1NPs^CD47siRNAD47siRNA can deliver the drug into the tumor cell line in vitro,and can be enriched in the tumor tissue of the tumor-bearing mouse in vivo and enter the tumor cell to exert an anti-tumor effect.5._JQ1NPs^CD47siRNAD47siRNA can significantly inhibit tumor growth in tumor-bearing mice.Conclusion:We designed and synthesized a nanocarrier combined with JQ1 and CD47 siRNA molecules for immunotherapy and chemotherapy combination in tumor-bearing mouse tumor models.The drug-loaded nanoparticle can be enriched in the tumor tissue of the tumor-bearing mouse,and can enter the tumor cell,disintegrate in the tumor cell,release the anti-tumor drug,and exert the tumor immunotherapy,thereby enhancing the anti-tumor effect and reducing the chemotherapy.The dosage of the drug is used to save costs and reduce its side effects.