Research On Reversing Drug Resistance Of SKOV3_TR Based On Mesoporous Silicon-gold Nanosystem Carrying PTX/miR Let-7a

Ovarian cancer,as a health killer for women,has increasingly become a hot topic of concern.Its main treatment is surgery combined with chemotherapy drugs,like paclitaxel and platinumy.However,multidrug resistance(MDR)can cause chemotherapy failure which resulted in tumor recurrence in 50%～75%of patients.In recent years,targeted drug delivery system based on nanotechnology have great application prospects in the prevention,diagnosis and treatment of ovarian cancer.Therefore,we constructed an argeted drug delivery system based on nanotechnology which used hyaluronic acid(HA)as the targeting molecular,loaded gene and chemotherapy drugs.The system with gold nanorods(GNRs)as the core and mesoporous silicon(MSN)for functionalization modification to simultaneously load the chemotherapy drug paclitaxel(PTX)and gene drug(miR let-7a),targeted drug to ovarian cancer resistance SKOV3TR cells and ovarian cancer tissues using HA as targeted CD44 molecular to explore the reverse effects of the co-delivery system about ovarian cancer drug resistance and its mechanism.Firstly,the Characterization and drug-loading performance of nano-drug delivery system were analyzed using transmission electron microscope(TEM),high angle annular dark field scanning transmission electron microscope(HAADF-STEM),high resolution transmission electron microscope(HRTEM),X-ray diffractometer(XRD),Malvern laser particle size-zeta-potential analyzer,Fourier transform infrared(FTIR)spectroscopy,high performance liquid chromatography(HPLC)and other analytical testing methods.The hemolysis experiment was performed to investigate their biological safety.The results showed that the nano co-delivery system was successfully synthesized and has good loading and release properties and could be used in the subsequent experiments in vivo and in vitro.Secondly,the effect of the MDR reversal by the nano-delivery system was examined at the cell level in vitro.The results showed that HA-pGNR@MSN could be ingested with a better targeting capacity The proliferation ability of SKOV3TR cells significantly reduced,and the number of dead cells increased,and the nuclei irregular morphology were found after treated by HA-PTX/miR let-7a-pGNR@MSN to induce the production of reactive oxygen species and significantly promote cell apoptosis.The number of normal cells in SKOV3TR cells was only 42.8%.Western blot results confirmed that HA-PTX/miR let-7a-pGNR@MSN could effectively reduce the expression of P-gp to overcome the multidrug-resistance,and enhance the inhibition effect on tumors proliferation,and induce apoptosis,and the synergistic anti-tumor effect of miR let-7a and PTX.Finally,we established a animal model of drug-resistant ovarian cancer with nude mice to further study the inhibitory effect of co-drug-loaded nanocarriers on tumors.The results showed that HA-PTX/miR let-7a-pGNR@MSN could significantly inhibit tumor growth and has low toxicity and good safety.In summary,the nanocarriers of HA targeting,PTX/miR let-7a high-efficiency and synchronous delivery were constructed in this study,could efficiently deliver drugs to the targeting SKOV3TR and target tissues to down-regulate the expression of P-gp protein to effectively reverse the MDR of ovarian cancer,and simultaneous delivery of PTX/miR let-7a produces a synergistic effect of inhibiting the growth of ovarian cancer,and further increases the apoptosis of ovarian cancer cells and tumor tissues.This research provides a reliable application and theoretical basis for overcoming MDR of ovarian cancer,and realizing efficient treatment of ovarian cancer.