Construction Of Core-shell Structured Theranostic System And Its Application In Combined SDT-chemotherapy Of Cancer

Cancer is one of the major diseases threatening the health of human beings. The treatment is always a challenge in the field of medical research for the following several reasons:the difficulty to carry out real-time monitoring of the carrier in vivo; multidrug resistance of cancer; inaccurate tumor targeting. To overcome the above problems, theranostic nanomedicine is emerging as a promising therapeutic paradigm. It takes advantage of various techniques of the nanoplatforms to carry out the real-time monitoring and individualized therapy.In this context, a multifucntional platform of dual-core@shell nanocomposites (DCSNCs) with NaYF4-based UCNPs and magnetic Fe3O4nanoparticles as cores and TiO2as shell was facile fabricated via the Stober method. To further improve the stability and targeting effect, hyaluronic acid (HA) was used to modify the DCSNCs (donated as HA-DCSNCs). As-prepared HA-DCSNCs exhibited good load capacity of doxorubicin (DOX) and pH-sensitive release. In addition, multiple functions including magnetic targeting drug delivery, in vivo real-time imaging, sonodynamic therapy (SDT) could also be achieved. During the experiment, excellent photothermal effect of the Fe3O4was also found and systematically evaluated in this study.Uniform Fe3O4NPs with good dispersion were synthesized by hydrothermal method and functionlized with carboxymethyl chitosan (CMCTS)(donated as Fe3O4@CMCTS). Transmission electronic microscopy (TEM), thermal gravimetric analysis (TGA) and FT-IR results revealed that CMCTS had been successfully introduced to Fe3O4particles. Transverse relaxation rate(r2) and absorbance of the Fe3O4@CMCTS were determined by MRI and UV-Vis. In a comparative study, Fe3O4@CMCTS particles exhibited a similar photothermal effect and fairly lower cytotoxicity than hollow gold nanospheres (HAuNS). The in vitro anti-tumor effect revealed that cancer cells were destructed when they were simultaneously exposed to Fe3O4@CMCTS and NIR laser. The in vivo magnetic resonance (MR) images of mice showed that by attaching a magnet to the tumor, Fe3O4@CMCTS particles accumulated in tumor after intravenous injection and maintain a high concentration for a long time. After being exposed to808nm laser for5min at a low power density of1.5W-cm-2, the tumors on Fe3O4@CMCTS-injected mice reached a temperature of-52℃and were completely destructed.Then, Er3+, Yb3+or Tm3+, Yb3+codoped NaYF4nanoparticles were synthesized by hydrothermal method. TEM imagings revealed the hydrothermal reaction time should be controlled within8h. X-ray powder diffraction (XRD) patterns of the NPs exhibited peak positions that could be well indexed in accord with cubic NaYF4crystals. In the upconversion emission spectra, both the NaYF4NPs showed high conversion efficiency. Strong upconversion light over650nm was observed even the NaYF4NPs were excited with low-power laser, which indicated the potential for in vivo imaging. In the MTT experiment, NaYF4nanoparticles showed no significant cytotoxicity.Based on the above synthesis, multifucntional dual-core@shell nanocomposites (DCSNCs) with NaYF4, Fe3O4cores and TiO2shell (NaYF4-Fe3O4@TiO2) were fabricated via the Stober method. Then, DCSNCs were modified with HA to improve the stability and targeting effect. The pH-sensitive release of doxorubicin from HA-DCSNCs was observed, which was beneficial to exert the cytotoxic effects of the NPs at the tumor site.HA-DCSNCs-DOX and HA-DCSNCs-mediated SDT anti-tumor effect were then assessed in vitro. HA-DCSNCs-mediated SDT could effectively inhibit the growth of MCF-7cells, while bare HA-DCSNCs showed no influence on the cell viability.In the combined therapy group, the irradiation of US exhibited significantly enhanced cytotoxicity of HA-DCSNCs-DOX, indicating the synergistic anti-tumor effect of SDT and DOX. The flow cytometry analysis results demonstrated that HA-DCSNCs-mediated SDT could induce the early apoptosis of MCF-7cells and the combined chemo- sonodynamic therapy would accelerate the apoptosis and necrosis of the cells. ROS that generated by HA-DCSNCs upon the activation of ultrasound might be responsible for the anti-tumor effect of SDT.Finally, the application of HA-DCSNCs-DOX and the combined cheno-sonodynamic therapy for S180tumor was investigated. HA-DCSNCs-DOX particles could accumulated in tumor after intravenous injection and maintain a high concentration over48h. The in vivo treatment results indicated that combined chemo-sonodynamic therapy could effectively suppressed the tumor growth and destroy the cancer cell completely. While the tumors were partially inhibited and destructed in other treatment groups. Besides, outstanding upconversion luminescence (UCL) bioimaging ability of HA-DCSNCs was observed in vivo experiments. The above results indicated not only the possibility of HA-DCSNCs for bioimaging and targeting drug delivery but also the potential of combined chemo-sonodynamic therapy in cancer treatment.