The Application Of MRI Tracing TiO₂-based Nanosystem For The Therapy Of Prostate Cancer

For recent years,prostate cancer?PCa?has been one of the greatest threats in men.And chemical drugs can often be used in the clinical treatment of PCa.However,due to the problems which existed in chemical drugs,such as poor solubility,disappointing selectivity,serious side effects,researchers usually adopt nanotechnology to achieve targeted therapy for tumor to increase efficiency.To overcome the difficulties in chemotherapy and increase the efficiency and safety of PCa treatment,thus,it's necessary to develop a simple but multi-mechanism system activated by ultrasound?US?with magnatic resonance imaging?MRI?for PCa.TiO₂nanoparticles?NPs?not only played a role in sonosensitizer,but also served as a nano-carrier with pH sensitivity in release of doxorubicin?DOX?.And it promoted the accumulation of DOX in the tumor site by the targeting of folic acid?FA?.The doping of Gd could attribute to give TiO₂ the performance of magnetic resonance imaging?MRI?,moreover,it further improves sonodynamic ability of TiO₂.In addition,except for as a activator trigger,the US also could produce hyperthermia to assist the tumor treatment to some extent.The experiment results of the as-prepared TiO₂:Gd@DOX/FA demonstrated sensitive drug release with pH responsivity,high reactive oxygen species?ROS?generation,good biocompatibility and T₁-MRI contrast performance.The vitro and vivo studies both verified the nanosysytem could efficiently inhibit tumor through the combined sonodynamic therapy and chemotherapy while normal organs were not damaged,and also showed high performance in MRI.In a word,TiO₂:Gd@DOX/FA nanosystem notably reduced the adverse effects arosed by DOX,amplied the production of ROS and obtained effective and safe therapy,exhibiting bright prospects of multifunctional therapy for PCa.Firstly,the preparation of TiO₂:Gd NPs was conducted according to the hydrosol-hydrothermal method.To improve hydrophilicity,TiO₂:Gd NPs were suspended in PEI solution to obtain TiO₂:Gd-NH₂ NPs.The chemotherapeutic drug DOX was linked with the TiO₂:Gd-NH₂ through a hydrazone bond by two steps.Next,TiO₂:Gd@DOX/FA NPs which can target tumor tissues were prepared by amidation with FA.Then,comprehensive characterization of the prepared TiO₂:Gd@DOX/FA involved in a range of physiochemical methods:TEM,EDS,dynamic light scattering?DLS?,FT-IR spectroscopy and UV-vis spectroscopy.The FT-IR,UV-Vis,EDS results proved the successful preparation of TiO₂:Gd@DOX/FA.TEM images demonstrated TiO₂:Gd@DOX/FA became uniform after modifying PEI and FA,agreeing well with DLS results.Finally the size and zeta potential of TiO₂:Gd@DOX/FA is 85 nm,-25 mV,respectively.The ROS generation ability of TiO₂:Gd NPs as a sonosensitizer under US was evaluated.Besides,the drug loading efficiency of TiO₂:Gd@DOX/FA was 10.2%as a nanocarrier for pH-responsitive drug delivery.In particular,approximately 78%of DOX was released under weak acid conditions at 48 h.The cytotoxicity study of the prostate cancer cell line?LNCaP cells?demonstrated TiO₂:Gd@DOX/FA as a nanocarrier possessed the excellent biocompatibility and the inhibition ratio of synergistic group?TiO₂:Gd@DOX+US?reached 91.68%at 48 h,indicating that the simultaneous synergistic effect was essential to improve therapeutic efficiency.Cell uptake experiments explained that TiO₂:Gd@DOX/FA NPs were rapidly internalized via FA receptor on LNCaP cells,which facilitated the NPs to accumulate at tumor site.These results further proved Gd could improve the sonodynamic ability of TiO₂ and also showed the great potential of TiO₂:Gd for sonodynamic therapy?SDT?.In vivo pharmacodynamics was studied and biodistribution evaluation was done using BALB/C nude mice bearing LNCaP tumors as model.The results demonstrated TiO₂:Gd@DOX/FA as an nanosystem is safe and applicable for tumor treatment.Additionally,it confirmed the active targeting efficiency and high accumulation in tumor issue of TiO₂:Gd@DOX/FA.In a word,the study indicated TiO₂:Gd@DOX/FA nanosystem as sonosensitizer is potential as well as the MRI agent for the therapy of PCa.