Targeted Therapy Of Spinal Metastatic Tumors In Mice With Drugs-loaded Hyaluronic Acid Nanoparticles

Objective:To investigate the application of CD44 receptor-targeted nanoparticles NP_DOX/CDDP in the treatment of spinal metastases,and to clarify its inhibitory effect on spine metastasis of breast cancer in mice.In order to explore the organic polymeric nanoparticle loaded with antineoplastic provide experimental basis for the treatment of spinal metastatic tumors.Methods:Hyaluronic acid?HA?was used to construct a breast cancer targeted nanoparticle via hydrophilic and hydrophobic interactions,and its particle size,stability,doxorubicin and cisplatin release profiles at different pH conditions were measured.Then,the spinal metastasis BALB/c mice model was developed by intraosseous implantation of 4T1 breast cancer tissue.The mice were randomized according to tumor volume and body mass,then treated with tail vein injection of PBS,free drug mixture?DOX/CDDP?and NP_DOX/CDDP.The antitumor effect and biosafety of the NP_DOX/CDDP were evaluated by detecting the motor function,mouse's weight,tumor imaging reconstruction and immunohistopathology.Moreover,the biological distribution of NP_DOX/CDDP in the mice was studied by biofluorescence imaging.Results:The average particle size of NP_DOX/CDDP was?80.0±17.4?nm,which was stable under pH 7.4.Under the acidic conditions,the particle size increased,it can effectively release DOX and CDDP.In tumor inhibition experiments,compared with the DOX/CDDP group,the body weight of mice in the NP_DOX/CDDP group increased?P<0.05?,the mouse BBB motor function score increased?P<0.01?,and the angle of the inclined plane test was increased?P<0.05?.Footprint experiments showed that the symptoms of paralysis in mice in the NP_DOX/CDDP group were significantly improved and only minor claudications remained.The HE staining showed that in the untreated group,alveolar septum widening,hepatocyte necrosis,and myocardial fiber were also damaged.Compared with the DOX/CDDP group,the visceral injury and bone marrow cell micronucleus rate was significantly reduced in the NP_DOX/CDDP group.For tumor imaging evaluation,the destruction of spinal bone tissue can be seen in DOX/CDDP group,NP_DOX/CDDP group and Untreated group.The severity of tumor damage to lamina,invasive segment,and bone structure has the following sequence:Untreated group>DOX/CDDP group>NP_DOX/CDDP group.Compared with DOX/CDDP group,the activity of Caspase-3 in NP_DOX/CDDP group was significantly increased?P<0.01?,while the Ki-67 activity was significantly decreased?P<0.01?.The biofluorescence imaging showed that the nanoparticles NP_DOX/CDDP could accumulate to the tumor site by targeting,and effectively release the drug.Conclusions:1.NP_DOX/CDDP nanoparticles can effectively accumulate in breast cancer spinal metastasis tumors through EPR effect and CD44 receptor targeting,effectively releasing DOX and CDDP;2.NP_DOX/CDDP can effectively improve the motor function of the mouse model of spinal metastasis and reduce the damage of the tumor to the bone tissue and nerve structure of the spine;3.NP_DOX/CDDP can effectively reduce the toxicity of chemotherapeutic drugs and enhance the therapeutic effect of metastatic spinal tumors.