Construction And Application Of Integrated Nano-platform For Osteosarcoma Diagnosis And Treatment

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents,the treatment of osteosarcoma includes chemotherapy and surgery.Large scale surgery（amputation）did not result in drastic improvements.High dose chemotherapy is very important for the long-term survival of patients with osteosarcoma.However,single drug treatment often has side effects on human body.With the development of modern medicine and the deepening understanding of the nature of tumor,people found that tumor microenvironment（TME）area has its own characteristics,such as faintly acid,high hydrogen peroxide（H₂O₂）content and hypoxia environment,etc.They play extremely important roles in the development and metastasis of tumor.With regarding to the particularity of tumor microenvironment（high H2O2 content and weak acidity）and the“Fenton reaction”principle inspired by environmental science,new therapeutic strategy will be established for tumor treatment.People have proposed a new concept of“chemodynamic therapy”,which utilizes ferrous ion(Fe²⁺)-mediated Fenton reaction to induce intracellular oxidative stress by converting less-reactive H₂O₂ into hydroxyl radicals（·OH）.Due to the multivalent state characteristics of transition metals,other metal ions such as Mn²⁺,Co²⁺and Cu²⁺also show Fenton-like activity.However,these nanomaterials are often ineffective.There are two main reasons for this result:on the one hand,it is difficult to target the bone marrow in situ;on the other hand,the reactive oxygen species produced will be consumed by excessive glutathione in the microenvironment.It is highly desirable to develop a new hybrid nanoplatform that integrates targeting and treatment elements for effective theranostics of tumors.Based on the above problems,the research work of this paper is mainly carried out from the following aspects:We demonstrated the engineered multifunctional based on Au core/manganese-doped mesoporous silica nanoparticles（Au@MMSN）nanoplatform.Alendronate（Ald）,a clinical bisphosphonate drug,was conjugated onto the Au@MMSN surface for bone targeted drug delivery because of the affinity to hydroxyapatite（Au@MMSN-Ald）.The results of cell experiment showed that high concentration of GSH in tumor microenvironment occurs redox reaction with Mn-O framework,which not only promote the biodegradation of Au@MMSN,but also yield Mn²⁺and GSSH.The released Mn²⁺turned endogenous H₂O₂ which produced by mitochondria into toxic·OH through Fenton-like reaction.Because of GSH depletion-induced impairment,this process intensified tumor CDT and realized chemo–chemodynamic combined therapeutic process.In the assessment of imaging function,gold nanoparticles（Au NP）and released Mn²⁺work together to achieve CT/MRI dual-modality imaging.Most importantly,after verifying that Au@MMSN-Ald has good biocompatibility,the drug-loaded particles DOX@Au@MMSN-Ald showed the best anti-tumor effects both in vivo and in vitro.Therefore,the DOX@Au@MMSN-Ald nano diagnosis and treatment platform is expected to promote the clinical conversion of chemodynamic therapy and the development of multimodal cancer diagnosis and treatment.