Reducing The Targeted Killing Effect Of Responsive Responsive Polyamino Acid-loaded Doxorubicin Micelles On Osteosarcoma

Background:Osteosarcoma(OS)is a kind of malignant tumor which origin from mesenchymal tissue.It's the primacy of primary malignant bone tumors,and has a tendency occurring in the young people.The five years survival rate now come to 60%?70%from less than 20%in 1970s,since the application of chemiotherapy and radiotherapy around the surgery in OS.Surgical resection combined with chemotherapy or radiotherapy is an effective meath for the treatment of osteosarcoma at present.But with the disadvantages of huge damage of surgery,poor special targeting and insensitive of mesenchymal tumors of chemotherapy,it always has a high rate of recrudescence or metastasis post operation.Despite a mass of researches have been performed by many international research institutions,the five years survival rate of osteosarcoma hasn't improved in last 30 years.Recrudescence and metastasis post chemotherapy are the leading cause of poor prognosis in osteosarcoma.Doxorubicin,cisplatin and high dose of methotrexate remain are the primary chemotherapy for osteosarcoma in clinical at present,others like isophosphamide,vincristine and so on are also used in treatment of osteosarcoma,because of the relative less side effects.Despite the chemotherapy has an important status in osteosarcoma treatment,but its over all effective rate is about only 60%.The severe system toxicity,poor ability of target,common resistance of primary or secondary and many other disadvantageous restrict the application and progress of chemotherapy in osteosarcoma.Nanometer loading drugs are designed beside on features of tumor tissue.It can realize to be released or activated at target tissue,decrease the drug distribution in no-target tissue,and improve the drug concentration locality.So nanometer loading drugs may solve the problem of poor target,system toxicity and so on.But its application in osteosarcoma is few now.Purpose:low response after system therapy and recurrence or metastasis after drug resistance of osteosarcoma,it's the main couse of poor prognosis.So we should search therapeutic regimens that can control the progress of osteosarcoma effectively.Inverstigaet the anti-osteosarcoma effect of nanometer loaded doxorubicin,especelly the targeted cytotoxicity and mechanism,which may provide a new sight to improve the progress of osteosarcoma.This topic is mainly studied in the following aspects:(1)Design nano-carrier system targeting osteosarcoma tissue which response to redox(mPEG-b-PtBMLC-DOX,abbreviating mPEG-DOX).(2)Verify the mPEG-DOX targeted absorb effect and mechanism on osteosarcoma in vitro and in vivo.(3)Inverstigate the targeted cytotoxicity effect and mechanism of mPEG-DOX on osteosarcoma.Method:besed on the difference of redox level between tumor cell with normal cell,using redox responsed polyamino acid bundles,we synthesized two nanometer loading doxorubicin systems.Analyse the absorb difference between normal doxorubicin and nanometer loaded doxorubicin on 143B osteosarcoma cell line under diverse redox levels using flow cytometry.Test the antitumor difference in vitro using CCK-8 analyse.Setting up tibia orthotopic osteosarcoma modle,determinate the organ distribution of nanometer loaded doxorubicin and antitumor effect using live image system of small animal.Results:nanometer loaded doxorubicin and normal doxorubicin have no difference on absorb and antitumor effect on 143B osteosarcoma cell line under normal condition.But under the condition of high level of redox,the nanometer loaded doxorubicin absorption was increased,antitumor effect was strengthened.On the other side,under the condition of low level of redox,the nanometer loaded doxorubicin absorption was decreased and antitumor effect was weakened.While the normal doxorubicin had no difference under the two condition.In mice orthotopic osteosarcoma model,the nanometer loaded doxorubicin had an increased distribution in tumor tissue and antitumor effect.Conclusions:this article designed a new redox response nanometer loaded doxorubicin micelle,and verified the targeted distribution and anti osteosarcoma effect in vitro and in vivo.This provide a new sight to improve therapeutic regimens on osteosarcoma.