Thermo-sensitive PLGA-PEG-PLGA Hydrogels Loaded Chemotherapeutic Drugs For In Situ Osteosarcoma Treatment

Background and purposeOsteosarcoma(OS),one of the most common primary tumors of the bone,occurs predominantly in childhood and young adults.OS usually affects the skeletal areas,include distal femur,proximal humerus,and proximal tibia.OS exhibits histological and molecular heterogeneities.Currently,the standard clinical managements in OS are surgical excision and systemic multiagent chemotherapy.However,the long-term survival rate of patients without metastasis is 65~70%.Various polymer materials have been investigated for drug delivery system.Thermo-sensitive PLGA-PEGPLGA hydrogel had been used as a perfect drug-carrier,because of its convenient synthesis and perfect gelling ability.The chemotherapeutic drugs loaded by PLGA-PEG-PLGA hydrogel for OS in situ treatment to evaluate the antitumor efficiency and the systemic security of this drug delivery system.Methods:1.The synthesis and characteristics of PLGA-PEG-PLGA hydrogel.PLGA-PEG-PLGA hydrogel synthesized by the ring opening copolymerization.The molecular structure of synthesized hydrogel has been determined by 1H NMR.The phase transition,rheological property,in vitro degragation and cytotoxicity of PLGA-PEG-PLGA hydrogel have also been investigated.The in vivo gel forming and biocompatibility of PLGA-PEG-PLGA hydrogel were evaluated by subcutaneous degradation study.2.The in vitro drug release and in vivo drug distribution of drug loaded hydrogel.The sustained release manner of drug loaded hydrogel has been studied by ex vivo imaging.We test the drug release behavior and the anti-proliferation efficacy to K-7and Saos-2 cells in vitro.Then we created a mice xenograft tumor model by K-7 cells,injected the DOX-loaded PLGA-PEG-PLGA into the tumor site for in vivo anti-tumor experiment.3.In this work,we synthesized the ?-CD-CUR inclusion complexes by ?-CD and Curcumin.The ?-CD-CUR had hgih solubility in aqueous solution and high stability.DOX combined by ?-CD-CUR co-loaded into PLGA-PEG-PLGA hydrogel forming stable drug-gel status.The dual drug delivery system could sustained release the CUR and DOX at a suitable release speed.MTT and live/desth cell study were adopted to evaluate the anti-tumor efficacy of DOX and CUR co-loaded hydrogel.The in vivo anti-tumor efficacy of DOX and CUR co-loaded hydrogel has been investigated by using tumor-bearing mice.Results:1.The tri-block PLGA-PEG-PLGA hydrogel has been synthesized successfully.The thermosensitive hydrogels exist as liquid solution at room temperature,and rapidly transform into gel status at physiologic temperature.PLGA-PEG-PLGA hydrogels exibite and excellent property of biocompatibility and syringeablity,can been used as perfect implanting materials.2.The DOX-loaded hydrogel,as a localized drug delivery system,can sustained release the DOX in tumor sites,significantly improving the drug retention time.The DOX-loaded hydrogel significantly enhanced the antitumor efficiency,compared to free DOX treatment.In addition,there was no obvious body weight loss in DOX-loaded hydrogel treated mice,even at a relatively higher dose of loaded DOX(15 mg/kg).3.MTT assays and live/desth cell study verified that the anti-tumor efficacy of CUR and DOX co-loaded hydrogel was much better than sole-drug treated strategies.As a result,this combination therapy possessed a robust anti-tumor efficacy than the sole-drug therapy.Conclusion:Thermo-sensitive PLGA-PEG-PLGA hydrogel can been used as a suitable drug-carrier,drug loaded PLGA-PEG-PLGA hydrogel possesses high antitumor efficiency and well systemic security for in situ OS treatment.