摘要
Postoperative anatomical reconstruction and prevention of local recurrence after tumor resection are two vital clinical challenges in osteosarcoma treatment.A three-dimensional(3D)-printed porous Ti6Al4V scaffold(3DTi)is an ideal material for reconstructing critical bone defects with numerous advantages over traditional implants,including a lower elasticity modulus,stronger bone-implant interlock,and larger drug-loading space.Simvastatin is a multitarget drug with anti-tumor and osteogenic potential;however,its efficiency is unsatisfactory when delivered systematically.Here,simvastatin was loaded into a 3DTi using a thermosensitive poly(lactic-co-gly-colic)acid(PLGA)-polyethylene glycol(PEG)-PLGA hydrogel as a carrier to exert anti-osteosarcoma and oste-ogenic effects.Newly constructed simvastatin/hydrogel-loaded 3DTi(Sim-3DTi)was comprehensively appraised,and its newfound anti-osteosarcoma mechanism was explained.Specifically,in a bone defect model of rabbit condyles,Sim-3DTi exhibited enhanced osteogenesis,bone in-growth,and osseointegration compared with 3DTi alone,with greater bone morphogenetic protein 2 expression.In our nude mice model,simvastatin loading reduced tumor volume by 59%-77%without organic damage,implying good anti-osteosarcoma activity and biosafety.Furthermore,Sim-3DTi induced ferroptosis by upregulating transferrin and nicotinamide adenine dinucleotide phosphate oxidase 2 levels in osteosarcoma both in vivo and in vitro.Sim-3DTi is a promising osteogenic bone substitute for osteosarcoma-related bone defects,with a ferroptosis-mediated anti-osteosarcoma effect.
基金
supported by National Natural Science Foundation of China(grant number 82272456 and 82202748)
China Postdoctoral Science Foundation(grant number 2022M720297).
作者简介
Corresponding author:Zhongjun Liu.Department of Orthopedics,Peking University Third Hospital,Beijing,100191,People’s Republic of China.E-mail addresses:zjliu@bjmu.edu.cn;Corresponding author:Hong Cai.Department of Orthopedics,Peking University Third Hospital,Beijing,100191,People’s Republic of China.E-mail addresses:hongcai@bjmu.edu.cn;Corresponding author:Yufeng Zheng,E-mail addresses:yfzheng@pku.edu.cn;Zehao Jing,E-mail addresses:1789081128@qq.com,contributed equally to this study;Wanqiong Yuan,E-mail addresses:yuanwanqiong@bjmu.edu.cn,contributed equally to this study;Jiedong Wang,E-mail addresses:xhwangjd@163.com,contributed equally to this study;Renhua Ni,E-mail addresses:tiffanyni@126.com;Yu Qin,E-mail addresses:qinyu95@126.com;Zhinan Mao,E-mail addresses:znmao@pku.edu.cn;Feng Wei,E-mail addresses:weifeng@bjmu.edu.cn;Chunli Song,E-mail addresses:schl@bjmu.edu.cn。
