Study On Novel Curcumin Prodrugs And Their Anti-osteosarcoma Effects

At present,most of the clinical-used anticancer drugs are toxic,anti-cancer treatment has brought lots of side effects to the patients,and 1/3 of the chemotherapy effect are unsatisfactory.So in recent years,anti-cancer drugs with low toxicity has become a hot spot in anti-cancer research.Current studies have shown that curcumin has a good anti-cancer activity,while high doses impact to normal cells is also at a safe level.However,monomeric curcumin has very poor water solubility,instability in body cycle environment and rapid metabolic rate,low oral bioavailability,which limits its property to be used in clinic.In order to mprove the stability of curcumin under physiological conditions,to deal with the problem in practical application,this study synthesized two kinds of micromolecular curcumin prodrugs by modifying the ketene structure of curcumin.The physicochemical properties,anti cancer activity and mechanism in vitro of these curcumin prodrugs were explored.The results showed that the stability of micromolecular prodrugs are significantly improved,for the degradation amount has decreased by about 2/3 within 4 hours.The addition of boron-fluorine structure enhanced the anti-cancer activity of rat osteosarcoma cells(UMR-106)while the mechanism remained the same.In the meantime,the addition of boron-benzene structure kept its anti-cancer activity through blocking cell cycle at G0/G1 phase but not promoting cell apoptosis.Further to improve curcumin's physiological stability and water solubility at the same time,a novel macromolecular curcumin prodrug was synthesized in this study.Curcumin was polymerized on the phenolic hydroxyl group by succinic anhydride and polyethylene glycol,a hydrophilic polymer.Afterwards,the physicochemical properties,anti cancer activity and mechanism in vitro were investigated.The results of physicochemical experiments showed that the macromolecular curcumin prodrug has had excellent water solubility,physiological stability and alkaline stability.The degradation amount of macromolecular prodrug has been 1/16 and 1/9 of curcumin's respectively in 4 hours,and it has had the ability of phosphatase degradation.Cytology experiments showed that the half lethal concentration of the macromolecular prodrug has been higher than curcumin itself because of the higher molecular weight,slower endocytosis rate and time required for drug degradation.The analysis of tumor suppressor mechanism showed that,for UMR-106 cells and human osteosarcoma cells(143B),macromolecular prodrug has inhibited the proliferation activity by promoting cell apoptosis and blocking cell cycle in S phase.The effect of macromolecular prodrug in vivo was then explored.The results of anti-tumor experiments in vivo showed that macromolecular prodrug has had a good biological safety while it could effectively inhibit cell proliferation and angiogenesis,induce apoptosis of tumor area cells and then achieve in vivo inhibition of osteosarcoma.The difference in water solubility of macromolecular prodrug and curcumin might have lead to the significant anti-tumor improvementBased on the difficulties in the treatment of osteosarcoma,such as large segmental bone defect,difficulties in resecting potential small lesions and large side effects of traditional radiotherapy/chemotherapy,a 3D printing scaffold with dual functions of anti-tumor and bone repair has been designed by combining macromolecular prodrug,polydopamine with excellent photothermal properties and hydroxyapatite with osteoinduction.The biocompatibility experiment results have showed that mouse bone marrow mesenchymal stem cells(mBMSCs)could adhere to the scaffold and then proliferated.The basic anti-tumor activity of this scaffold has also been proved.