| Due to population growth,aging and environmental pollution,the incidence of cancer is increasing.Cisplatin(CDDP)is known as the penicillin of anticancer drugs,but because of the lack of tumor selectivity,it often shows serious dose-limiting side effect.Therefore,CDDP is often used in combination with other drugs in clinical practice,hoping to kill tumor cells more effectively through different mechanisms and different targets.However,it is difficult to accurately control the distribution of each drug in the body,effectively reach the target,the proportion and dosage of drug and pharmacokinetics,while PPt(Ⅳ)prodrugs can effectively overcome the defects of CDDP combination.The PPt(Ⅳ)complex oxoplatin is the oxidation state of the Pt(II)complex CDDP,has a six-coordinated octahedral structure and good stability,and the-OH ligand of the oxoplatin axis is easy to carry out chemical modification,can couple ligands with different biological activities,and synergistically exerts anti-tumor effect through multiple targets and multiple paths.In view of this background,we first oxidized CDDP to oxoplatin,coupling cinnamic acid(Cin)as matrix metalloproteinase(MMP)inhibitor,valproic acid(Val)as histone deacetylase(HDAC)inhibitor,aspirin(Asp)as cyclooxygenase(COX)inhibitor and dichloroacetic acid(Dic)as pyruvate dehydrogenase kinase(PDK)inhibitor through axial-OH ligand,thereby obtaining five PPt(Ⅳ)complexes.Then through in vitro and in vivo experiments,the reducible,efficient and low-toxic PPt(Ⅳ)prodrugs were screened out.The anti-proliferative activity of Cin-PPt(Ⅳ)-Val complex was the highest in Hep G-2 cells,which was 103 times that of CDDP,and the lowest in 4T1 cells,which was 29 times that of CDDP.The results of cell migration experiment showed that the Cin-PPt(Ⅳ)-Val complex could effectively inhibit the migration of mouse bladder cancer cells MB49,and the migration rates were only 2.2% at the concentration of 5.0 μM.Reduction assay showed that Cin-PPt(Ⅳ)-Val complex could be reduced by ascorbic acid(As A)or glutathione(GSH).Cyclic voltammetry showed that Cin-PPt(Ⅳ)-Val complex had stronger reduction ability in tumor microenvironment(p H6.4)than in normal tissue(p H7.4).ICP-MS analysis of cellular uptake and DNA platination showed that the coupled axial ligand could significantly increase the lipophilicity of Cin-PPt(Ⅳ)-Val and promote cellular uptake,resulting in the Pt content of Cin-PPt(Ⅳ)-Val in MB49 cells being 26 times that of CDDP.The binding capacity of DNA to Pt was 52 times that of CDDP.The results of ELISA Kit experiment showed that the Cin-PPt(Ⅳ)-Val complex could effectively inhibit the expression content of HDAC,MMP-2 and MMP-9 in MB49 cells.The results of flow cytometry showed that the cell cycle arrest induced by Cin-PPt(Ⅳ)-Val complex was similar to that of CDDP,which mainly occurred in S phase and G2/M phase.However,Cin-PPt(Ⅳ)-Val complex could induce 56.42% of MB49 cells into late apoptosis,indicating that it had a strong pro-apoptotic ability.An in vivo anti-tumor experiment result showed that the Cin-PPt(Ⅳ)-Val could inhibit the growth of 4T1 tumor xenograft,the tumor inhibition rate was 89.5%(5mg/kg Pt),and compared with CDDP,the Cin-PPt(Ⅳ)-Val complex had smaller influence on the body weight and emotion.Moreover,H&E staining results indicated that Cin-PPt(Ⅳ)-Val complex did not cause significant damage to major organs,effectively overcome the severe damage of CDDP to the kidney.In this study,we present new PPt(Ⅳ)derivatives of CDDP bearing valproic acid and cinnamic acid as axial ligands.Upon entry into cancer cells,Cin-PPt(Ⅳ)-Val complex was reduced by intracellular GSH reducing agents,releasing the Pt(II)moiety(CDDP),which had DNA damaging effects,and the axial ligands(Cin and Val),which specifically inhibit the activities of HDAC,MMP-2 and-9.The released CDDP,Cin and Val have synergistic anti-tumor effects through the triple effects of DNA damage,tumor migration inhibition and increasing the binding capacity of CDDP and DNA. |
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