| ObjectiveTranscatheter arterial chemoembolization using microspheres carrying antitumor drugs is a new method for advanced liver cancer treatment.Compared with traditional TACE(Transcatheter arterial chemoembolization),this method can realize both chemoembolization and delivery of antitumor drugs to tumor tissue simultaneously.However,the antitumor effect of the drug-loaded microspheres is limited,because clogging blood vessels can induce thrombosis formation on the surfaces of the microspheres and prevent drug release from the microspheres and spreading to liver cancer.The advantage of traditional TACE is that it is of a large amount of drug delivery,in which antitumor drugs are dispersed into lipiodol,but the lipiodol may damage liver.?-cyanoacrylate is a vascular embolization agent for the treatment of gastric varices,and also a drug carrier of good biocompatibility.In this paper,a-cyanoacrylate polymer microspheres were prepared to carry doxorubicin(DXR),to which anticoagulant was also added for chemoembolization of liver cancer.In combination with traditional embolization methods,lipiodol was replaced using hypertonic glucose while the dosage of chemotherapeutic drugs was increased and thrombosis formation on the surefaces of the microspheres was prevented.It is possible to further improve the effect of arterial chemoembolization of liver cancer.Methodsa-butyl cyanoacrylate polymer microspheres were prepared by polymerization with a-butyl cyanoacrylate as monomer.The particle size and surface morphology of drug-loaded microspheres were observed and analyzed by optical microscope and scanning electron microscope.The particle size changes during the long-term storage of the embolized microspheres were measured at different storage temperatures.The drug loading amount,drug loading time and drug release rate were measured by UV-Vis spectrophotometer.The transplanted VX2 liver cancer model was used to evaluate the safety and efficacy of hepatic artery embolization using microspheres.Rabbit VX2 liver cancer model was established by tumor tissue implantation,and doxorubicin was injected through hepatic artery intubation at two weeks after tumor tissue implantation.The concentration of doxorubicin in peripheral blood of rabbits was determined using high performance liquid chromatograPhy(HPLC).The distribution of doxorubicin and the capillary density of tumor mass were observed following the immunofluorescence staining method.The survival time(days)of tumor-bearing rabbits in each experimental group were determined and the survival rate of each experimental group was longer than that of the control group.The tumor volume and tumor weights were measured on the 14th day after treatment of hepatic artery chemoembolization.Resultsa-butyl cyanoacrylate polymer microspheres were prepared by polymerization of a-butyl-cyanoacrylate monomer.Under the light microscope,the shape of the microspheres is regular and its size distribution is uniform.The diameter range of the microspheres is 50-290 ?m and more than 80%of the diameter of the microspheres is in the range of 80-230 ?m.Scanning electron microscopy analysis showed that the surface of the microspheres was full of pores,which was helpful for the loading and release of doxorubicin.UV-Vis spectrophotometer analysis showed that the drug load efficiency of the microspheres was 25.33mg/mL,the loading time of doxorubicin was about 12 hours,and the release time of doxorubicin in microsPheres was more than 72 hours.At 4?,within half year,no siginifcant changes in the size of the microspheres.The passage preservation of rabbit VX2 tumor were realized following subcutaneous or muscle implantation.The tumor model of rabbit VX2 liver cancer were successfully established as follows:the size of the blocks of VX2 tumor tissue for inoculation was 2×2×2(mm3)and the liver cancer size was 1.2-1.4(cm3)on the 14th day after the liver inoculation of the blocks of VX2 tumor tissue while there was no significant difference in tumor volume(n=6,P=0.589).The results showed that the liver VX2 tumor model was successful.and could be used for the following experim-ents.Doxorubicin plasma concentration was determined using high performance liquid chromatography(HPLC).The results showed that there was a transient high plasma concentration of doxorubicin in the traditional TACE group.However,compared with the traditional TACE group,the drug release was slower,the peak concentration was lower and the half-life was longer in the microsphere group and the anticoagulant microsphere group.Immunofluorescence staining method was used to study the distribution of doxorubicin in tumor tissue.The fluorescence points of doxorubicin in each group were 1911.67 ± 389.11 in traditional TACE group,2861.92 ± 458.83 in microsphere TACE group and 4299.58 ± 521,61 in anticoagulant microsphere TACE group.The results of the statistical analysis showed that there were significant differences between the traditional TACE group and the microsphere TACE group(n=6,P<0.01),the difference between the traditional TACE group and the anticoagulant microsphere TACE group(n=6,P<0.01),and the difference between the microsphere TACE group and the anticoagulant microsphere TACE group(n=6,P<0.01).The content of doxorubicin in tumor of anticoagulant microsphere TACE group was higher than that of microsphere TACE group and traditional TACE group while the content of doxorubicin of the microsphere TACE group was higher than the traditional TACE group.The statistical analysis of MVD(Microvessel density)showed that the microvessel density of the five groups was different or not equal,and the difference was statistically significant(n=6,P<0.01).The mean survival time of each experimental group was 29.00 ± 1.93(days)in the control group,33.67 ± 2.66(days)in the blank microsphere group,38.17± 2.73(days)in the traditional TACE group,42.33 ± 2.15(days)in the microsphere TACE group and 50.17 ± 2.60 days in the anticoagulant microsphere TACE group.The results of statistical analysis showed that the difference of survival times among the five groups above was statistically significant(n=6,P<0.01).The mean tumor volume of each group was 9.27 ± 0.14(cm3)in the control group,6.95 ± 0.06(cm3)in the blank microsphere group,6.25 ± 0.16(cm3)in the traditional TACE group,6.22 ± 0.09(cm3)in the microsphere TACE group and 5.83 ± 0.24(cm3)in the anticoagulant microsphere TACE group.The mean tumor weight in each group was 10.18 ± 0.14(g)in control group,7.95 ± 0.15(g)in blank microsphere group,7.21 ± 0.19(g)in traditional TACE group and 6.65 ± 0.28(g)in TACE group.There was significant difference in tumor volume and tumor weight among the five groups above(n=6,P<0.01).ConclusionsIn this experiment,the drug-loaded microspheres of a-butyl cyanoacrylate polymer were successfully prepared using a-butyl cyanoacrylate as monomer.The microspheres have the advantages of good dispersion,uniform particle size distribution,high drug loading efficiency and easy operation.Doxorubicin loading time is short while drug release is slow and lasting.The microspheres we prepared could inhibit the growth and proliferation of rabbit VX2 tumor,prolong the survival time of experimental rabbits.The effect of arterial chemoembolization of liver cancer was significantly improved by adding anticoagulant. |
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