CREKA-modified, doxorubicin(DOX)-loaded Liposomes in Combination with Dichloroacetate for the Treatment of Glioma Synergistically

【作者】 张爽； Xuan ZHANG；

【Author】 Shuang ZHANG;Xuan ZHANG;Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University;

【机构】 Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University；

【摘要】 Introduction: As an ROS inducer, dichloroacetate(DCA) could combine with a lot of drugs to obtain satisfactory antitumor effect both in vitro and in vivo. Factors, such as drug-delivery order, would influence the combination effect of drugs. Since liposomes could change the release behavior of encapsulated drug which means the drug-delivery order is changed, it is hypothesized that the combination effect will be altered after one of the two drugs used in combination is encapsulated into liposomes. In the present research, the combination effect of DCA and free DOX was studied to obtain the best ratio for combination. And the combination effect was re-studied after DOX was loaded in CREKA-modified liposomes(DOX-SSLCREKA) to learn the influence of delivery system on the combination effect, and get the best ratio for the administration of DCA and DOX-SSL-CREKA in vivo. And then the best combined ratio of DCA and DOXSSL-CREKA was evaluated on U-89 MG tumor model in vivo. Methods: The ROS levels of DCA and free DOX as well as the combination of DCA and free DOX were tested on U87-MG tumor cells. The combination effect of DCA and free DOX was analyzed by the medianeffect method to obtain the best ratio for combination. After prepared by a thin-film hydration method, the DOX-SSL-CREKA was combined with DCA to learn the effect of drug delivery system on combination of drugs. And the best combined ratio of DCA and DOX-SSL-CREKA obtained was tested on U87-MG orhtotopic tumor model in vivo. Results: The combination of DCA and free DOX had the best effect on increasing ROS level when compared with that treated by DCA or free DOX alone(Fig.1), and the combination effect of DCA and free DOX was evaluated by combination index(CI) and dose reduction index(DRI)(Fig.2) to get the best combined ratio(DCA:DOX=1 k:1). DOX-SSL-CREKA characterized by DLS and TEM were shown in Fig.3, and the combination effect of DCA and DOX-SSL-CREKA was also evaluated by CI and DRI(Fig.4) to get the best combined ratio(DCA: DOX=2 k: 1). Then the in vivo antitumor effect of DCA and DOX-SSL-CREKA at the ratio of 2 k: 1(DCA:DOX) showed that the combination of DCA and DOX-SSL-CREKA had the best antitumor activity in all of the groups(Fig.5). Conclusion:This research examined the combination effect between DCA and free DOX, and the influence on combination after DOX was loaded in liposomes. The antitumor effect of DCA and DOX-SSL-CREKA at the best ratio indicated that the combination of DCA and DOX-SSL-CREKA was an effective treatment for glioma.更多还原

【Abstract】 Introduction: As an ROS inducer, dichloroacetate(DCA) could combine with a lot of drugs to obtain satisfactory antitumor effect both in vitro and in vivo. Factors, such as drug-delivery order, would influence the combination effect of drugs. Since liposomes could change the release behavior of encapsulated drug which means the drug-delivery order is changed, it is hypothesized that the combination effect will be altered after one of the two drugs used in combination is encapsulated into liposomes. In the present research, the combination effect of DCA and free DOX was studied to obtain the best ratio for combination. And the combination effect was re-studied after DOX was loaded in CREKA-modified liposomes(DOX-SSLCREKA) to learn the influence of delivery system on the combination effect, and get the best ratio for the administration of DCA and DOX-SSL-CREKA in vivo. And then the best combined ratio of DCA and DOXSSL-CREKA was evaluated on U-89 MG tumor model in vivo. Methods: The ROS levels of DCA and free DOX as well as the combination of DCA and free DOX were tested on U87-MG tumor cells. The combination effect of DCA and free DOX was analyzed by the medianeffect method to obtain the best ratio for combination. After prepared by a thin-film hydration method, the DOX-SSL-CREKA was combined with DCA to learn the effect of drug delivery system on combination of drugs. And the best combined ratio of DCA and DOX-SSL-CREKA obtained was tested on U87-MG orhtotopic tumor model in vivo. Results: The combination of DCA and free DOX had the best effect on increasing ROS level when compared with that treated by DCA or free DOX alone(Fig.1), and the combination effect of DCA and free DOX was evaluated by combination index(CI) and dose reduction index(DRI)(Fig.2) to get the best combined ratio(DCA:DOX=1 k:1). DOX-SSL-CREKA characterized by DLS and TEM were shown in Fig.3, and the combination effect of DCA and DOX-SSL-CREKA was also evaluated by CI and DRI(Fig.4) to get the best combined ratio(DCA: DOX=2 k: 1). Then the in vivo antitumor effect of DCA and DOX-SSL-CREKA at the ratio of 2 k: 1(DCA:DOX) showed that the combination of DCA and DOX-SSL-CREKA had the best antitumor activity in all of the groups(Fig.5). Conclusion:This research examined the combination effect between DCA and free DOX, and the influence on combination after DOX was loaded in liposomes. The antitumor effect of DCA and DOX-SSL-CREKA at the best ratio indicated that the combination of DCA and DOX-SSL-CREKA was an effective treatment for glioma.更多还原