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HM30181A,a potent P-glycoprotein inhibitor,potentiates the absorption and in vivo antitumor efficacy of paclitaxel in an orthotopic brain tumor model
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作者 Wu Zeng Betty Yuen Kwan Law +12 位作者 Vincent Kam Wai Wong Denise So Bik Chan Simon Wing Fai Mok Joyce Jia Ying Gao Rebecca Ka Yan Ho Xu Liang Jia Hao Li Ming Tsung Lee Weng Li Yoon Michael P Smolinski Johnson Yiu Nam Lau Christopher Wai Kei Lam Manson Fok 《Cancer Biology & Medicine》 SCIE CAS CSCD 2020年第4期986-1001,共16页
Objective:Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma,owing to the presence of the blood-brain barrier and the activity of P-gp,which pumps its substrate ba... Objective:Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma,owing to the presence of the blood-brain barrier and the activity of P-gp,which pumps its substrate back into the systemic circulation.The aim of the present study was to develop an intravenous formulation of HM30181 A(HM)to inhibit P-gp in the brain to effectively deliver paclitaxel(PTX)for the treatment of malignant glioma.Methods:Two formulations of solubilized HM were designed on the basis of different solid dispersion strategies:i)spray-drying[polyvinlypyrrolidone(PVP)-HM]and ii)solvent evaporation[HP-β-cyclodextrin(cyclodextrin)-HM].The P-gp inhibition of these 2 formulations was assessed on the basis of rhodamine 123 uptake in cancer cells.Blood and brain pharmacokinetic parameters were also determined,and the antitumor effect of cyclodextrin-HM with PTX was evaluated in an orthotopic glioma xenograft mouse model.Results:Although both PVP-HM and cyclodextrin-HM formulations showed promising P-gp inhibition activity in vitro,cyclodextrin-HM had a higher maximum tolerated dose in mice than did PVP-HM.Pharmacokinetic study of cyclodextrin-HM revealed a plasma concentration plateau at 20 mg/kg,and the mice began to lose weight at doses above this level.Cyclodextrin-HM(10 mg/kg)administered with PTX at 10 mg/kg showed optimal antitumor activity in a mouse model,according to both tumor volume measurement and survival time(P<0.05).Conclusions:In a mouse orthotopic brain tumor model,the intravenous co-administration of cyclodextrin-HM with PTX showed potent antitumor effects and therefore may have potential for glioma therapy in humans. 展开更多
关键词 HM30181A GLIOMA PHARMACOKINETICS PACLITAXEL P-GLYCOPROTEIN
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