PT - JOURNAL ARTICLE AU - Wu Zeng AU - Betty Yuen Kwan Law AU - Vincent Kam Wai Wong AU - Denise So Bik Chan AU - Simon Wing Fai Mok AU - Joyce Jia Ying Gao AU - Rebecca Ka Yan Ho AU - Xu Liang AU - Jia Hao Li AU - Ming Tsung Lee AU - Weng Li Yoon AU - Michael P Smolinski AU - Johnson Yiu Nam Lau AU - Christopher Wai Kei Lam AU - Manson Fok TI - HM30181A, a potent P-glycoprotein inhibitor, potentiates the absorption and <em>in vivo</em> antitumor efficacy of paclitaxel in an orthotopic brain tumor model AID - 10.20892/j.issn.2095-3941.2020.0128 DP - 2020 Nov 15 TA - Cancer Biology and Medicine PG - 986--1001 VI - 17 IP - 4 4099 - http://www.cancerbiomed.org/content/17/4/986.short 4100 - http://www.cancerbiomed.org/content/17/4/986.full SO - Cancer Biol Med2020 Nov 15; 17 AB - 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 HM30181A (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 &lt; 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.