State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China.
Athenex Hong Kong Innovative Limited, Hong Kong, China.
Cancer Biol Med. 2020 Nov 15;17(4):986-1001. doi: 10.20892/j.issn.2095-3941.2020.0128. Epub 2020 Dec 15.
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.
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.
Although both PVP-HM and cyclodextrin-HM formulations showed promising P-gp inhibition activity , 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 ( < 0.05).
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.
由于血脑屏障的存在和 P-糖蛋白（P-gp）的活性，化疗药物递送至脑部一直是治疗脑胶质瘤的主要障碍，P-gp 会将其底物泵回全身循环。本研究旨在开发 HM30181A（HM）的静脉制剂，以抑制脑部的 P-gp，从而有效地输送紫杉醇（PTX）治疗恶性脑胶质瘤。
基于不同的固体分散策略设计了两种 HM 的溶解制剂：i）喷雾干燥[聚乙烯吡咯烷酮（PVP）-HM]和 ii）溶剂蒸发[HP-β-环糊精（环糊精）-HM]。根据 rhodamine 123 在癌细胞中的摄取情况，评估这 2 种制剂的 P-gp 抑制作用。还测定了血液和脑部药代动力学参数，并在原位脑胶质瘤异种移植小鼠模型中评估了环糊精-HM 与 PTX 的抗肿瘤作用。
虽然 PVP-HM 和环糊精-HM 制剂均显示出有希望的 P-gp 抑制活性，但环糊精-HM 在小鼠中的最大耐受剂量高于 PVP-HM。环糊精-HM 的药代动力学研究显示，在 20mg/kg 时血浆浓度达到平台期，超过该水平时，小鼠开始出现体重减轻。在小鼠模型中，以 10mg/kg 给予环糊精-HM（10mg/kg）并联合 10mg/kg 的 PTX 显示出最佳的抗肿瘤活性，根据肿瘤体积测量和生存时间（<0.05）。
在小鼠原位脑肿瘤模型中，静脉联合给予环糊精-HM 与 PTX 显示出强大的抗肿瘤作用，因此可能具有治疗人类脑胶质瘤的潜力。
