Dataset Information

HM30181A, a potent P-glycoprotein inhibitor, potentiates the absorption and in vivo antitumor efficacy of paclitaxel in an orthotopic brain tumor model.

ABSTRACT:

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 < 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.

SUBMITTER: Zeng W

PROVIDER: S-EPMC7721091 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Publications

HM30181A, a potent P-glycoprotein inhibitor, potentiates the absorption and <i>in vivo</i> antitumor efficacy of paclitaxel in an orthotopic brain tumor model.

Zeng Wu W Kwan Law Betty Yuen BY Wai Wong Vincent Kam VK Bik Chan Denise So DS Fai Mok Simon Wing SW Ying Gao Joyce Jia JJ Yan Ho Rebecca Ka RK Liang Xu X Li Jia Hao JH Lee Ming Tsung MT Yoon Weng Li WL Smolinski Michael P MP Nam Lau Johnson Yiu JY Kei Lam Christopher Wai CW Fok Manson M

Cancer biology & medicine 20201101 4

<h4>Objective</h4>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.<h4>Methods</h4>Two formulations of solubili ...[more]

PMID: 33299648

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