Development of cancer-specific drug carriers possessing comprehensive inhibitory effect of ABC transporters

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K06790
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Tohoku Medical and Pharmaceutical University
• Principal Investigator: Morimoto Kaori 東北医科薬科大学, 薬学部, 講師 (90401009)
• Co-Investigator(Kenkyū-buntansha): 荻原 琢男 高崎健康福祉大学, 薬学部, 教授 (80448886) ; 石井 敬 東北医科薬科大学, 薬学部, 講師 (00735714)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: トランスポーター / デキストラン誘導体 / 薬物送達システム / 多剤耐性

Outline of Final Research Achievements

We investigated whether dextran and its derivatives inhibit BCRP, MRP1, and P-gp in vitro. In Sf-9 membrane vesicles overexpressing BCRP, MRP1, and P-gp, BCRP and MRP1 were significantly inhibited by 2-hydroxypropyl-trimethylammonium-dextran of 4 kDa and 70 kDa (Q-D4 and Q-D70); however, P-gp was not inhibited. A structure-activity study showed that Q-D4, Q-D70, and 40 kDa diethylaminoethyl-dextran (DEAE-D40) significantly inhibited BCRP, while 4 kDa, 40 kDa, and 70 kDa dextrans, dextran sulfate, and the saccharide components of dextran did not. These results suggest that the cationic moieties are important for BCRP inhibition. However, cell-based efflux assay revealed that Q-D4, Q-D70, and DEAE-D40 did not increase the retention of fluorescent substrates in BCRP-, MRP1- and P-gp-overexpressing KB cells. The ineffectiveness in cellular systems is presumably due to inability of the dextran derivatives to access transporters located on the cytoplasmic side of the cell membrane.

Free Research Field

薬物動態学

Academic Significance and Societal Importance of the Research Achievements

本研究でカチオン修飾デキストランがBCRPとMRP1を阻害する能力を有するが、細胞レベルでは効果がないことを明らかにした。複数の薬物排出トランスポーターを同時に阻害するがん組織特異的ドラッグデリバリーシステムは、がん化学療法の有効性と安全性を高めるために有効である可能性があり、そのための基礎データとして有用な情報を得ることが出来たと考える。