Enhanced antitumor efficacy of bile acid-lipid complex-anchored docetaxel nanoemulsion via oral metronomic scheduling
- Authors
- Jha, Saurav Kumar; Chung, Jee Young; Pangeni, Rudra; Choi, Hyeong Seok; Subedi, Laxman; Kweon, Seho; Choi, Jeong Uk; Byun, Youngro; Kim, Yong-Hee; Park, Jin Woo
- Issue Date
- Dec-2020
- Publisher
- ELSEVIER
- Keywords
- Docetaxel; Nanoemulsion; Bile acid transporter-mediated uptake; Oral absorption; Metronomic chemotherapy
- Citation
- JOURNAL OF CONTROLLED RELEASE, v.328, pp.368 - 394
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF CONTROLLED RELEASE
- Volume
- 328
- Start Page
- 368
- End Page
- 394
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/1693
- DOI
- 10.1016/j.jconrel.2020.08.067
- ISSN
- 0168-3659
- Abstract
- In this study, a system for oral delivery of docetaxel (DTX) was prepared to enhance the oral absorption and anticancer efficacy of DTX via metronomic chemotherapy. DTX was complexed with low-molecular-weight methylcellulose (LMC) and loaded into a nanoemulsion (NE), yielding DTX/LMC-NE (DLNE). To further enhance the oral bioavailability, D-alpha-tocopherol polyethylene glycol succinate and sodium deoxycholate (DOCA) complexed with cationic lipid 1,2-dioleyl-3-trimethylammonium propane (DOTAP) (DOCA-DOTAP [DA-TAP] complex) was incorporated into DLNE, yielding the formulation DLNE#10. As expected, DLNE#10 showed 11.3- and 5.81-fold increases in artificial membrane (P-e) and Caco-2 permeability (P-app), respectively, resulting in 249% greater oral bioavailability, compared to free DTX. In contrast, inhibition of clathrin- and caveolamediated endocytosis, macropinocytosis, and bile acid transporters by chlorpromazine, genistein, amiloride, and actinomycin D in the Caco-2 monolayer reduced the P-app by 55.3%, 44.2%, 35.9%, and 36.5%, respectively; these findings suggest that these routes play important roles in enhancing the oral absorption of DLNE#10. In addition, our mechanistic study suggested that P-glycoprotein (P-gp) did not have an inhibitory effect on the permeation of DLNE#10. Notably, the half-maximal inhibitory concentrations (IC50) of DLNE#10 were 43.5% and 16.8% greater than those of Taxotere (R) in MCF-7 and 4T1 cells, respectively. Finally, the tumor inhibitory rates in 4T1 cell tumor-bearing mice after oral metronomic dosing of DLNE#10 (20 mg/kg DTX) were 5.02- and 1.65-fold greater than the rates in the untreated control group and intravenously injected DTX (10 mg/kg) group, respectively. These observations support the improved oral absorption and enhanced chemotherapeutic efficacy of DTX in DLNE#10 via metronomic chemotherapy, suggesting that it is a better alternative than intravenous Taxotere (R).
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