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Formulating a single thioether-bridged oleate prodrug into a self-nanoemulsifying drug delivery system to facilitate oral absorption of docetaxel

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Abstract

Oral chemotherapy of docetaxel (DTX) is restricted by active P-glycoprotein (P-gp) efflux, hepatic first-pass metabolism and then poor oral absorption. Herein, a lipophilic thioether-bridged oleate prodrug (DTX-S-OA) and an ester-bond linked oleate prodrug of docetaxel (DTX-OA) were synthesized and efficiently incorporated into a self-nanoemulsifying drug delivery system (SNEDDS) using core-matching technology with a high drug-loading rate. DTX-S-OA SNEDDS produced a uniform droplet size of about 30 nm and a significantly high drug loading capability (60 mg mL−1), compared with DTX SNEDDS (20 mg mL−1). Additionally, DTX-S-OA SNEDDS exhibited a markedly slower drug release property and higher (>2-fold) drug solubilization in the aqueous phase after 60 min lipolysis compared with DTX SNEDDS. In situ single-pass intestinal perfusion and intestinal biodistribution studies demonstrated that the membrane permeability and intestinal bioadhesion of SNEDDS were significantly increased. Moreover, DTX-S-OA showed a comparable ability with verapamil in inhibiting P-gp efflux. Lymphatic transport studies confirmed that DTX-S-OA SNEDDS could significantly enhance intestinal lymphatic transport. Notably, the bioavailability of DTX-S-OA SNEDDS was 6.2-fold and 2.0-fold higher than that of the DTX solution and DTX SNEDDS, respectively. Furthermore, DTX-S-OA achieved a more rapid release of free DTX from the prodrug in systemic circulation than DTX-OA. Therefore, such a unique combination strategy of the single thioether-bridged DTX-oleate prodrug and SNEDDS is a promising platform to enable effective oral delivery of DTX.

Graphical abstract: Formulating a single thioether-bridged oleate prodrug into a self-nanoemulsifying drug delivery system to facilitate oral absorption of docetaxel

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Publication details

The article was received on 08 Aug 2018, accepted on 26 Dec 2018 and first published on 26 Dec 2018


Article type: Paper
DOI: 10.1039/C8BM00947C
Citation: Biomater. Sci., 2019, Advance Article
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    Formulating a single thioether-bridged oleate prodrug into a self-nanoemulsifying drug delivery system to facilitate oral absorption of docetaxel

    W. Cui, S. Zhang, H. Zhao, C. Luo, B. Sun, Z. Li, M. Sun, Q. Ye, J. Sun and Z. He, Biomater. Sci., 2019, Advance Article , DOI: 10.1039/C8BM00947C

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