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Synthesis, Biological Evaluation and Low-Toxic Formulation Development of Glycosylated Paclitaxel Prodrugs

by Yukang Mao 1,2,3, Yili Zhang 1,2,3, Zheng Luo 1,2,3, Ruoting Zhan 1,2,3, Hui Xu 1,2,3, Weiwen Chen 1,2,3,* and Huicai Huang 1,2,3,*
Research Center of Chinese Herbal Resource Science and Engineering, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China
Joint Laboratory of National Engineering Research Center for the Pharmaceutics of Traditional Chinese Medicines, Guangzhou 510006, China
Authors to whom correspondence should be addressed.
Molecules 2018, 23(12), 3211;
Received: 21 November 2018 / Revised: 3 December 2018 / Accepted: 3 December 2018 / Published: 5 December 2018
Paclitaxel (PTX) is a famous anti-cancer drug with poor aqueous solubility. In clinical practices, Cremophor EL (polyethoxylated castor oil), a toxic surfactant, is used for dissolution of PTX, which accounts for serious side effects. In the present study, a single glucose-conjugated PTX prodrug (SG-PTX) and a double glucose-conjugated PTX prodrug (DG-PTX) were synthesized with a glycosylated strategy via succinate linkers. Both of the two prodrugs presented significant solubility improvement and drug-like lipophilicities. Compared to DG-PTX, SG-PTX manifested more promising release of the parent drug in serum. A high percentage of PTX released from SG-PTX could be detected after enzymatic hydrolysis of β-glucuronidase. Besides, both of the two prodrugs exhibited effective cytotoxicity against breast cancer cells and ovarian cancer cells, but presented reduced cytotoxicity against normal breast cells. Moreover, SG-PTX manifested impressive solubility in a low toxic formulation (without ethanol) with a different percentage of Cremophor EL. These results indicated that glycosylation is a promising strategy for PTX modification and SG-PTX may be a feasible and potential type of PTX prodrug. In addition, ethanol-free formulation with a low percentage of Cremophor EL might have the potential to develop a safer formulation for further studies of glycosylated PTX prodrugs. View Full-Text
Keywords: paclitaxel; prodrug; solubility; anti-cancer; toxic surfactant paclitaxel; prodrug; solubility; anti-cancer; toxic surfactant
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MDPI and ACS Style

Mao, Y.; Zhang, Y.; Luo, Z.; Zhan, R.; Xu, H.; Chen, W.; Huang, H. Synthesis, Biological Evaluation and Low-Toxic Formulation Development of Glycosylated Paclitaxel Prodrugs. Molecules 2018, 23, 3211.

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