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Open AccessArticle

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,*
1
Research Center of Chinese Herbal Resource Science and Engineering, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
2
Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China
3
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; https://doi.org/10.3390/molecules23123211
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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