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

Molecules. 2018 Dec 5;23(12):3211. doi: 10.3390/molecules23123211.

Yukang Mao ¹ ² ³, Yili Zhang ⁴ ⁵ ⁶, Zheng Luo ⁷ ⁸ ⁹, Ruoting Zhan ¹⁰ ¹¹ ¹², Hui Xu ¹³ ¹⁴ ¹⁵, Weiwen Chen ¹⁶ ¹⁷ ¹⁸, Huicai Huang ¹⁹ ²⁰ ²¹

Affiliations

1 Research Center of Chinese Herbal Resource Science and Engineering, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. [email protected].
2 Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China. [email protected].
3 Joint Laboratory of National Engineering Research Center for the Pharmaceutics of Traditional Chinese Medicines, Guangzhou 510006, China. [email protected].
4 Research Center of Chinese Herbal Resource Science and Engineering, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. [email protected].
5 Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China. [email protected].
6 Joint Laboratory of National Engineering Research Center for the Pharmaceutics of Traditional Chinese Medicines, Guangzhou 510006, China. [email protected].
7 Research Center of Chinese Herbal Resource Science and Engineering, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. [email protected].
8 Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China. [email protected].
9 Joint Laboratory of National Engineering Research Center for the Pharmaceutics of Traditional Chinese Medicines, Guangzhou 510006, China. [email protected].
10 Research Center of Chinese Herbal Resource Science and Engineering, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. [email protected].
11 Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China. [email protected].
12 Joint Laboratory of National Engineering Research Center for the Pharmaceutics of Traditional Chinese Medicines, Guangzhou 510006, China. [email protected].
13 Research Center of Chinese Herbal Resource Science and Engineering, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. [email protected].
14 Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China. [email protected].
15 Joint Laboratory of National Engineering Research Center for the Pharmaceutics of Traditional Chinese Medicines, Guangzhou 510006, China. [email protected].
16 Research Center of Chinese Herbal Resource Science and Engineering, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. [email protected].
17 Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China. [email protected].
18 Joint Laboratory of National Engineering Research Center for the Pharmaceutics of Traditional Chinese Medicines, Guangzhou 510006, China. [email protected].
19 Research Center of Chinese Herbal Resource Science and Engineering, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. [email protected].
20 Key Laboratory of Chinese Medicinal Resource from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education, Guangzhou 510006, China. [email protected].
21 Joint Laboratory of National Engineering Research Center for the Pharmaceutics of Traditional Chinese Medicines, Guangzhou 510006, China. [email protected].

PMID: 30563132 DOI: 10.3390/molecules23123211

Abstract

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.

Keywords

anti-cancer; paclitaxel; prodrug; solubility; toxic surfactant.

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