Development of Taccalonolide AJ-Hydroxypropyl-beta-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma

doi:10.3390/molecules25235586

	Development of Taccalonolide AJ-Hydroxypropyl-beta-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma
	Han, Jing 1; Zhang, Siwang 1; Niu, Junxin 2; Zhang, Chunli 1; Dai, Weichen 1; Wu, Yuanyuan 1; Hu, Lihong 1,2
刊名	MOLECULES
	2020-12-01
卷号	25 期号:23 页码:14
关键词	taccalonolide AJ microtubule stabilizer hydroxypropyl-β -cyclodextrin inclusion complex clear-cell renal-cell carcinoma
DOI	10.3390/molecules25235586
通讯作者	Wu, Yuanyuan(ywu@njucm.edu.cn) ; Hu, Lihong(lhhu@njucm.edu.cn)
英文摘要	Background: Microtubule-targeted drugs are the most effective drugs for adult patients with certain solid tumors. Taccalonolide AJ (AJ) can stabilize tubulin polymerization by covalently binding to beta-tubulin, which enables it to play a role in the treatment of tumors. However, its clinical applications are largely limited by low water solubility, chemical instability in water, and a narrow therapeutic window. Clear-cell renal-cell carcinoma (cc RCC) accounts for approximately 70% of RCC cases and is prone to resistance to particularly targeted therapy drugs. Methods: we prepared a water-soluble cyclodextrin-based carrier to serve as an effective treatment for cc RCC. Results: Compared with AJ, taccalonolide AJ-hydroxypropyl-beta-cyclodextrin (AJ-HP-beta-CD) exhibited superior selectivity and activity toward the cc RCC cell line 786-O vs. normal kidney cells by inducing apoptosis and cell cycle arrest and inhibiting migration and invasion of tumor cells in vitro. According to acute toxicity testing, the maximum tolerated dose (MTD) of AJ-HP-beta-CD was 10.71 mg/kg, which was 20 times greater than that of AJ. Assessment of weight changes showed that mouse body weight recovered over 7-8 days, and the toxicity could be greatly reduced by adjusting the injections from once every three days to once per week. In addition, we inoculated 786-O cells to generate xenografted mice to evaluate the anti-tumor activity of AJ-HP-beta-CD in vivo and found that AJ-HP-beta-CD had a better tumor inhibitory effect than that of docetaxel and sunitinib in terms of tumor growth and endpoint tumor weight. These results indicated that cyclodextrin inclusion greatly increased the anti-tumor therapeutic window of AJ. Conclusions: the AJ-HP-beta-CD complex developed in this study may prove to be a novel tubulin stabilizer for the treatment of cc RCC. In addition, this drug delivery system may broaden the horizon in the translational study of other chemotherapeutic drugs.
资助项目	National Natural Science Foundation of China[30973944] ; National Natural Science Foundation of China[81703765] ; National Natural Science Foundation of China[31900283] ; Natural Science Foundation of Nanjing University of Chinese Medicine[NZY31900283] ; Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica[JKLPSE201817] ; Postgraduate Research & Practice Innovation Program of Jiangsu Province[KYCX19_1269] ; Natural Science Foundation of Jiangsu Higher Education Institutions[17KJA360004] ; Outstanding Scientific and Technological Innovation Team Program of Jiangsu Higher Education Institutions ; foundation for High-level Talent on Six Areas of Jiangsu Province ; Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
WOS关键词	MICROTUBULE ; RESISTANCE ; BINDING ; TUBULIN ; AF
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
语种	英语
出版者	MDPI
WOS记录号	WOS:000597498200001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/296337]
专题	中国科学院上海药物研究所
通讯作者	Wu, Yuanyuan; Hu, Lihong
作者单位	1.Nanjing Univ Chinese Med, Jiangsu Collaborat Innovat Ctr Chinese Med Resour, State Key Lab Cultivat Base TCM Qual & Efficacy, Jiangsu Key Lab Funct Subst Chinese Med,Nanjing U, Nanjing 210023, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Han, Jing,Zhang, Siwang,Niu, Junxin,et al. Development of Taccalonolide AJ-Hydroxypropyl-beta-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma[J]. MOLECULES,2020,25(23):14.
APA	Han, Jing.,Zhang, Siwang.,Niu, Junxin.,Zhang, Chunli.,Dai, Weichen.,...&Hu, Lihong.(2020).Development of Taccalonolide AJ-Hydroxypropyl-beta-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma.MOLECULES,25(23),14.
MLA	Han, Jing,et al."Development of Taccalonolide AJ-Hydroxypropyl-beta-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma".MOLECULES 25.23(2020):14.