Development of Taccalonolide AJ-Hydroxypropyl-β-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma
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 β-tubulin, which enables it to play a role in the treatment of tumors. However, its clinical applicati...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-11-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/25/23/5586 |
| _version_ | 1797546499969646592 |
|---|---|
| author | Jing Han Siwang Zhang Junxin Niu Chunli Zhang Weichen Dai Yuanyuan Wu Lihong Hu |
| author_facet | Jing Han Siwang Zhang Junxin Niu Chunli Zhang Weichen Dai Yuanyuan Wu Lihong Hu |
| author_sort | Jing Han |
| collection | DOAJ |
| description | 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 β-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-β-cyclodextrin (AJ-HP-β-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-β-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-β-CD in vivo and found that AJ-HP-β-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-β-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. |
| first_indexed | 2024-03-10T14:30:08Z |
| format | Article |
| id | doaj.art-f51d0880623c41caa5bf24d982a77475 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T14:30:08Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-f51d0880623c41caa5bf24d982a774752023-11-20T22:40:14ZengMDPI AGMolecules1420-30492020-11-012523558610.3390/molecules25235586Development of Taccalonolide AJ-Hydroxypropyl-β-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell CarcinomaJing Han0Siwang Zhang1Junxin Niu2Chunli Zhang3Weichen Dai4Yuanyuan Wu5Lihong Hu6Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medical, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medical, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaState Key Laboratory of Drug Research, Shanghai Institute of Material Medical, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, ChinaJiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medical, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medical, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medical, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medical, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaBackground: 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 β-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-β-cyclodextrin (AJ-HP-β-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-β-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-β-CD in vivo and found that AJ-HP-β-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-β-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.https://www.mdpi.com/1420-3049/25/23/5586taccalonolide AJmicrotubule stabilizerhydroxypropyl-β-cyclodextrininclusion complexclear-cell renal-cell carcinoma |
| spellingShingle | Jing Han Siwang Zhang Junxin Niu Chunli Zhang Weichen Dai Yuanyuan Wu Lihong Hu Development of Taccalonolide AJ-Hydroxypropyl-β-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma Molecules taccalonolide AJ microtubule stabilizer hydroxypropyl-β-cyclodextrin inclusion complex clear-cell renal-cell carcinoma |
| title | Development of Taccalonolide AJ-Hydroxypropyl-β-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma |
| title_full | Development of Taccalonolide AJ-Hydroxypropyl-β-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma |
| title_fullStr | Development of Taccalonolide AJ-Hydroxypropyl-β-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma |
| title_full_unstemmed | Development of Taccalonolide AJ-Hydroxypropyl-β-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma |
| title_short | Development of Taccalonolide AJ-Hydroxypropyl-β-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma |
| title_sort | development of taccalonolide aj hydroxypropyl β cyclodextrin inclusion complexes for treatment of clear cell renal cell carcinoma |
| topic | taccalonolide AJ microtubule stabilizer hydroxypropyl-β-cyclodextrin inclusion complex clear-cell renal-cell carcinoma |
| url | https://www.mdpi.com/1420-3049/25/23/5586 |
| work_keys_str_mv | AT jinghan developmentoftaccalonolideajhydroxypropylbcyclodextrininclusioncomplexesfortreatmentofclearcellrenalcellcarcinoma AT siwangzhang developmentoftaccalonolideajhydroxypropylbcyclodextrininclusioncomplexesfortreatmentofclearcellrenalcellcarcinoma AT junxinniu developmentoftaccalonolideajhydroxypropylbcyclodextrininclusioncomplexesfortreatmentofclearcellrenalcellcarcinoma AT chunlizhang developmentoftaccalonolideajhydroxypropylbcyclodextrininclusioncomplexesfortreatmentofclearcellrenalcellcarcinoma AT weichendai developmentoftaccalonolideajhydroxypropylbcyclodextrininclusioncomplexesfortreatmentofclearcellrenalcellcarcinoma AT yuanyuanwu developmentoftaccalonolideajhydroxypropylbcyclodextrininclusioncomplexesfortreatmentofclearcellrenalcellcarcinoma AT lihonghu developmentoftaccalonolideajhydroxypropylbcyclodextrininclusioncomplexesfortreatmentofclearcellrenalcellcarcinoma |