Please wait a minute...
J Zhejiang Univ (Med Sci)  2017, Vol. 46 Issue (2): 144-152    DOI: 10.3785/j.issn.1008-9292.2017.04.05
Preparation, characterization and antitumor of cyclodextrin inclusion of an anti-cancer drug regorafenib
LIU Kai-hang(),SUN Mengying,TANG Guping,HU Xiurong*()
Department of Chemistry, Zhejiang University, Hangzhou, 310012 China
Download: HTML     PDF(5282KB)
Export: BibTeX | EndNote (RIS)      


Objective: In order to improve the drug’s solubility, dissolution and bioavailability, RG-β-CD, RG-γ-CD and RG-Hp-β-CD were prepared by co-crystallization between Regorafenib (RG) and β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD) and Hydroxypropyl-β-cyclodextrin (Hp-β-CD). Methods: Three inclusion complexes were prepared by recrystallization and solvent evaporation methods and characterized by fourier transform infrared spectroscopy (FT-IR), thermal analysis (TG), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), 1H nuclear magnetic resonance (1H-NMR), nuclear overhauser effect spectroscopy (NOESY). In vivo experiments, tumor suppression assay were made with SW620 colon cancer cell. Results: The ability of solubility and dissolution were improved after inclusion with three kinds of cyclodextrins. The regorafenib-β-cyclodextrin inclusionis proved to have the best stability. The less enhanced was regorafenib-γ-cycl-odextrin inclusion. The best dissolution of regorafenib-β-cyclodextrin inclusion complex was to bring as the tumor suppression assay, the result shows that regorafenib inclusion with β-cyclodextrin is better than regorafenib itself. Conclusion: The bioavailability of regorafenib by inclusion with cyclodextrin can enhance due to the solubility enhancement of RG, which can provide an effective method for improving solubility and dissolution of insoluble drug in clinical medication.

Key wordsProtein kinase inhibitors      Beta-cyclodextrins      Drug compounding      Antineoplastic agents      Solubility      Biological availability     
Received: 02 November 2016      Published: 31 October 2017
Corresponding Authors: HU Xiurong     E-mail:;
Cite this article:

LIU Kai-hang,SUN Mengying,TANG Guping,HU Xiurong. Preparation, characterization and antitumor of cyclodextrin inclusion of an anti-cancer drug regorafenib. J Zhejiang Univ (Med Sci), 2017, 46(2): 144-152.

URL:     OR



关键词: 蛋白激酶抑制剂,  β环糊精类,  药物调剂,  抗肿瘤药物,  溶解度,  生物利用度 
Fig 1 Power X-ray diffraction patterns of RG, CD and RG-CD
Fig 2 Comparison of TGA and DSC profiles for RG、CD and RG-CD
Fig 3 The fourier transform infrared spectroscopy (FT-IR) of the RG, CD and Regorafenib inclusion complexes
Fig 4 1H-NMR of RG, β-CD, γ-CD, HP-β-CD and their inclusion complexes
Fig 5 NOESY of RG-β-CD(a), RG-γ-CD(b)and RG-Hp-β-CD(c) inclusion complexes
Fig 6 The schematic diagram of regorafenib cyclodexyrin inclusion complex
Fig 7 In vitro dissolution profile of regorafenib, regorafenib-γ-CD inclusion complex, regorafenib-Hp-β-CD inclusion complex and regorafenib-β-CD inclusion complex in distilled water, in simulated gastric fluid (pH=1.2) and in phosphate buffer (pH=6.8) with SDS
Fig 8 In vivo tumor suppressor curve of regorafenib and regorafenib-β-cyclodextrin inclusion complex
Fig 9 Comparison of tumor harvested from nude mouse after treatment for 21 days
Fig 10 Nude mice weight curve of regorafenib and regorafenib-β-cyclodextrin inclusion complex
[1]   WILHELM S M , DUMAS J , ADNANE L et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity[J]. Int J Cancer, 2011, 129 (1): 245- 255
doi: 10.1002/ijc.v129.1
[2]   GROTHEY A , VAN CUTSEM E , SOBRERO A et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial[J]. Lancet, 2013, 381 (9863): 303- 312
doi: 10.1016/S0140-6736(12)61900-X
[3]   李 进 . 新型口服多激酶抑制剂瑞戈非尼治疗癌症的研究进展[J]. 临床肿瘤学杂志, 2014, 19 (5): 385- 390
LI Jin . Research progress of new oral multikinase inhibitor regorafenib in the treatment of cancer[J]. Chinese Clinical Oncology, 2014, 19 (5): 385- 390
[4]   STRUMBERG D , SCHEULEN M , SCHULTHEIS B et al. Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase Ⅰ study[J]. Br J Cancer, 2012, 106 (11): 1722- 1727
doi: 10.1038/bjc.2012.153
[5]   DIRK S , BEATE S . Regorafenib for cancer[J]. Expert Opin Inv Drugs, 2012, 21 (6): 879- 889
doi: 10.1517/13543784.2012.684752
[6]   KLAUS M , ANNETTE F , SIMONE S et al. A phase Ⅰ dose-escalation study of regorafenib (bay 73 -4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors[J]. Clin Cancer Res, 2012, 18 (9): 2658- 2667
doi: 10.1158/1078-0432.CCR-11-1900
[7]   刘 正平 , 刘 军田 , 王 明森 et al. 瑞戈非尼固体分散体的制备及体外溶出度考察[J]. 药学研究, 2015, 34 (9): 524- 526
LIU Zhengping , LIU Juntian , WANG Mingshen . Preparation and dissolution of Regorafenib Solid Dispersion in vitro[J]. Journal of Pharmaceutical Research, 2015, 34 (9): 524- 541
[8]   JOENSUU H . Adjuvant treatment of GIST: patient selection and treatment strategies[J]. Nat Rev Oncol, 2012, 9 (6): 351- 358
doi: 10.1038/nrclinonc.2012.74
[9]   DAS B , BARUAH J B . Assemblies of cytosine within H-bonded net-work of adipic acid and citric acid[J]. J Mot Struct, 2011, 1001 (1-3): 134- 138
doi: 10.1016/j.molstruc.2011.06.029
[10]   VANDELLI M , SALVIOLI G , MUCCI A et al. 2-hydroxypropyl-β-cyclodextrin complexation with ursodeoxycholic acid[J]. Int J Pharm, 1995, 118 (1): 77- 83
doi: 10.1016/0378-5173(94)00342-3
[11]   TAKAYAMA K , NAMBU N , NAGAI T . Dissolution kinetics for coprecipitates of indomethacin with polyvinylpyrrolidone[J]. Chem Pharm Bull, 1980, 28 (11): 3304- 3309
doi: 10.1248/cpb.28.3304
[12]   ARCHONTAKI H A , VERTZONI M V , ATHANASSIOU-MALAKI M H . Study on the inclusion complexes of bromazepam with β-and β-hydroxypropyl-cyclodextrins[J]. J Pharm Biomed Anal, 2002, 28 (3-4): 761- 769
doi: 10.1016/S0731-7085(01)00679-3
[13]   RIEKES M K , TAGLIARI M P , GRANADA A et al. Enhanced solubility and dissolution rate of amiodarone by complexation with β-cyclodextrin through different methods[J]. Mater Sci Eng C, 2010, 30 (7): 1008- 1013
doi: 10.1016/j.msec.2010.05.001
[14]   GE X , HUANG G , TIAN S et al. Complexation of carbendazim with hydroxypropyl-β-cyclodextrin to improve solubility and fungicidal activity[J]. Carbohyd Polym, 2012, 89 (1): 208- 212
doi: 10.1016/j.carbpol.2012.02.072
[15]   GIDWAM B , VYAS A . Synthesis, characterization and application of epichlorohydrin-β-cyclodextrin polymer[J]. Coll SurfaceB Biointerfaces, 2014, 114 130- 137
doi: 10.1016/j.colsurfb.2013.09.035
[16]   高 缘 , 祖 卉 , 张 建军 . 药物共晶研究进展[J]. 化学进展, 2010, 22 (5): 829- 836
GAO Yuan , ZU Hui , ZHANG Jianjun . Pharmaceutical co-crystals[J]. Progress in Chemistry, 2010, 22 (5): 829- 836
[1] LIU Kai-hang,SUN Mengying,TANG Guping,HU Xiurong. Preparation, characterization and antitumor of cyclodextrin inclusion of an anti-cancer drug regorafenib[J]. J Zhejiang Univ (Med Sci), 2017, 46(2): 151-159.
[2] LOU Xiao-e, CHEN Min, YANG Bo. Research progress in toxicology of molecular targeted anticancer drugs[J]. J Zhejiang Univ (Med Sci), 2015, 44(5): 473-478.
[3] ZHOU Duo, ZHAO Zheng-yan. Advances in measles virus for cancer therapy[J]. J Zhejiang Univ (Med Sci), 2015, 44(4): 458-464.
[4] WANG Shi-zhuo, ZHAO Yun-feng, SUN Jia-yi, GUO Xing-jie. Determination of enantiomeric impurity in levocetirizine tablets by capillary electrophoresis[J]. J Zhejiang Univ (Med Sci), 2014, 43(2): 150-154.
[5] . Killing effect of aurora kinase inhibitor ENMD-2076 on acute myelogenous leukemia cells[J]. J Zhejiang Univ (Med Sci), 2012, 41(5): 479-484.
[6] . 201Tl and 99mTc-MIBI scintigraphy in evaluation of neoadjuvant chemotherapy for osteosarcoma[J]. J Zhejiang Univ (Med Sci), 2012, 41(2): 183-187.
[7] . Serial recombinant expression and anti-tumor activity in vitro of antibiotic peptide Alloferon-1[J]. J Zhejiang Univ (Med Sci), 2011, 40(5): 501-507.
[8] .
Anti-tumor activity of components isolated from purple sweet potato polysaccharides
[J]. J Zhejiang Univ (Med Sci), 2011, 40(4): 365-373.
[9] . Effect of Luteolin and its combination with chemotherapeutic drugs on cytotoxicity of cancer cells[J]. J Zhejiang Univ (Med Sci), 2010, 39(1): 30-36.
[10] . 4,8-Disubstituted-8,9-dihydro-pyrazine[2,3-g]quinazoline-7(6H)-ketones:A novel class of antitumor agents[J]. J Zhejiang Univ (Med Sci), 2010, 39(1): 49-56.