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Instrumental analysis and molecular modelling of inclusion complexes containing artesunate

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Abstract

A series of five guest–host inclusion complexes containing the antimalarial and anticancer agent artesunate (ATS) were obtained and characterized in the present study. Different cyclodextrins (CDNs) were used as hosts [α-cyclodextrin (CDN1), β-cyclodextrin (CDN2), γ-cyclodextrin (CDN3), (2-hydroxypropyl)-β-cyclodextrin (CDN4) and (2-hydroxypropyl)-γ-cyclodextrin (CDN5)], and the formation of the adducts was simulated using molecular modelling. The results indicating the hypothetical formation of all complexes were confirmed on the prepared samples by FTIR spectroscopy and thermal analysis (TG—thermogravimetric/DTG—derivative thermogravimetric/HF—heat flow). Our results showed that the partially entrapment of ATS inside the cavity of each cyclodextrin is a consequence of H-bonds formation, electrostatic interactions (dipole–dipole) and hydration water substitution. Also, all complexes formed in a 1:1 molecular ratio presented with higher thermal stability than pure ATS, making the analysed adducts possible alternatives in the drug design process of new and improved pharmaceutical formulations containing ATS.

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References

  1. Xie DY. Artemisia annua, artemisinin, and the Nobel Prize: beauty of natural products and educational significance. Sci Bull. 2016;61(1):42–4.

    Article  Google Scholar 

  2. WHO. Treatment. In: Compendium of WHO malaria guidance-prevention, diagnosis, treatment, surveillance and elimination. World Health Organization. 2019. https://apps.who.int/iris/bitstream/handle/10665/312082/WHO-CDS-GMP-2019.03-eng.pdf?ua=1. Accessed 21 Dec 2019.

  3. Efferth T. Artemisinin-second career as anticancer drug? World J Tradit Chin Med. 2015;1(4):2–25.

    Article  Google Scholar 

  4. Jeong DE, Song HJ, Lim S, et al. Repurposing the anti-malarial drug artesunate as a novel therapeutic agent for metastatic renal cell carcinoma due to its attenuation of tumor growth, metastasis, and angiogenesis. Oncotarget. 2015;6(32):33046–64.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Efferth T. From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Semin Cancer Biol. 2017;46:65–83.

    Article  CAS  PubMed  Google Scholar 

  6. Antoszczak M, Markowska A, Markowska J, Huczyński A. Old wine in new bottles: drug repurposing in oncology. Eur J Pharmacol. 2020. https://doi.org/10.1016/j.ejphar.2019.172784.

    Article  PubMed  Google Scholar 

  7. Wikman-Jorgensen PE, Henríquez-Camacho CA, Serrano-Villar S, Pérez-Molina JA. The role of artesunate for the treatment of urinary schistosomiasis in schoolchildren: a systematic review and meta-analysis. Pathog Glob Health. 2012;106(7):397–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Egbe-Nwiyi TN, Igwenagu E, Ndueidem UIT, Zira LJ. The therapeutic efficacy of artesunate and diminazene in the treatment of experimental Trypanosoma bruceibrucei infection in rats. Afr J Biomed Res. 2014;17(1):9–14.

    Google Scholar 

  9. Ho WE, Peh HY, Chan TK, Wong WSF. Artemisinins: pharmacological actions beyond anti-malarial. Pharmacol Ther. 2014;142(1):126–39.

    Article  CAS  PubMed  Google Scholar 

  10. Ansari MT, Pervez H, Shehzad MT, Saeed-ul-Hassan S, Mehmood Z, Shah SNH, Razi MT, Murtaza G. Improved physicochemical characteristics of artemisinin using succinic acid. Acta Pol Pharm. 2014;71(3):451–62.

    PubMed  Google Scholar 

  11. Scheibel LW. WHO model prescribing information, drugs used in parasitic diseases. J Parasitol. 1991;77(6):957.

    Article  Google Scholar 

  12. Kouakou YI, Tod M, Leboucher G, Lavoignat A, Bonnot G, Bienvenu AL, Picot S. Systematic review of artesunate pharmacokinetics: implication for treatment of resistant malaria. Int J Infect Dis. 2019;89:30–44.

    Article  CAS  PubMed  Google Scholar 

  13. Morris CA, Duparc S, Borghini-Fuhrer I, Jung D, Shin CS, Fleckenstein L. Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration. Malar J. 2011;10(1):263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. von Hagens C, Walter-Sack I, Goeckenjan M, et al. Prospective open uncontrolled phase I study to define a well-tolerated dose of oral artesunate as add-on therapy in patients with metastatic breast cancer (ARTIC M33/2). Breast Cancer Res Treat. 2017;164(2):359–69.

    Article  CAS  Google Scholar 

  15. König M, Von Hagens C, Hoth S, Baumann I, Walter-Sack I, Edler L, Sertel S. Investigation of ototoxicity of artesunate as add-on therapy in patients with metastatic or locally advanced breast cancer: new audiological results from a prospective, open, uncontrolled, monocentric phase I study. Cancer Chemother Pharmacol. 2016;77(2):413–27.

    Article  PubMed  CAS  Google Scholar 

  16. Ericsson T, Blank A, Von Hagens C, Ashton M, Äbelö A. Population pharmacokinetics of artesunate and dihydroartemisinin during long-term oral administration of artesunate to patients with metastatic breast cancer. Eur J Clin Pharmacol. 2014;70(12):1453–63.

    Article  CAS  PubMed  Google Scholar 

  17. Deeken JF, Wang H, Hartley M, et al. A phase I study of intravenous artesunate in patients with advanced solid tumor malignancies. Cancer Chemother Pharmacol. 2018;81(3):587–96.

    Article  CAS  PubMed  Google Scholar 

  18. Davis ME, Brewster ME. Cyclodextrin-based pharmaceutics: past, present and future. Nat Rev Drug Discov. 2004;3(12):1023–35.

    Article  CAS  PubMed  Google Scholar 

  19. Duchêne D, Bochot A. Thirty years with cyclodextrins. Int J Pharm. 2016;514(1):58–72.

    Article  PubMed  CAS  Google Scholar 

  20. Vyas A, Saraf S, Saraf S. Cyclodextrin based novel drug delivery systems. J Incl Phenom Macrocycl Chem. 2008;62(1–2):23–422.

    Article  CAS  Google Scholar 

  21. Gidwani B, Vyas A. A comprehensive review on cyclodextrin-based carriers for delivery of chemotherapeutic cytotoxic anticancer drugs. Biomed Res Int. 2015;2015:1–15.

    Article  CAS  Google Scholar 

  22. Circioban D, Ledeti A, Vlase G, Coricovac D, Moaca A, Farcas C, Vlase T, Ledeti I, Dehelean C. Guest–host interactions and complex formation for artemisinin with cyclodextrins: instrumental analysis and evaluation of biological activity. J Therm Anal Calorim. 2018;134(2):1375–84.

    Article  CAS  Google Scholar 

  23. Şuta LM, Vlaia L, Vlaia V, Olariu I, Hǎdǎrugǎ DI, Mircioiu C. Study of the complexation behavior of tenoxicam with cyclodextrins. Farmacia. 2012;60(4):475–83.

    Google Scholar 

  24. Suta L-M, Vlaia L, Fulias A, Ledeti I, Hadaruga D, Mircioiu C. Evaluation study of the inclusion complexes of some oxicams with 2-hydroxypropyl-beta-cyclodextrin. Rev Chim. 2013;64(11):1279–83.

    CAS  Google Scholar 

  25. Loftsson T, Duchêne D. Cyclodextrins and their pharmaceutical applications. Int J Pharm. 2007;329(1–2):1–11.

    Article  CAS  PubMed  Google Scholar 

  26. Chadha R, Gupta S, Shukla G, Jain DVS, Pissurlenkar RRS, Coutinho EC. Interaction of artesunate with β-cyclodextrin: characterization, thermodynamic parameters, molecular modeling, effect of PEG on complexation and antimalarial activity. Results Pharma Sci. 2011;1(1):38–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Xie H, Yang B, Wang F, Zhao Y. Host–guest inclusion system of artesunate with β-cyclodextrin and its derivatives: characterization and antitumor activity. J Mol Struct. 2015;1085:90–6.

    Article  CAS  Google Scholar 

  28. Al Hayder M, Sunderland VB. Effect of hydroxypropyl-ß-cyclodextrin complexation on the aqueous solubility and stability of artesunate. Int J Pharm Pharm Sci. 2014;6(7):598–601.

    CAS  Google Scholar 

  29. Zhang D, Zhou C, Lv P, Zhao Y, Liang J, Liao X, Yang B. Preparation and characterization of a novel host–guest complex based on folate-modified β-cyclodextrin and artesunate. Mater Sci Eng C. 2018;86:48–55.

    Article  CAS  Google Scholar 

  30. Sbârcea L, Udrescu L, Ledeţi I, Szabadai Z, Fuliaş A, Sbârcea C. β-Cyclodextrin inclusion complexes of lisinopril and zofenopril: physicochemical characterization and compatibility study of lisinopril-β-cyclodextrin with lactose. J Therm Anal Calorim. 2016;123(3):2377–90.

    Article  CAS  Google Scholar 

  31. Frisch MJ, Trucks GW, Schlegel HB et al. Gaussian 09. Wallingford CT: Gaussian, Inc. 2009.

    Google Scholar 

  32. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem. 2009;30(16):2785–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schrodinger LLC. The AxPyMOL molecular graphics plugin for Microsoft PowerPoint, version 1.8, November 2015.

  34. Schrodinger LLC. The JyMOL molecular graphics development component, version 1.8, November 2015.

  35. Schrodinger LLC. The PyMOL molecular graphics system, version 1.8, November 2015.

  36. Dassault Systèmes BIOVIA. BIOVIA workbook, release 2017; BIOVIA pipeline pilot, release 2017. San Diego: Dassault Systèmes; 2019.

    Google Scholar 

  37. Huey R, Morris GM, Olson AJ, Goodsell DS. A semiempirical free energy force field with charge-based desolvation. J Comput Chem. 2007;28(6):1145–52.

    Article  CAS  PubMed  Google Scholar 

  38. Circioban D, Ledeţi I, Vlase G, Ledeţi A, Axente C, Vlase T, Dehelean C. Kinetics of heterogeneous-induced degradation for artesunate and artemether. J Therm Anal Calorim. 2018;134(1):749–56.

    Article  CAS  Google Scholar 

  39. Rachmawati H, Edityaningrum CA, Mauludin R. Molecular inclusion complex of curcumin–β-cyclodextrin nanoparticle to enhance curcumin skin permeability from hydrophilic matrix gel. AAPS PharmSciTech. 2013;14(4):1303–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Misiuk W, Tykocka A. Sensitive extractive spectrophotometric methods for the determination of nortriptyline hydrochloride in pharmaceutical formulations. Chem Pharm Bull (Tokyo). 2007;55(12):1655–61.

    Article  CAS  Google Scholar 

  41. Aderibigbe B. Design of drug delivery systems containing artemisinin and its derivatives. Molecules. 2017;22(2):323.

    Article  PubMed Central  CAS  Google Scholar 

  42. Brusnikina M, Silyukov O, Chislov M, Volkova T, Proshin A, Mazur A, Tolstoy P, Terekhova I. Effect of cyclodextrin complexation on solubility of novel anti-Alzheimer 1,2,4-thiadiazole derivative. J Therm Anal Calorim. 2017;130(1):443–50.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Faculty of Pharmacy, University of Medicine and Pharmacy “Victor Babes”, 2 Eftimie Murgu Square, 300041, Timisoara, Romania

    Denisa Circioban, Ionut Ledeti, Lenuta-Maria Suta, Adriana Ledeti, Laura Sbarcea, Cristina Trandafirescu & Cristina Dehelean

  2. Research Centre for Thermal Analysis in Environmental Problems, West University of Timisoara, 16 Pestalozzi Street, 300115, Timisoara, Romania

    Gabriela Vlase & Titus Vlase

  3. Faculty of Pharmacy, University of Medicine and Pharmacy Craiova, 2-4 Petru Rares Street, 200349, Craiova, Romania

    Renata Varut

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  1. Denisa Circioban
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Circioban, D., Ledeti, I., Suta, LM. et al. Instrumental analysis and molecular modelling of inclusion complexes containing artesunate. J Therm Anal Calorim 142, 1951–1961 (2020). https://doi.org/10.1007/s10973-020-09975-3

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  • DOI: https://doi.org/10.1007/s10973-020-09975-3

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