Repositioning of Anti-parasitic Drugs in Cyclodextrin Inclusion Complexes for Treatment of Triple-Negative Breast Cancer

Abstract

Drug repositioning refers to the identification of new therapeutic indications for drugs already approved. Albendazole and ricobendazole have been used as anti-parasitic drugs for many years; their therapeutic action is based on the inhibition of microtubule formation. Therefore, the study of their properties as antitumor compounds and the design of an appropriate formulation for cancer therapy is an interesting issue to investigate. The selected compounds are poorly soluble in water, and consequently, they have low and erratic bioavailability. In order to improve their biopharmaceutics properties, several formulations employing cyclodextrin inclusion complexes were developed. To carefully evaluate the in vitro and in vivo antitumor activity of these drugs and their complexes, several studies were performed on a breast cancer cell line (4T1) and BALB/c mice. In vitro studies showed that albendazole presented improved antitumor activity compared with ricobendazole. Furthermore, albendazole:citrate-β-cyclodextrin complex decreased significantly 4T1 cell growth both in in vitro and in vivo experiments. Thus, new formulations for anti-parasitic drugs could help to reposition them for new therapeutic indications, offering safer and more effective treatments by using a well-known drug.

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References

  1. 1.

    Castro LSEPW, Kviecinski MR, Ourique F, Parisotto EB, Grinevicius VMAS, Correia JFG, et al. Albendazole as a promising molecule for tumor control. Redox Biol. 2016;10:90–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Gupta SC, Sung B, Prasad S, Webb LJ, Aggarwal BB. Cancer drug discovery by repurposing: teaching new tricks to old dogs. Trends Pharmacol Sci. 2013;34(9):508–17.

    CAS  PubMed  Google Scholar 

  3. 3.

    Bhatnagar S, Kumari P, Pattarabhiran SP, Venuganti VVK. Zein microneedles for localized delivery of chemotherapeutic agents to treat breast cancer: drug loading, release behavior, and skin permeation studies. AAPS PharmSciTech. 2018;19(4):1818–26.

    CAS  PubMed  Google Scholar 

  4. 4.

    Kassem MA, Megahed MA, Abu Elyazid SK, Abd-Allah FI, Abdelghany TM, Al-Abd AM, et al. Enhancing the therapeutic efficacy of tamoxifen citrate loaded span-based nano-vesicles on human breast adenocarcinoma cells. AAPS PharmSciTech. 2018;19(4):1529–43.

    CAS  PubMed  Google Scholar 

  5. 5.

    Boguski MS, Mandl KD, Sukhatme VP. Repurposing with a difference. Science. 2009;324(5933):1394–5.

    CAS  PubMed  Google Scholar 

  6. 6.

    Dudley J, Berliocchi L. Drug repositioning: approaches and applications for neurotherapeutics. Boca Raton: CRC press; 2017.

    Google Scholar 

  7. 7.

    Yoshida GJ. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment. J Hematol Oncol. 2017;10(1):67.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Luther MA. Systems pharmacology and drug repositioning- an integrated approach to metabolic diseases. J Transl Med. 2012;10(2):A18.

    PubMed Central  Google Scholar 

  9. 9.

    Wu C, Gudivada RC, Aronow BJ, Jegga AG. Computational drug repositioning through heterogeneous network clustering. BMC Syst Biol. 2013;7(5):S6.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Andre N, Banavali S, Snihur Y, Pasquier E. Has the time come for metronomics in low-income and middle-income countries? Lancet Oncol. 2013;14(6):e239–48.

    PubMed  Google Scholar 

  11. 11.

    Liang X-J, Chen C, Zhao Y, Wang PC. Circumventing tumor resistance to chemotherapy by nanotechnology. Multi-Drug Resistance in Cancer. Berlin: Springer; 2010. p. 467–88.

    Google Scholar 

  12. 12.

    Tobinick EL. The value of drug repositioning in the current pharmaceutical market. Drug News Perspect. 2009;22(2):119–25.

    PubMed  Google Scholar 

  13. 13.

    Bisgin H, Liu Z, Kelly R, Fang H, Xu X, Tong W. Investigating drug repositioning opportunities in FDA drug labels through topic modeling. BMC Bioinformatics. 2012;13(15):S6.

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Ferrero E, Agarwal P. Connecting genetics and gene expression data for target prioritisation and drug repositioning. BioData Mining. 2018;11(1):7.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Napolitano F, Zhao Y, Moreira VM, Tagliaferri R, Kere J, D’Amato M, et al. Drug repositioning: a machine-learning approach through data integration. J Cheminform. 2013;5(1):30.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Nygren P, Fryknäs M, Ågerup B, Larsson R. Repositioning of the anthelmintic drug mebendazole for the treatment for colon cancer. J Cancer Res Clin Oncol. 2013;139(12):2133–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Bongioanni A, Araujo BS, de Oliveira YS, Longhi MR, Ayala A, Garnero C. Improving properties of albendazole desmotropes by supramolecular systems with maltodextrin and glutamic acid. AAPS PharmSciTech. 2018;19(3):1468–76. https://doi.org/10.1208/s12249-018-0952-0.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Priotti J, Leonardi D, Pico G, Lamas MC. Application of fluorescence emission for characterization of albendazole and ricobendazole micellar systems: elucidation of the molecular mechanism of drug solubilization process. AAPS PharmSciTech. 2018;19(3):1152–9. https://doi.org/10.1208/s12249-017-0927-6.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Riviere JE, Papich MG. Veterinary pharmacology and therapeutics. Hoboken: Wiley; 2009.

    Google Scholar 

  20. 20.

    Priotti J, Codina AV, Leonardi D, Vasconi MD, Hinrichsen LI, Lamas MC. Albendazole microcrystal formulations based on chitosan and cellulose derivatives: physicochemical characterization and in vitro parasiticidal activity in Trichinella spiralis adult worms. AAPS PharmSciTech. 2017;18(4):947–56.

    CAS  PubMed  Google Scholar 

  21. 21.

    García A, Barrera MG, Piccirilli G, Vasconi MD, Di Masso RJ, Leonardi D, et al. Novel albendazole formulations given during the intestinal phase of Trichinella spiralis infection reduce effectively parasitic muscle burden in mice. Parasitol Int. 2013;62(6):568–70. https://doi.org/10.1016/j.parint.2013.08.009.

    PubMed  Google Scholar 

  22. 22.

    Walter HS, Ahmed S. Targeted therapies in cancer. Surgery (Oxford). 2018;36(3):122–7.

    Google Scholar 

  23. 23.

    Chu SWL, Badar S, Morris DL, Pourgholami MH. Potent inhibition of tubulin polymerisation and proliferation of paclitaxel-resistant 1A9PTX22 human ovarian cancer cells by albendazole. Anticancer Res. 2009;29(10):3791–6.

    CAS  PubMed  Google Scholar 

  24. 24.

    Noorani L, Stenzel M, Liang R, Pourgholami MH, Morris DL. Albumin nanoparticles increase the anticancer efficacy of albendazole in ovarian cancer xenograft model. J Nanobiotech. 2015;13(1):25.

    Google Scholar 

  25. 25.

    Ehteda A, Galettis P, Chu SW, Pillai K, Morris DL. Complexation of albendazole with hydroxypropyl-beta-cyclodextrin significantly improves its pharmacokinetic profile, cell cytotoxicity and antitumor efficacy in nude mice. Anticancer Res. 2012;32(9):3659–66.

    CAS  PubMed  Google Scholar 

  26. 26.

    Ehteda A, Galettis P, Pillai K, Morris DL. Combination of albendazole and 2-methoxyestradiol significantly improves the survival of HCT-116 tumor-bearing nude mice. BMC Cancer. 2013;13(1):86.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Kutlehria S, Behl G, Patel K, Doddapaneni R, Vhora I, Chowdhury N, et al. Cholecalciferol-PEG conjugate based nanomicelles of doxorubicin for treatment of triple-negative breast cancer. AAPS PharmSciTech. 2018;19(2):792–802.

    CAS  PubMed  Google Scholar 

  28. 28.

    Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A. 2003;100(14):8418–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Haser A, Zhang F. New strategies for improving the development and performance of amorphous solid dispersions. AAPS PharmSciTech. 2018;19(3):978–90.

    CAS  PubMed  Google Scholar 

  30. 30.

    Zhang Y, Huang Y, Li S. Polymeric micelles: nanocarriers for cancer-targeted drug delivery. AAPS PharmSciTech. 2014;15(4):862–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Priotti J, Leonardi D, Pico G, Lamas MC. Application of fluorescence emission for characterization of albendazole and ricobendazole micellar systems: elucidation of the molecular mechanism of drug solubilization process. AAPS PharmSciTech. 2017:1–8.

  32. 32.

    Brough C, Williams Iii RO. Amorphous solid dispersions and nano-crystal technologies for poorly water-soluble drug delivery. Int J Pharm. 2013;453(1):157–66.

    CAS  PubMed  Google Scholar 

  33. 33.

    Zhang Y, Hu X, Liu X, Dandan Y, Di D, Yin T, et al. Dry state microcrystals stabilized by an HPMC film to improve the bioavailability of andrographolide. Int J Pharm. 2015;493(1–2):214–23.

    CAS  PubMed  Google Scholar 

  34. 34.

    Bavishi DD, Borkhataria CH. Spring and parachute: how cocrystals enhance solubility. Prog Cryst Growth Charact Mater. 2016;62(3):1–8.

    CAS  Google Scholar 

  35. 35.

    Real D, Leonardi D, Williams RO III, Repka MA, Salomon CJ. Solving the delivery problems of triclabendazole using cyclodextrins. AAPS PharmSciTech. 2018;19:2311–21.

    CAS  PubMed  Google Scholar 

  36. 36.

    García A, Leonardi D, Lamas MC. Promising applications in drug delivery systems of a novel β-cyclodextrin derivative obtained by green synthesis. Bioorg Med Chem Lett. 2016;26(2):602–8.

    PubMed  Google Scholar 

  37. 37.

    García A, Leonardi D, Salazar MO, Lamas MC. Modified β-cyclodextrin inclusion complex to improve the physicochemical properties of albendazole. Complete in vitro evaluation and characterization. PLoS One. 2014;9(2):e88234.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Ferreira MJG, García A, Leonardi D, Salomon CJ, Lamas MC, Nunes TG. 13C and 15N solid-state NMR studies on albendazole and cyclodextrin albendazole complexes. Carbohydr Polym. 2015;123:130–5.

    CAS  PubMed  Google Scholar 

  39. 39.

    García A, Leonardi D, Vasconi MD, Hinrichsen LI, Lamas MC. Characterization of albendazole-randomly methylated-β-cyclodextrin inclusion complex and in vivo evaluation of its antihelmitic activity in a murine model of trichinellosis. PLoS One. 2014;9(11):e113296.

    PubMed  PubMed Central  Google Scholar 

  40. 40.

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

    PubMed  Google Scholar 

  41. 41.

    Conceição J, Adeoye O, Cabral-Marques HM, Lobo JMS. Cyclodextrins as excipients in tablet formulations. Drug Discov Today. 2018;23:1274–84.

    PubMed  Google Scholar 

  42. 42.

    Kurkov SV, Loftsson T. Cyclodextrins. Int J Pharm. 2013;453(1):167–80.

    CAS  PubMed  Google Scholar 

  43. 43.

    Szente L, Szejtli J. Highly soluble cyclodextrin derivatives: chemistry, properties, and trends in development. Adv Drug Deliv Rev. 1999;36(1):17–28.

    CAS  PubMed  Google Scholar 

  44. 44.

    Leonardi D, Bombardiere ME, Salomon CJ. Effects of benznidazole:cyclodextrin complexes on the drug bioavailability upon oral administration to rats. Int J Biol Macromol. 2013;62:543–8.

    CAS  PubMed  Google Scholar 

  45. 45.

    Codina AV, García A, Leonardi D, Vasconi MD, Di Masso RJ, Lamas MC, et al. Efficacy of albendazole:β-cyclodextrin citrate in the parenteral stage of Trichinella spiralis infection. Int J Biol Macromol. 2015;77:203–6.

    CAS  PubMed  Google Scholar 

  46. 46.

    Mura P. Analytical techniques for characterization of cyclodextrin complexes in the solid state: a review. J Pharm Biomed Anal. 2015;113:226–38.

    CAS  PubMed  Google Scholar 

  47. 47.

    Hay WT, Behle RW, Fanta GF, Felker FC, Peterson SC, Selling GW. Effect of spray drying on the properties of amylose-hexadecylammonium chloride inclusion complexes. Carbohyd Polym. 2017;157:1050–6.

    CAS  Google Scholar 

  48. 48.

    Medarević D, Kachrimanis K, Djurić Z, Ibrić S. Influence of hydrophilic polymers on the complexation of carbamazepine with hydroxypropyl-β-cyclodextrin. Eur J Pharm Sci. 2015;78:273–85.

    PubMed  Google Scholar 

  49. 49.

    United States Pharmacopeial Convention. The United States Pharmacopeia. Rockville, Maryland 2012;35th ed.

  50. 50.

    Baar M, Dale J, Griffin G. Chapter 3 - Canada’s oversight of animal ethics and care in science. In: Guillén J, editor. Laboratory Animals. 2nd ed. Cambridge: Academic Press; 2018. p. 69–90.

    Google Scholar 

  51. 51.

    Rico M, Baglioni M, Bondarenko M, Laluce NC, Rozados V, Nicolas A, et al. Metformin and propranolol combination prevents cancer progression and metastasis in different breast cancer models. Oncotarget. 2017;8(2):2874–89.

    PubMed  Google Scholar 

  52. 52.

    Wu Z, Razzak M, Tucker IG, Medlicott NJ. Physicochemical characterization of ricobendazole: I. solubility, lipophilicity, and ionization characteristics. J Pharm Sci. 2005;94(5):983–93.

    CAS  PubMed  Google Scholar 

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Acknowledgements

J.P. and M.V.B. are grateful to CONICET for Doctoral Fellowships. The authors also thank Ferromet S.A. (agent of Roquette in Argentina) for their donation of β-CD.

Funding

This study received financial support from the Universidad Nacional de Rosario and CONICET (Project N° PIP 112-201001-00194) and “Instituto Nacional del Cáncer.”

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Correspondence to María Celina Lamas.

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All experiments were performed in accordance with the Canadian Council on Animal Care guidelines.

Animal Studies

All institutional and national guidelines for the care and use of laboratory animals were followed. This study was authorized by the Ethics Committee for Animal Use (registration number 1659/2016).

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Priotti, J., Baglioni, M.V., García, A. et al. Repositioning of Anti-parasitic Drugs in Cyclodextrin Inclusion Complexes for Treatment of Triple-Negative Breast Cancer. AAPS PharmSciTech 19, 3734–3741 (2018). https://doi.org/10.1208/s12249-018-1169-y

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KEY WORDS

  • albendazole
  • repositioning
  • breast cancer cell line
  • cyclodextrin