화학공학소재연구정보센터
홈 로그인 로그아웃 연락처 사이트맵
Journal of Industrial and Engineering Chemistry, Vol.93, 361-374, January, 2021
DOI10.1016/j.jiec.2020.10.013  Export Citation
Production of elastin-like recombinamer-based nanoparticles for docetaxel encapsulation and use as smart drug-delivery systems using a supercritical anti-solvent process
R. Vallejo1, 2, J. Gonzalez-Valdivieso2, M. Santos2, S. Rodriguez-Rojo1, †, and F.J. Arias2, †
  • 1BioEcoUVa, Research Institute on Bioeconomy, High Pressure Process Group, Department of Chemical Engineering and Environmental Technology, Escuela de Ingenierías Industriales, University of Valladolid, Sede Mergelina, 47011 Valladolid, Spain
  • 2IOFORGE Research Group, University of Valladolid, CIBER-BBN, LUCIA Building, Paseo Belén 19, 47011 Valladolid, Spain
E-mail:,
This study presents a new groundbreaking methodology for integrating innovative concepts to develop novel drug-delivery strategies. This methodology combines genetically engineered elastin-like recombinamers (ELRs) with supercritical fluid (SCF) techniques to encapsulate a poorly water-soluble drug in a one-step process. The chemotherapeutic agent docetaxel (DTX) is encapsulated with a block copolymer ELR containing the RGD peptide, a specific target sequence for cancer cells, using the supercritical anti-solvent (SAS) technique in a high process yield of up to 70%. SEM studies show spherical microparticles of 10 μm after encapsulation. After dispersion under physiological conditions, microparticles disaggregate into stable monodisperse nanoparticles of 40 nm size and -30 mV ζ-potential. This protects the drug, as confirmed by NMR analysis, thereby increasing the water solubility of DTX up to fifty orders of magnitude. The delivery process is governed by the Fick diffusion mechanism and indicates that the presence of DTX on the particles surface is practically negligible. Cellular assays showed that, due to the presence of the cancer target sequence RGD, breast cancer cells were more affected than human endothelial cells, thus meaning that the strategy developed in this work opens the way to new controlled release systems more precise than non-selective chemotherapeutic drugs.
Keywords:Elastin-like recombinamers (ELRs);Supercritical anti-solvent (SAS);Docetaxel;Drug delivery;Cancer therapy
  1. Langer R, Science, 249, 1527 (1990)
  2. Santos M, Serrano-Ducar S, Gonzalez-Valdivieso J, et al., Curr. Med. Chem., 26, 7117 (2018)
  3. Rodriguez-Cabello JC, Martin L, Girotti A, et al., Nanomedicine, 6, 111 (2011)
  4. Rodriguez-Cabello JC, Gonzalez de Torre I, Ibanez-Fonseca A, et al., Adv. Drug Deliv. Rev., 129, 118 (2018)
  5. Pina MJ, Girotti A, Serrano S, et al., Cancer Lett., 470, 43 (2019)
  6. Gonzalez-Valdivieso J, Girotti A, Munoz R, Rodriguez-Cabello JC, Arias FJ, Biomacromolecules, 20(5), 1996 (2019)
  7. Rodriguez-Cabello JC, Girotti A, Ribeiro A, et al., Methods and Protocols, Humana Press, Totowa, NJ, pp.17 2011.
  8. Urry DW, Prog. Biophys. Mol. Biol., 57, 23 (1992)
  9. San Biagio PL, Madonia F, Trapane TL, et al., Chem. Phys. Lett., 145, 571 (1988)
  10. Pinedo-Martin G, Santos M, Testera A, et al., Polymer, 55, 5314 (2014)
  11. Fernandez-Colino A, Bermudez JM, Arias FJ, et al., Mater. Sci. Eng. C-Biomimetic Supramol. Syst., 61, 286 (2016)
  12. Ryu JS, Raucher D, Cancer Lett., 348, 177 (2014)
  13. Wang W, Despanie J, Shi P, et al., J. Mater. Chem. B, 2, 8131 (2014)
  14. Hu J, Xie L, Zhao W, et al., Chem. Commun., 51, 11405 (2015)
  15. Nawroth JF, McDaniel JR, Chilkoti A, et al., Macromol. Biosci., 16, 322 (2016)
  16. Yildirimer L, Thanh NTK, Loizidou M, et al., Nano Today, 6, 585 (2011)
  17. Ma G, J. Control. Release, 193, 324 (2014)
  18. Elhenshir A, Subkha A, Energy Procedia, 37, 6964 (2013)
  19. Fernandez-Colino A, Quinteros DA, Allemandi DA, et al., Mol. Pharm., 14, 4498 (2017)
  20. Reverchon E, Ind. Eng. Chem. Res., 41(10), 2405 (2002)
  21. Santos DT, Meireles MA, J. Food Process Eng., 36, 36 (2013)
  22. Campardelli R, Baldino L, Reverchon E, J. Supercrit. Fluids, 101, 193 (2015)
  23. Zheng H, Zhang J, Yan J, et al., J. CO2 Util., 16, 272 (2016)
  24. Martin A, Cocero MJ, Adv. Drug Deliv. Rev., 60, 339 (2008)
  25. Cocero MJ, Martin A, Mattea F, Varona S, J. Supercrit. Fluids, 47(3), 546 (2009)
  26. Martin A, Scholle K, Mattea F, et al., Cryst. Growth Des., 9, 2504 (2009)
  27. Santos DT, Santana AL, Meireles MA, et al., SpringerBriefs in Applied Sciences and Technology, pp.75 (2019).
  28. Franco P, De Marco I, Processes, 8, 938 (2020)
  29. Uzun IN, Sipahigil O, Dincer S, J. Supercrit. Fluids, 55(3), 1059 (2011)
  30. Montes A, Gordillo MD, Pereyra C, De los Santos DM, de la Ossa EJM, J. Supercrit. Fluids, 94, 91 (2014)
  31. Prosapio V, Reverchon E, De Marco I, J. Supercrit. Fluids, 118, 19 (2016)
  32. Palazzo I, Trucillo P, Campardelli R, et al., Food Bioprod. Process., 123, 312 (2020)
  33. Annabi N, Mithieux SM, Weiss AS, et al., Biomaterials, 30, 1 (2009)
  34. Huang X, Yi C, Fan Y, et al., Mater. Sci. Eng. C-Biomimetic Supramol. Syst., 42, 325 (2014)
  35. Guo Y, He W, Yang S, et al., Colloids Surf. B: Biointerfaces, 151, 119 (2017)
  36. Jafari S, Soleimani M, Salehi R, Int. J. Polym. Mater., 68, 859 (2019)
  37. Jadon RS, Sharma M, J. Drug Deliv. Sci. Technol., 51, 475 (2019)
  38. http://www.hmdb.ca/metabolites/HMDB0015378 (accessed January 2020).
  39. Cheng J, Teply BA, Sherifi I, et al., Biomaterials, 28, 869 (2007)
  40. Martin L, Arias FJ, Alonso M, et al., Soft Matter, 6, 1121 (2010)
  41. Hao Y, Zhang B, Zheng C, et al., J. Control. Release, 220, 545 (2015)
  42. Meyer DE, Chilkoti A, Nat. Biotechnol., 17, 1112 (1999)
  43. Goodman SL, Grote HJ, Wilm C, Biol. Open, 1, 329 (2012)
  44. Lang FF, Conrad C, Gomez-Manzano C, et al., J. Clin. Oncol., 36, 1419 (2018)
  45. Urry DW, Angew. Chem.-Int. Edit., 32, 819 (1993)
  46. Natolino A, Da Porto C, Rodriguez-Rojo S, Moreno T, Cocero MJ, J. Supercrit. Fluids, 118, 54 (2016)
  47. Akhtartavan S, Karimi M, Karimian K, et al., Biomed. Pharmacother., 109, 2427 (2019)
  48. https://www.ema.europa.eu/en/documents/product-information/taxotere-epar-product-information_es.pdf (accessed April 2020).
  49. ten Tije AJ, Verweij J, Loos WJ, et al., Clin. Pharmacokinet., 42, 665 (2003)
  50. https://www.ema.europa.eu/en/ich-q3c-r6-residual-solvents (accessed May 2020).
  51. Haimer E, Wendland M, Potthast A, et al., J. Nanomater., 2008, 1 (2008)
  52. Kalani M, Yunus R, Int. J. Nanomed., 6, 1429 (2011)
  53. Stetefeld J, McKenna SA, Patel TR, Biophys. Rev., 8, 409 (2016)
  54. Meyer T, Marshall JF, Hart IR, Br. J. Cancer, 77, 530 (1998)
  55. Saw PE, Yu M, Choi M, et al., Biomaterials, 123, 118 (2017)
  56. Battogtokh G, Gotov O, Kang JH, et al., Nanomedicine, 13, 325 (2018)
  57. Pescador D, Ibanez-Fonseca A, Sanchez-Guijo F, et al., J. Mater. Sci., 28, 115 (2017)
  58. Wang X, Wang Y, Chen X, et al., J. Control. Release, 139, 56 (2009)
  59. Liu F, Li M, Liu C, et al., Pharm. Res., 31, 475 (2014)