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Analytical and Bioanalytical Chemistry

, Volume 410, Issue 21, pp 5245–5253 | Cite as

Flow field-flow fractionation and multi-angle light scattering as a powerful tool for the characterization and stability evaluation of drug-loaded metal–organic framework nanoparticles

  • Barbara RodaEmail author
  • Valentina Marassi
  • Andrea Zattoni
  • Francesco Borghi
  • Resmi Anand
  • Valentina Agostoni
  • Ruxandra Gref
  • Pierluigi Reschiglian
  • Sandra Monti
Research Paper

Abstract

Asymmetric flow field-flow fractionation (AF4) coupled with UV-Vis spectroscopy, multi-angle light scattering (MALS) and refractive index (RI) detection has been applied for the characterization of MIL-100(Fe) nanoMOFs (metal–organic frameworks) loaded with nucleoside reverse transcriptase inhibitor (NRTI) drugs for the first time. Empty nanoMOFs and nanoMOFs loaded with azidothymidine derivatives with three different degrees of phosphorylation were examined: azidothymidine (AZT, native drug), azidothymidine monophosphate (AZT-MP), and azidothymidine triphosphate (AZT-TP). The particle size distribution and the stability of the nanoparticles when interacting with drugs have been determined in a time frame of 24 h. Main achievements include detection of aggregate formation in an early stage and monitoring nanoMOF morphological changes as indicators of their interaction with guest molecules. AF4-MALS proved to be a useful methodology to analyze nanoparticles engineered for drug delivery applications and gave fundamental data on their size distribution and stability.

Graphical abstract

Keywords

Flow field-flow fractionation Multi-angle light scattering Metal–organic frameworks Azidothymidine NRTI Metal–organic framework nanoparticles characterization 

Notes

Compliance with ethical standards

Conflict of interest

Andrea Zattoni, Barbara Roda, and Pierluigi Reschiglian are associates of the academic spinoff company byFlow Srl (Bologna, Italy). The company mission includes know-how transfer, development, and application of novel technologies and methodologies for the analysis and characterization of samples of nanobiotechnological interest. Valentina Marassi, Francesco Borghi, Resmi Anand, Valentina Agostoni, Ruxandra Gref, and Sandra Monti declare no conflicts of interest.

References

  1. 1.
    Furman PA, Fyfe JA, Stclair MH, Weinhold K, Rideout JL, Freeman GA, et al. Phosphorylation of 3′-azido-3′-deoxythymidine and selective interaction of the 5′-triphosphate with human-immunodeficiency-virus reverse-transcriptase. PNAS. 1986;83(21):8333–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Kukhanova M, Krayevsky A, Prusoff W, Cheng YC. Design of anti-HIV compounds: from nucleoside to nucleoside 5'-triphosphate analogs. Problems and perspectives. Curr Pharm Des. 2000;6(5):585–98.CrossRefPubMedGoogle Scholar
  3. 3.
    Loke SL, Stein CA, Zhang XH, Mori K, Nakanishi M, Subasinghe C, et al. Characterization of oligonucleotide transport into living cells. PNAS. 1989;86(10):3474–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Li XL, Chan WK. Transport, metabolism and elimination mechanisms of anti-HIV agents. Adv Drug Deliv Rev. 1999;39(1–3):81–103.CrossRefPubMedGoogle Scholar
  5. 5.
    Hillaireau H, Le Doan T, Appel M, Couvreur P. Hybrid polymer nanocapsules enhance in vitro delivery of azidothymidine-triphosphate to macrophages. J Control Release. 2006;116(3):346–52.CrossRefPubMedGoogle Scholar
  6. 6.
    Hillaireau H, Le Doan T, Besnard M, Chacun H, Janin J, Couvreur P. Encapsulation of antiviral nucleotide analogues azidothymidine-triphosphate and cidofovir in poly(iso-butylcyanoacrylate) nanocapsules. Int J Pharm. 2006;324(1):37–42.CrossRefPubMedGoogle Scholar
  7. 7.
    Hillaireau H, Le Doan T, Chacun H, Janin J, Couvreur P. Encapsulation of mono- and oligo-nucleotides into aqueous-core nanocapsules in presence of various water-soluble polymers. Int J Pharm. 2007;331(2):148–52.CrossRefPubMedGoogle Scholar
  8. 8.
    Kohli E, Han HY, Zeman AD, Vinogradov SV. Formulations of biodegradable Nanogel carriers with 5′-triphosphates of nucleoside analogs that display a reduced cytotoxicity and enhanced drug activity. J Control Release. 2007;121(1–2):19–27.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Saiyed ZM, Gandhi NH, Nair MPNAZT. 5'-triphosphate nanoformulation suppresses human immunodeficiency virus type 1 replication in peripheral blood mononuclear cells. J Neuro-Oncol. 2009;15(4):343–7.Google Scholar
  10. 10.
    Saiyed ZM, Gandhi NH, Nair MPN. Magnetic nanoformulation of azidothymidine 5'-triphosphate for targeted delivery across the blood-brain barrier. Int J Nanomedicine. 2010;5:157–66.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Vinogradov SV. Polymeric nanogel formulations of nucleoside analogs. Expert Opin Drug Deliv. 2007;4(1):5–17.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Vinogradov SV, Kabanov AV. Synthesis of nanogel carriers for delivery of active phosphorylated nucleoside analogues. Abstr Pap Am Chem Soc. 2004;228:U369-U.Google Scholar
  13. 13.
    Gerson T, Makarov E, Senanayake TH, Gorantla S, Poluektova LY, Vinogradov SV. Nano-NRTIs demonstrate low neurotoxicity and high antiviral activity against HIV infection in the brain. Nanomedicine. 2014;10(1):177–85.CrossRefPubMedGoogle Scholar
  14. 14.
    Horcajada P, Chalati T, Serre C, Gillet B, Sebrie C, Baati T, et al. Porous metal-organic-framework nanoscale carriers as a potential platform for drug delivery and imaging. Nat Mater. 2010;9(2):172–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Kuppler RJ, Timmons DJ, Fang QR, Li JR, Makal TA, Young MD, et al. Potential applications of metal-organic frameworks. Coord Chem Rev. 2009;253(23–24):3042–66.CrossRefGoogle Scholar
  16. 16.
    Della Rocca J, Liu DM, Lin WB. Nanoscale metal-organic frameworks for biomedical imaging and drug delivery. Acc Chem Res. 2011;44(10):957–68.CrossRefPubMedGoogle Scholar
  17. 17.
    Horcajada P, Gref R, Baati T, Allan PK, Maurin G, Couvreur P, et al. Metal-organic frameworks in biomedicine. Chem Rev. 2012;112(2):1232–68.CrossRefPubMedGoogle Scholar
  18. 18.
    Simon-Yarza MT, Baati T, Paci A, Lesueur LL, Seck A, Chiper M, et al. Antineoplastic busulfan encapsulated in a metal organic framework nanocarrier: first in vivo results. J Mater Chem B. 2016;4(4):585–8.CrossRefGoogle Scholar
  19. 19.
    Chalati T, Horcajada P, Couvreur P, Serre C, Ben Yahia M, Maurin G, et al. Porous metal organic framework nanoparticles to address the challenges related to busulfan encapsulation. Nanomedicine. 2011;6(10):1683–95.CrossRefPubMedGoogle Scholar
  20. 20.
    Horcajada P, Serre C, McKinlay AC, Morris RE. Biomedical applications of metal-organic frameworks. Metal-organic frameworks: applications from catalysis to gas storage 2011. p. 215–50.Google Scholar
  21. 21.
    Anand R, Borghi F, Manoli F, Manet I, Agostoni V, Reschiglian P, et al. Host-guest interactions in Fe(III)-trimesate MOF nanoparticles loaded with doxorubicin. J Phys Chem B. 2014;118(29):8532–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Agostoni V, Anand R, Monti S, Hall S, Maurin G, Horcajada P, et al. Impact of phosphorylation on the encapsulation of nucleoside analogues within porous iron(III) metal-organic framework MIL-100(Fe) nanoparticles. J Mater Chem B. 2013;1(34):4231–42.CrossRefGoogle Scholar
  23. 23.
    Simon-Yarza T, Giménez-Marqués M, Mrimi R, Mielcarek A, Gref R, Horcajada P, et al. A smart metal-organic framework nanomaterial for lung targeting. Angew Chem Int Ed Engl. 2017;56(49):15565–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Rodriguez-Ruiz V, Maksimenko A, Anand R, Monti S, Agostoni V, Couvreur P, et al. Efficient “green” encapsulation of a highly hydrophilic anticancer drug in metal-organic framework nanoparticles. J Drug Target. 2015;23(7–8):759–67.CrossRefPubMedGoogle Scholar
  25. 25.
    Horcajada P, Surble S, Serre C, Hong DY, Seo YK, Chang JS, et al. Synthesis and catalytic properties of MIL-100(Fe), an iron(III) carboxylate with large pores. Chem Commun. 2007 (27):2820–2.Google Scholar
  26. 26.
    Baati T, Njim L, Neffati F, Kerkeni A, Bouttemi M, Gref R, et al. In depth analysis of the in vivo toxicity of nanoparticles of porous iron(III) metal-organic frameworks. Chem Sci. 2013;4(4):1597–607.CrossRefGoogle Scholar
  27. 27.
    Brar SK, Verma M. Measurement of nanoparticles by light-scattering techniques. TrAC Trends Anal Chem. 2011;30(1):4–17.CrossRefGoogle Scholar
  28. 28.
    Kaasalainen M, Aseyev V, von Haartman E, Karaman DŞ, Mäkilä E, Tenhu H, et al. Size, stability, and porosity of mesoporous nanoparticles characterized with light scattering. Nanoscale Res Lett. 2017;12(1):74.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Giddings JC. Field-flow fractionation: analysis of macromolecular, colloidal, and particulate materials. Science. 1993;260(5113):1456.CrossRefPubMedGoogle Scholar
  30. 30.
    Contado C. Field flow fractionation techniques to explore the “nano-world”. Anal Bioanal Chem. 2017;409(10):2501–18.CrossRefPubMedGoogle Scholar
  31. 31.
    Rigaux G, Gheran CV, Callewaert M, Cadiou C, Voicu SN, Dinischiotu A, et al. Characterization of Gd loaded chitosan-TPP nanohydrogels by a multi-technique approach combining dynamic light scattering (DLS), asymetrical flow-field-flow-fractionation (AF4) and atomic force microscopy (AFM) and design of positive contrast agents for molecular resonance imaging (MRI). Nanotechnology. 2017;28(5):055705.CrossRefPubMedGoogle Scholar
  32. 32.
    Schimpf ME, Caldwell K, Giddings JC. Field-flow fractionation handbook. Hoboken: Wiley; 2000.Google Scholar
  33. 33.
    Wyatt PJ. Light-scattering and the absolute characterization of macromolecules. Anal Chim Acta. 1993;272(1):1–40.CrossRefGoogle Scholar
  34. 34.
    Thielking H, Roessner D, Kulicke W-M. Online coupling of flow field-flow fractionation and multiangle laser light scattering for the characterization of polystyrene particles. Anal Chem. 1995;67(18):3229–33.CrossRefGoogle Scholar
  35. 35.
    Wyatt PJ. Submicrometer particle sizing by multiangle light scattering following fractionation. J Colloid Interface Sci. 1998;197(1):9–20.CrossRefPubMedGoogle Scholar
  36. 36.
    Reschiglian P, Rambaldi DC, Zattoni A. Flow field-flow fractionation with multiangle light scattering detection for the analysis and characterization of functional nanoparticles. Anal Bioanal Chem. 2011;399(1):197–203.CrossRefPubMedGoogle Scholar
  37. 37.
    Zattoni A, Rambaldi DC, Reschiglian P, Melucci M, Krol S, Garcia AMC, et al. Asymmetrical flow field-flow fractionation with multi-angle light scattering detection for the analysis of structured nanoparticles. J Chromatogr A. 2009;1216(52):9106–12.CrossRefPubMedGoogle Scholar
  38. 38.
    Marassi V, Roda B, Zattoni A, Tanase M, Reschiglian P. Hollow fiber flow field-flow fractionation and size-exclusion chromatography with MALS detection: a complementary approach in biopharmaceutical industry. J Chromatogr A. 2014;1372C:196–203.CrossRefPubMedGoogle Scholar
  39. 39.
    Hupfeld S, Moen HH, Ausbacher D, Haas H, Brandl M. Liposome fractionation and size analysis by asymmetrical flow field-flow fractionation/multi-angle light scattering: influence of ionic strength and osmotic pressure of the carrier liquid. Chem Phys Lipids. 2010;163(2):141–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Kaluderovic GN, Dietrich A, Kommera H, Kuntsche J, Mader K, Mueller T, et al. Liposomes as vehicles for water insoluble platinum-based potential drug: 2-(4-(tetrahydro-2H-pyran-2-yloxy)-undecyl)-propane-1,3-diamminedichloro platinum(II). Eur J Med Chem. 2012;54:567–72.CrossRefPubMedGoogle Scholar
  41. 41.
    Kang DY, Kim MJ, Kim ST, Oh KS, Yuk SH, Lee SH. Size characterization of drug-loaded polymeric core/shell nanoparticles using asymmetrical flow field-flow fractionation. Anal Bioanal Chem. 2008;390(8):2183–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Gaulding JC, South AB, Lyon LA. Hydrolytically degradable shells on thermoresponsive microgels. Colloid Polym Sci. 2013;291(1):99–107.CrossRefGoogle Scholar
  43. 43.
    Schadlich A, Caysa H, Mueller T, Tenambergen F, Rose C, Gopferich A, et al. Tumor accumulation of NIR fluorescent PEG PLA nanoparticles: impact of particle size and human xenograft tumor model. ACS Nano. 2011;5(11):8710–20.CrossRefPubMedGoogle Scholar
  44. 44.
    Schadlich A, Rose C, Kuntsche J, Caysa H, Mueller T, Gopferich A, et al. How stealthy are PEG-PLA nanoparticles? An NIR in vivo study combined with detailed size measurements. Pharm Res. 2011;28(8):1995–2007.CrossRefPubMedGoogle Scholar
  45. 45.
    Shimoda A, Sawada S, Kano A, Maruyama A, Moquin A, Winnik FM, et al. Dual crosslinked hydrogel nanoparticles by nanogel bottom-up method for sustained-release delivery. Colloids Surf B Biointerfaces. 2012;99:38–44.CrossRefPubMedGoogle Scholar
  46. 46.
    Ma PL, Buschmann MD, Winnik FM. One-step analysis of DNA/chitosan complexes by field-flow fractionation reveals particle size and free chitosan content. Biomacromolecules. 2010;11(3):549–54.CrossRefPubMedGoogle Scholar
  47. 47.
    Augsten C, Mader K. Characterizing molar mass distributions and molecule structures of different chitosans using asymmetrical flow field-flow fractionation combined with multi-angle light scattering. Int J Pharm. 2008;351(1–2):23–30.CrossRefPubMedGoogle Scholar
  48. 48.
    Pease LF, Lipin DI, Tsai DH, Zachariah MR, Lua LHL, Tarlov MJ, et al. Quantitative characterization of virus-like particles by asymmetrical flow field flow fractionation, electrospray differential mobility analysis, and transmission electron microscopy. Biotechnol Bioeng. 2009;102(3):845–55.CrossRefPubMedGoogle Scholar
  49. 49.
    Chuan YP, Fan YY, Lua L, Middelberg APJ. Quantitative analysis of virus-like particle size and distribution by field-flow fractionation. Biotechnol Bioeng. 2008;99(6):1425–33.CrossRefPubMedGoogle Scholar
  50. 50.
    Zillies JC, Zwiorek K, Winter G, Coester C. Method for quantifying the PEGylation of gelatin nanoparticle drug carrier systems using asymmetrical flow field-flow fractionation and refractive index detection. Anal Chem. 2007;79(12):4574–80.CrossRefPubMedGoogle Scholar
  51. 51.
    Garcea RL, Gissmann L. Virus-like particles as vaccines and vessels for the delivery of small molecules. Curr Opin Biotechnol. 2004;15(6):513–7.CrossRefPubMedGoogle Scholar
  52. 52.
    Fraunhofer W, Winter G, Coester C. Asymmetrical flow field-flow fractionation and multiangle light scattering for analysis of gelatin nanoparticle drug carrier systems. Anal Chem. 2004;76(7):1909–20.CrossRefPubMedGoogle Scholar
  53. 53.
    Agostoni V, Horcajada P, Rodriguez-Ruiz V, Willaime H, Couvreur P. Serre C, et al. ‘Green’ fluorine-free mesoporous iron(III) trimesate nanoparticles for drug delivery. Green Mat. 2013;1(4):209–17.CrossRefGoogle Scholar
  54. 54.
    Marassi V, Roda B, Casolari S, Ortelli S, Blosi M, Zattoni A, et al. Hollow-fiber flow field-flow fractionation and multi-angle light scattering as a new analytical solution for quality control in pharmaceutical nanotechnology. Microchem J. 2018;136:149–56.Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Barbara Roda
    • 1
    • 2
    Email author
  • Valentina Marassi
    • 1
  • Andrea Zattoni
    • 1
    • 2
  • Francesco Borghi
    • 1
  • Resmi Anand
    • 3
  • Valentina Agostoni
    • 4
  • Ruxandra Gref
    • 4
  • Pierluigi Reschiglian
    • 1
    • 2
  • Sandra Monti
    • 3
  1. 1.Department of Chemistry “G.Ciamician”University of BolognaBolognaItaly
  2. 2.byFlow srlBolognaItaly
  3. 3.CNR-Istituto per la Sintesi Organica e la FotoreattivitàBolognaItaly
  4. 4.Institut des Sciences Moléculaires d’Orsay, UMR CNRS 8214, Paris-Sud University, Paris SaclayOrsayFrance

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