Preparation and characterization of nanostructured ferric hydroxyphosphate adjuvants

  • 1 University of Sofia “St. Kliment Ohridski”, Faculty of Chemistry and Pharmacy, Sofia, Bulgaria

Abstract

This article describes part of the results obtained during the development of a new generation of vaccine adjuvants based on nanostructured hydroxyphosphates of tunable composition and physicochemical characteristics. Colloidal gels of ferric hydroxyphosphates of various iron/phosphate ratios were prepared by precipitation techniques, sterilized by autoclaving and analyzed by transmission electron microscopy (TEM) and dark-field optical microscopy. The obtained materials were composed of a network of amorphous nanoparticles (<20 nm in size) that were aggregated into micron-sized structures in physiological saline. Preliminary adsorption experiments indicated the ability of the obtained materials to adsorb protein substances, which is an important prerequisite for their potential application as vaccine adjuvants and further optimization of the production process to achieve reproducibility of the physicochemical characteristics.

Keywords

References

  1. Lieu P, Heiskala M, Peterson P, Yang Y (2001) The roles of iron in health and disease. Mol Aspects Med 22:1–87.
  2. Antonova J (2007) Pharmacy in medieval Bulgaria. Pharmazie 62:467–469.
  3. Danielson B (2004) Structure, chemistry, and pharmacokinetics of intravenous iron agents. J Am Soc Nephrol 15:S93–S98.
  4. Kudasheva D, Lai J, Ulman A, Cowman M (2004) Structure of carbohydrate-bound polynuclear iron oxyhydroxide nanoparticles in parenteral formulations. J Inorg Biochem 98:1757–1769.
  5. Fütterera S, Andrusenko I, Kolb U, Hofmeister W, Langguth P (2013) Structural characterization of iron oxide/hydroxide nanoparticles in nine different parenteral drugs for the treatment of iron deficiency anaemia by electron diffraction (ED) and X ray powder diffraction (XRPD). J Pharm Biomed Analysis 86:151–160.
  6. Bernhardt D (1993) Solutions containing antigen and zinc hydroxide or iron hydroxide as an adjuvant and processes for preparing such solutions. US Patent No. 5,252,327. Washington DC: US Patent and Trademark Office.
  7. Eibl J, Leibl H, Mannhalter J (1999) Adjuvant based on colloidal iron compounds, US Patent No. 5,895,653. Washington DC: US Patent and Trademark Office.
  8. Sauzeat E (2004) Vaccine composition iron phosphate as vaccine adjuvant. US Patent No. 20,040,228,880. Washington DC: US Patent and Trademark Office.
  9. Leibl H, Tomasits R, Brühl P, Kerschbaum A, Eibl MM, Mannhalter JW (1999) Humoral and cellular immunity induced by antigens adjuvanted with colloidal iron hydroxide. Vaccine 17:1017–1023.
  10. Iyer S, HogenEsch H, Hem S (2003) Effect of the degree of phosphate substitution in aluminum hydroxide adjuvant on the adsorption of phosphorylated proteins. Pharm Dev Technol 8:81–86.
  11. Jiang D, Johnston C, Hem S (2003) Using rate of acid neutralization to characterize aluminum phosphate adjuvant. Pharm Dev Technol 8:349–356.
  12. Angelova, N., Yordanov, G. (2017). Iron(III) and aluminium(III) based mixed nanostructured hydroxyphosphates as potential vaccine adjuvants: preparation and physicochemical characterization. Colloids and Surfaces A, 535, 184–193.
  13. Hem S, White J (1995) Structure and properties of aluminumcontaining adjuvants. Pharm Biotechnol 6:249–276.
  14. Harris J, Soliakov A, Lewis R, Depoix F, Watkinson A, Lakey J (2012) Alhydrogel® adjuvant, ultrasonic dispersion and protein binding: a TEM and analytical study. Micron 43:192– 200.
  15. Gupta R (1998) Aluminum compounds as vaccine adjuvants. Adv Drug Deliv Rev 32:155–172.
  16. Huang M, Wang W (2014) Factors affecting alum–protein interactions. Int J Pharm 466:139–146.
  17. Mannhalter, J., Neychev, H., Zlabinger, G., Ahmad, R., Eibl, M. (1985). Modulation of the human immune response by the non-toxic and non-pyrogenic adjuvant aluminium hydroxide: Effect of antigen uptake and antigen presentation. Clin. Exp. Immunol., 61, 143–151.
  18. Li, H., Willingham, S., Ting, J., Re, F. (2008). Cutting Edge: Inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3. The Journal of Immunology, 181, 17–21.
  19. Morefield, G., Sokolovska, A., Jiang, D., HogenEsch, H., J. Robinson, Hem, S. (2005). Role of aluminum-containing adjuvants in antigen internalization by dendritic cells in vitro. Vaccine, 23, 1588–1595.
  20. Richter, G.W. (1959). The cellular transformation of injected colloidal iron complexes into ferritin and hemosiderin in experimental animals. A study with the aid of electron microscopy. J. Exp. Med., 109, 197–216.
  21. Wang, J., Pantopoulos, K. (2011). Regulation of cellular iron metabolism. Biochem. J., 434, 365–381.
  22. Petrovsky, N. (2015). Comparative safety of vaccine adjuvants: a summary of current evidence and future needs. Drug Saf., 38, 1059–1074.
  23. Batista-Duharte, A., Martínez, D., Carlos, I. (2018). Efficacy and safety of immunological adjuvants. Where is the cut-off?. Biomedicine & Pharmacotherapy, 105, 616–624.
  24. Massona, J.-D., Crépeaux, G., Authier, F.-J., Exley, C., Gherardi, R. (2018). Critical analysis of reference studies on the toxicokinetics of aluminum-based adjuvants. Journal of Inorganic Biochemistry, 181, 87–95.
  25. Mold, M., Shardlow, E., Exley, C. (2016). Insight into the cellular fate and toxicity of aluminium adjuvants used in clinically approved human vaccinations. Sci. Rep., 6, 31578.

Article full text

Download PDF