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The AAPS Journal

, Volume 15, Issue 1, pp 85–94 | Cite as

Biodegradable Particles as Vaccine Delivery Systems: Size Matters

  • Vijaya B. Joshi
  • Sean M. Geary
  • Aliasger K. Salem
Research Article

Abstract

Poly(lactide-co-glycolide) (PLGA) particles have strong potential as antigen delivery systems. The size of PLGA particles used to vaccinate mice can affect the magnitude of the antigen-specific immune response stimulated. In this study, we fabricated and characterized 17 μm, 7 μm, 1 μm, and 300 nm PLGA particles coloaded with a model antigen ovalbumin (OVA) and CpG oligodeoxynucleotides (CpG ODN). PLGA particles demonstrated a size-dependent burst release followed by a more sustained release of encapsulated molecules. PLGA particles that were 300 nm in size showed the highest internalization by, and maximum activation of, dendritic cells. The systemic antigen-specific immune response to vaccination was measured after administration of two intraperitoneal injections, 7 days apart, of 100 μg OVA and 50 μg CpG ODN in C57BL/6 mice. In vivo studies showed that 300 nm sized PLGA particles generated the highest antigen-specific cytotoxic T cell responses by days  14 and 21. These mice also showed the highest IgG2a:IgG1 ratio of OVA-specific antibodies on day  28. This study suggests that the smaller the PLGA particle used to deliver antigen and adjuvants the stronger the antigen-specific cytotoxic T cell response generated.

KEY WORDS

CpG ODN cytotoxic T lymphocytes dendritic cells nanoparticles poly (lactide-co-glycolide) vaccine 

Notes

ACKNOWLEDGMENTS

We gratefully acknowledge support from the American Cancer Society (RSG-09-015-01-CDD) and the National Cancer Institute at the National Institutes of Health (1R21CA128414-01A2/UI Mayo Clinic Lymphoma SPORE). We acknowledge Y. Krishnamachari, Senior Scientist, Merck, Inc. for contributing her expertise to the manuscript. We thank the staff of the Central Microscopy Research Facility, University of Iowa for their assistance with microscopy.

REFERENCES

  1. 1.
    Bremers AJA, Parmiani G. Immunology and immunotherapy of human cancer: present concepts and clinical developments. Crit Rev Oncol Hematol. 2000;34(1):1–25.PubMedCrossRefGoogle Scholar
  2. 2.
    Weiner GJ, Liu HM, Wooldridge JE, Dahle CE, Krieg AM. Immunostimulatory oligodeoxynucleotides containing the CpG motif are effective as immune adjuvants in tumor antigen immunization. Proc Natl Acad Sci U S A. 1997;94(20):10833–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Wooldridge JE, Ballas Z, Krieg AM, Weiner GJ. Immunostimulatory oligodeoxynucleotides containing CpG motifs enhance the efficacy of monoclonal antibody therapy of lymphoma. Blood. 1997;89(8):2994–8.PubMedGoogle Scholar
  4. 4.
    Kim JJ, Nottingham LK, Tsai A, Lee DJ, Maguire HC, Oh J, et al. Antigen-specific humoral and cellular immune responses can be modulated in rhesus macaques through the use of IFN-γ, IL-12, or IL-18 gene adjuvants. J Med Primatol. 1999;28(4–5):214–23.PubMedCrossRefGoogle Scholar
  5. 5.
    Gamvrellis A, Leong D, Hanley JC, Xiang SD, Mottram P, Plebanski M. Vaccines that facilitate antigen entry into dendritic cells. Immunol Cell Biol. 2004;82(5):506–16.PubMedCrossRefGoogle Scholar
  6. 6.
    Waeckerle-Men Y, Groettrup M. PLGA microspheres for improved antigen delivery to dendritic cells as cellular vaccines. Advanced Drug Delivery Reviews. 2005;57(3):475–82.PubMedCrossRefGoogle Scholar
  7. 7.
    Couvreur P, Vauthier C. Nanotechnology: intelligent design to treat complex disease. Pharm Res. 2006;23(7):1417–50.PubMedCrossRefGoogle Scholar
  8. 8.
    Elamanchili P, Lutsiak CM, Hamdy S, Diwan M, Samuel J. “Pathogen-mimicking” nanoparticles for vaccine delivery to dendritic cells. J Immunother. 2007;30(4):378–95.PubMedCrossRefGoogle Scholar
  9. 9.
    Elamanchili P, Diwan M, Cao M, Samuel J. Characterization of poly(d, l-lactic-co-glycolic acid) based nanoparticulate system for enhanced delivery of antigens to dendritic cells. Vaccine. 2004;22(19):2406–12.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang XQ, Dahle CE, Baman NK, Rich N, Weiner GJ, Salem AK. Potent antigen-specific immune responses stimulated by codelivery of CpG ODN and antigens in degradable microparticles. J Immunother. 2007;30(5):469–78.PubMedCrossRefGoogle Scholar
  11. 11.
    Shen H, Ackerman AL, Cody V, Giodini A, Hinson ER, Cresswell P, et al. Enhanced and prolonged cross-presentation following endosomal escape of exogenous antigens encapsulated in biodegradable nanoparticles. Immunology. 2006;117(1):78–88.PubMedCrossRefGoogle Scholar
  12. 12.
    Krishnamachari Y, Salem AK. Innovative strategies for co-delivering antigens and CpG oligonucleotides. Adv Drug Deliv Rev. 2009;61(3):205–17.PubMedCrossRefGoogle Scholar
  13. 13.
    Ludwig C, Wagner R. Virus-like particles—universal molecular toolboxes. Curr Opin Biotechnol. 2007;18(6):537–45.PubMedCrossRefGoogle Scholar
  14. 14.
    Coester C, Nayyar P, Samuel J. In vitro uptake of gelatin nanoparticles by murine dendritic cells and their intracellular localisation. Eur J Pharm Biopharm. 2006;62(3):306–14.PubMedCrossRefGoogle Scholar
  15. 15.
    Chikh G, Schutze-Redelmeier MP. Liposomal delivery of CTL epitopes to dendritic cells. Biosci Rep. 2002;22(2):339–53.PubMedCrossRefGoogle Scholar
  16. 16.
    Torres MP, Wilson-Welder JH, Lopac SK, Phanse Y, Carrillo-Conde B, Ramer-Tait AE, et al. Polyanhydride microparticles enhance dendritic cell antigen presentation and activation. Acta Biomater. 2011;7(7):2857–64.PubMedCrossRefGoogle Scholar
  17. 17.
    Wise DL. Encyclopedic handbook of biomaterials and bioengineering. New York: Marcel Dekker; 1995.Google Scholar
  18. 18.
    Singh M, Briones M, Ott G, O’Hagan D. Cationic microparticles: a potent delivery system for DNA vaccines. Proc Natl Acad Sci U S A. 2000;97(2):811–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Conway MA, Madrigal-Estebas L, McClean S, Brayden DJ, Mills KH. Protection against Bordetella pertussis infection following parenteral or oral immunization with antigens entrapped in biodegradable particles: effect of formulation and route of immunization on induction of Th1 and Th2 cells. Vaccine. 2001;19(15–16):1940–50.PubMedCrossRefGoogle Scholar
  20. 20.
    Moghimi SM, Porter CJ, Muir IS, Illum L, Davis SS. Non-phagocytic uptake of intravenously injected microspheres in rat spleen: influence of particle size and hydrophilic coating. Biochem Biophys Res Commun. 1991;177(2):861–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Audran R, Peter K, Dannull J, Men Y, Scandella E, Groettrup M, et al. Encapsulation of peptides in biodegradable microspheres prolongs their MHC class-I presentation by dendritic cells and macrophages in vitro. Vaccine. 2003;21(11–12):1250–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Men Y, Thomasin C, Merkle HP, Gander B, Corradin G. A single administration of tetanus toxoid in biodegradable microspheres elicits T cell and antibody responses similar or superior to those obtained with aluminum hydroxide. Vaccine. 1995;13(7):683–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Peter K, Men Y, Pantaleo G, Gander B, Corradin G. Induction of a cytotoxic T-cell response to HIV-1 proteins with short synthetic peptides and human compatible adjuvants. Vaccine. 2001;19(30):4121–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Panda AK, Kanchan V. Interactions of antigen-loaded polylactide particles with macrophages and their correlation with the immune response. Biomaterials. 2007;28(35):5344–57.PubMedCrossRefGoogle Scholar
  25. 25.
    Lavasanifar A, Hamdy S, Molavi O, Ma ZS, Haddadi A, Alshamsan A, et al. Co-delivery of cancer-associated antigen and Toll-like receptor 4 ligand in PLGA nanoparticles induces potent CD8(+) T cell-mediated anti-tumor immunity. Vaccine. 2008;26(39):5046–57.PubMedCrossRefGoogle Scholar
  26. 26.
    Plebanski M, Gamvrellis A, Leong D, Hanley JC, Xiang SD, Mottram P. Vaccines that facilitate antigen entry into dendritic cells. Immunol Cell Biol. 2004;82(5):506–16.PubMedCrossRefGoogle Scholar
  27. 27.
    Katsikogianni G, Avgoustakis K. Poly(lactide-co-glycolide)-methoxy-poly(ethylene glycol) nanoparticles: drug loading and release properties. J Nanosci Nanotechnol. 2006;6(9–10):3080–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Tamber H, Johansen P, Merkle HP, Gander B. Formulation aspects of biodegradable polymeric microspheres for antigen delivery. Adv Drug Deliv Rev. 2005;57(3):357–76.PubMedCrossRefGoogle Scholar
  29. 29.
    Weeratna RD, McCluskie MJ, Xu Y, Davis HL. CpG DNA induces stronger immune responses with less toxicity than other adjuvants. Vaccine. 2000;18(17):1755–62.PubMedCrossRefGoogle Scholar
  30. 30.
    Yasuda K, Richez C, Uccellini MB, Richards RJ, Bonegio RG, Akira S, et al. Requirement for DNA CpG content in TLR9-dependent dendritic cell activation induced by DNA-containing immune complexes. J Immunol. 2009;183(5):3109–17.PubMedCrossRefGoogle Scholar
  31. 31.
    Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, et al. Cpg motifs in bacterial-DNA trigger direct B-cell activation. Nature. 1995;374(6522):546–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Lutz MB, Kukutsch N, Ogilvie ALJ, Rößner S, Koch F, Romani N, et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods. 1999;223(1):77–92.PubMedCrossRefGoogle Scholar
  33. 33.
    Karan D, Krieg AM, Lubaroff DM. Paradoxical enhancement of CD8 T cell-dependent anti-tumor protection despite reduced CD8 T cell responses with addition of a TLR9 agonist to a tumor vaccine. Int J Cancer. 2007;121(7):1520–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Lee SW, Sung YC. Immuno-stimulatory effects of bacterial-derived plasmids depend on the nature of the antigen in intramuscular DNA inoculations. Immunology. 1998;94(3):285–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Prabha S, Zhou WZ, Panyam J, Labhasetwar V. Size-dependency of nanoparticle-mediated gene transfection: studies with fractionated nanoparticles. Int J Pharm. 2002;244(1–2):105–15.PubMedCrossRefGoogle Scholar
  36. 36.
    Zauner W, Farrow NA, Haines AMR. In vitro uptake of polystyrene microspheres: effect of particle size, cell line and cell density. J Control Release. 2001;71(1):39–51.PubMedCrossRefGoogle Scholar
  37. 37.
    Gil-Torregrosa BC, Lennon-Dumenil AM, Kessler B, Guermonprez P, Ploegh HL, Fruci D, et al. Control of cross-presentation during dendritic cell maturation. Eur J Immunol. 2004;34(2):398–407.PubMedCrossRefGoogle Scholar
  38. 38.
    Schuler G, Schuler-Thurner B, Steinman RM. The use of dendritic cells in cancer immunotherapy. Curr Opin Immunol. 2003;15(2):138–47.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2012

Authors and Affiliations

  • Vijaya B. Joshi
    • 1
  • Sean M. Geary
    • 1
  • Aliasger K. Salem
    • 1
  1. 1.Department of Pharmaceutical Sciences and Experimental Therapeutics, College of PharmacyUniversity of IowaIowa CityUSA

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