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Safety and Biocompatibility of Carbohydrate-Functionalized Polyanhydride Nanoparticles

  • Research Article
  • Theme: Nanoparticles in Vaccine Delivery
  • Published:
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ABSTRACT

Carbohydrate functionalization of nanoparticles allows for targeting of C-type lectin receptors. This family of pattern recognition receptors expressed on innate immune cells, such as macrophages and dendritic cells, can be used to modulate immune responses. In this work, the in vivo safety profile of carbohydrate-functionalized polyanhydride nanoparticles was analyzed following parenteral and intranasal administration in mice. Polyanhydride nanoparticles based on 1,6-bis-(p-carboxyphenoxy)hexane and 1,8-bis-(p-carboxyphenoxy)-3,6-dioxaoctane were used. Nanoparticle functionalization with di-mannose (specifically carboxymethyl-α-d-mannopyranosyl-(1,2)-d-mannopyranoside), galactose (specifically carboxymethyl-β-galactoside), or glycolic acid induced no adverse effects after administration based on histopathological evaluation of liver, kidneys, and lungs. Regardless of the polymer formulation, there was no evidence of hepatic or renal damage or dysfunction observed in serum or urine samples. The histological profile of cellular infiltration and the cellular distribution and kinetics in the lungs of mice administered with nanoparticle treatments followed similar behavior as that observed in the lungs of animals administered with saline. Cytokine and chemokine profiles in bronchoalveolar lavage fluid indicated surface chemistry dependence on modest secretion of IL-6, IP-10, and MCP-1; however, there was no evidence of any deleterious histopathological changes. Based on these analyses, carbohydrate-functionalized nanoparticles are safe for in vivo applications. These results provide foundational information towards the evaluation of the capabilities of these surface-modified nanoparticles as vaccine delivery formulations.

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REFERENCES

  1. Engering A, Geijtenbeek TB, van Vliet SJ, Wijers M, van Liempt E, Demaurex N, et al. The dendritic cell-specific adhesion receptor DC-SIGN internalizes antigen for presentation to T cells. J Immunol. 2002;168(5):2118–26.

    Article  CAS  PubMed  Google Scholar 

  2. Azarmi S, Roa WH, Lobenberg R. Targeted delivery of nanoparticles for the treatment of lung diseases. Adv Drug Deliv Rev. 2008;60(8):863–75.

    Article  CAS  PubMed  Google Scholar 

  3. Geijtenbeek TB, Gringhuis SI. Signalling through C-type lectin receptors: shaping immune responses. Nat Rev Immunol. 2009;9(7):465–79.

    Article  CAS  PubMed  Google Scholar 

  4. Irache JM, Salman HH, Gamazo C, Espuelas S. Mannose-targeted systems for the delivery of therapeutics. Expert Opin Drug Deliv. 2008;5(6):703–24.

    Article  CAS  PubMed  Google Scholar 

  5. Ulery BD, Nair LS, Laurencin CT. Biomedical applications of biodegradable polymers. J Polym Sci B Polym Phys. 2011;49(12):832–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Carrillo-Conde B, Song EH, Chavez-Santoscoy A, Phanse Y, Ramer-Tait AE, Pohl NL, et al. Mannose-functionalized “pathogen-like” polyanhydride nanoparticles target C-type lectin receptors on dendritic cells. Mol Pharm. 2011;8(5):1877–86.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Petersen LK, Xue L, Wannemuehler MJ, Rajan K, Narasimhan B. The simultaneous effect of polymer chemistry and device geometry on the in vitro activation of murine dendritic cells. Biomaterials. 2009;30(28):5131–42.

    Article  CAS  PubMed  Google Scholar 

  9. Ross KA, Haughney SL, Petersen LK, Boggiatto P, Wannemuehler MJ, Narasimhan B. Lung deposition and cellular uptake behavior of pathogen-mimicking nanovaccines in the first 48 hours. Adv Healthc Mater. 2014;3(7):1071–7.

  10. Carrillo-Conde BR, Ramer-Tait AE, Wannemuehler MJ, Narasimhan B. Chemistry-dependent adsorption of serum proteins onto polyanhydride microparticles differentially influences dendritic cell uptake and activation. Acta Biomater. 2012;8(10):3618–28.

    Article  CAS  PubMed  Google Scholar 

  11. Semete B, Booysen L, Lemmer Y, Kalombo L, Katata L, Verschoor J, et al. In vivo evaluation of the biodistribution and safety of PLGA nanoparticles as drug delivery systems. Nanomedicine. 2010;6(5):662–71.

    Article  CAS  PubMed  Google Scholar 

  12. Mansour HM, Rhee YS, Wu X. Nanomedicine in pulmonary delivery. Int J Nanomedicine. 2009;4:299–319.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Nguyen J, Steele TW, Merkel O, Reul R, Kissel T. Fast degrading polyesters as siRNA nano-carriers for pulmonary gene therapy. J Control Release. 2008;132(3):243–51.

    Article  CAS  PubMed  Google Scholar 

  14. Torres MP, Determan AS, Anderson GL, Mallapragada SK, Narasimhan B. Amphiphilic polyanhydrides for protein stabilization and release. Biomaterials. 2007;28(1):108–16.

    Article  CAS  PubMed  Google Scholar 

  15. Torres MP, Vogel BM, Narasimhan B, Mallapragada SK. Synthesis and characterization of novel polyanhydrides with tailored erosion mechanisms. J Biomed Mater Res A. 2006;76(1):102–10.

    Article  PubMed  Google Scholar 

  16. Carrillo-Conde B, Schiltz E, Yu J, Chris Minion F, Phillips GJ, Wannemuehler MJ, et al. Encapsulation into amphiphilic polyanhydride microparticles stabilizes Yersinia pestis antigens. Acta Biomater. 2010;6(8):3110–9.

    Article  CAS  PubMed  Google Scholar 

  17. Chavez-Santoscoy AV, Roychoudhury R, Pohl NL, Wannemuehler MJ, Narasimhan B, Ramer-Tait AE. Tailoring the immune response by targeting C-type lectin receptors on alveolar macrophages using “pathogen-like” amphiphilic polyanhydride nanoparticles. Biomaterials. 2012;33(18):4762–72.

    Article  CAS  PubMed  Google Scholar 

  18. Vela Ramirez JE, Roychoudhury R, Habte HH, Cho MW, Pohl NL, Narasimhan B. Carbohydrate-functionalized nanovaccines preserve HIV-1 antigen stability and activate antigen presenting cells. J Biomater Sci Polym Ed. 2014;25(13):1387–406.

    Article  CAS  PubMed  Google Scholar 

  19. Huntimer LM, Ross KA, Darling RJ, Winterwood NE, Boggiatto P, Narasimhan B, et al. Polyanhydride nanovaccine platform enhances antigen-specific cytotoxic T cell responses. Technology. 2014;02(02):171–5.

    Article  Google Scholar 

  20. Ulery BD, Kumar D, Ramer-Tait AE, Metzger DW, Wannemuehler MJ, Narasimhan B. Design of a protective single-dose intranasal nanoparticle-based vaccine platform for respiratory infectious diseases. PLoS One. 2011;6(3):e17642.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Patton JS, Byron PR. Inhaling medicines: delivering drugs to the body through the lungs. Nat Rev Drug Discov. 2007;6(1):67–74.

    Article  CAS  PubMed  Google Scholar 

  22. Sung JC, Pulliam BL, Edwards DA. Nanoparticles for drug delivery to the lungs. Trends Biotechnol. 2007;25(12):563–70.

    Article  CAS  PubMed  Google Scholar 

  23. Bailey MM, Berkland CJ. Nanoparticle formulations in pulmonary drug delivery. Med Res Rev. 2009;29(1):196–212.

    Article  CAS  PubMed  Google Scholar 

  24. Phanse Y, Carrillo-Conde BR, Ramer-Tait AE, Roychoudhury R, Pohl NL, Narasimhan B, et al. Functionalization of polyanhydride microparticles with di-mannose influences uptake by and intracellular fate within dendritic cells. Acta Biomater. 2013;9(11):8902–9.

    Article  CAS  PubMed  Google Scholar 

  25. Napoletano C, Zizzari IG, Rughetti A, Rahimi H, Irimura T, Clausen H, et al. Targeting of macrophage galactose-type C-type lectin (MGL) induces DC signaling and activation. Eur J Immunol. 2012;42(4):936–45.

    Article  CAS  PubMed  Google Scholar 

  26. Cambi A, Figdor CG. Dual function of C-type lectin-like receptors in the immune system. Curr Opin Cell Biol. 2003;15(5):539–46.

    Article  CAS  PubMed  Google Scholar 

  27. Conix A. Poly[1,3-bis(p-carxoyphenoxy)-propane anhydride]. Macro Synth. 1966;2:95–8.

    CAS  Google Scholar 

  28. Ulery BD, Phanse Y, Sinha A, Wannemuehler MJ, Narasimhan B, Bellaire BH. Polymer chemistry influences monocytic uptake of polyanhydride nanospheres. Pharm Res. 2009;26(3):683–90.

    Article  CAS  PubMed  Google Scholar 

  29. Curran DP, Luo Z. Fluorous synthesis with fewer fluorines (light fluorous synthesis): separation of tagged from untagged products by solid-phase extraction with fluorous reverse-phase silica gel. J Am Chem Soc. 1999;121(39):9069–72.

    Article  CAS  Google Scholar 

  30. Zhang W, Curran DP. Synthetic applications of fluorous solid-phase extraction (F-SPE). Tetrahedron. 2006;62(51):11837–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Zhang W. Fluorous linker-facilitated chemical synthesis. Chem Rev. 2009;109(2):749–95.

    Article  CAS  PubMed  Google Scholar 

  32. Masuko T, Minami A, Iwasaki N, Majima T, Nishimura S, Lee YC. Carbohydrate analysis by a phenol-sulfuric acid method in microplate format. Anal Biochem. 2005;339(1):69–72.

    Article  CAS  PubMed  Google Scholar 

  33. Huntimer L, Ramer-Tait AE, Petersen LK, Ross KA, Walz KA, Wang C, et al. Evaluation of biocompatibility and administration site reactogenicity of polyanhydride-particle-based platform for vaccine delivery. Adv Healthc Mater. 2013;2(2):369–78.

    Article  CAS  PubMed  Google Scholar 

  34. Mazzaccara C, Labruna G, Cito G, Scarfo M, De Felice M, Pastore L, et al. Age-related reference intervals of the main biochemical and hematological parameters in C57BL/6J, 129SV/EV and C3H/HeJ mouse strains. PLoS One. 2008;3(11):e3772.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Cheetham SA, Smith AL, Armstrong SD, Beynon RJ, Hurst JL. Limited variation in the major urinary proteins of laboratory mice. Physiol Behav. 2009;96(2):253–61.

    Article  CAS  PubMed  Google Scholar 

  36. Kirby AC, Raynes JG, Kaye PM. CD11b regulates recruitment of alveolar macrophages but not pulmonary dendritic cells after pneumococcal challenge. J Infect Dis. 2006;193(2):205–13.

    Article  CAS  PubMed  Google Scholar 

  37. Kirby AC, Coles MC, Kaye PM. Alveolar macrophages transport pathogens to lung draining lymph nodes. J Immunol. 2009;183(3):1983–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Kipper MJ, Shen E, Determan A, Narasimhan B. Design of an injectable system based on bioerodible polyanhydride microspheres for sustained drug delivery. Biomaterials. 2002;23(22):4405–12.

    Article  CAS  PubMed  Google Scholar 

  39. Lopac SK, Torres MP, Wilson-Welder JH, Wannemuehler MJ, Narasimhan B. Effect of polymer chemistry and fabrication method on protein release and stability from polyanhydride microspheres. J Biomed Mater Res B Appl Biomater. 2009;91(2):938–47.

    Article  PubMed Central  PubMed  Google Scholar 

  40. Petersen LK, Ramer-Tait AE, Broderick SR, Kong CS, Ulery BD, Rajan K, et al. Activation of innate immune responses in a pathogen-mimicking manner by amphiphilic polyanhydride nanoparticle adjuvants. Biomaterials. 2011;32(28):6815–22.

    Article  CAS  PubMed  Google Scholar 

  41. O’Bryan T, Weiher H, Rennke HG, Kren S, Hostetter TH. Course of renal injury in the Mpv17-deficient transgenic mouse. J Am Soc Nephrol. 2000;11(6):1067–74.

    PubMed  Google Scholar 

  42. Dunn SR, Qi Z, Bottinger EP, Breyer MD, Sharma K. Utility of endogenous creatinine clearance as a measure of renal function in mice. Kidney Int. 2004;65(5):1959–67.

    Article  CAS  PubMed  Google Scholar 

  43. Eaton KA, Friedman DI, Francis GJ, Tyler JS, Young VB, Haeger J, et al. Pathogenesis of renal disease due to enterohemorrhagic Escherichia coli in germ-free mice. Infect Immun. 2008;76(7):3054–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Lee PY, Wang JX, Parisini E, Dascher CC, Nigrovic PA. Ly6 family proteins in neutrophil biology. J Leukoc Biol. 2013;94(4):585–94.

    Article  CAS  PubMed  Google Scholar 

  45. Lai L, Alaverdi N, Maltais L, Morse 3rd HC. Mouse cell surface antigens: nomenclature and immunophenotyping. J Immunol. 1998;160(8):3861–8.

    CAS  PubMed  Google Scholar 

  46. Vermaelen K, Pauwels R. Pulmonary dendritic cells. Am J Respir Crit Care Med. 2005;172(5):530–51.

    Article  PubMed  Google Scholar 

  47. Lohmann-Matthes ML, Steinmuller C, Franke-Ullmann G. Pulmonary macrophages. Eur Respir J. 1994;7(9):1678–89.

    CAS  PubMed  Google Scholar 

  48. Petersen LK, Phanse Y, Ramer-Tait AE, Wannemuehler MJ, Narasimhan B. Amphiphilic polyanhydride nanoparticles stabilize Bacillus anthracis protective antigen. Mol Pharm. 2012;9(4):874–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Haughney SL, Petersen LK, Schoofs AD, Ramer-Tait AE, King JD, Briles DE, et al. Retention of structure, antigenicity, and biological function of pneumococcal surface protein A (PspA) released from polyanhydride nanoparticles. Acta Biomater. 2013;9(9):8262–71.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Harush-Frenkel O, Bivas-Benita M, Nassar T, Springer C, Sherman Y, Avital A, et al. A safety and tolerability study of differently-charged nanoparticles for local pulmonary drug delivery. Toxicol Appl Pharmacol. 2010;246(1–2):83–90.

    Article  CAS  PubMed  Google Scholar 

  51. Nguyen J, Reul R, Betz T, Dayyoub E, Schmehl T, Gessler T, et al. Nanocomposites of lung surfactant and biodegradable cationic nanoparticles improve transfection efficiency to lung cells. J Control Release. 2009;140(1):47–54.

    Article  CAS  PubMed  Google Scholar 

  52. Alarifi S, Ali D, Al-Doaiss AA, Ali BA, Ahmed M, Al-Khedhairy AA. Histologic and apoptotic changes induced by titanium dioxide nanoparticles in the livers of rats. Int J Nanomedicine. 2013;8:3937–43.

    PubMed Central  PubMed  Google Scholar 

  53. Yamagishi Y, Watari A, Hayata Y, Li X, Kondoh M, Yoshioka Y, et al. Acute and chronic nephrotoxicity of platinum nanoparticles in mice. Nanoscale Res Lett. 2013;8(1):395.

    Article  PubMed Central  PubMed  Google Scholar 

  54. Kelley VE, Winkelstein A. Age- and sex-related glomerulonephritis in New Zealand white mice. Clin Immunol Immunopathol. 1980;16(2):142–50.

    Article  CAS  PubMed  Google Scholar 

  55. Yang Y, Pan D, Luo K, Li L, Gu Z. Biodegradable and amphiphilic block copolymer-doxorubicin conjugate as polymeric nanoscale drug delivery vehicle for breast cancer therapy. Biomaterials. 2013;34(33):8430–43.

    Article  CAS  PubMed  Google Scholar 

  56. Italia JL, Bhatt DK, Bhardwaj V, Tikoo K, Kumar MN. PLGA nanoparticles for oral delivery of cyclosporine: nephrotoxicity and pharmacokinetic studies in comparison to Sandimmune Neoral. J Control Release. 2007;119(2):197–206.

    Article  CAS  PubMed  Google Scholar 

  57. Zhang XD, Wu D, Shen X, Liu PX, Fan FY, Fan SJ. In vivo renal clearance, biodistribution, toxicity of gold nanoclusters. Biomaterials. 2012;33(18):4628–38.

    Article  CAS  PubMed  Google Scholar 

  58. Goldstein SL. Urinary kidney injury biomarkers and urine creatinine normalization: a false premise or not? Kidney Int. 2010;78(5):433–5.

    Article  CAS  PubMed  Google Scholar 

  59. Peralta CA, Shlipak MG, Judd S, Cushman M, McClellan W, Zakai NA, et al. Detection of chronic kidney disease with creatinine, cystatin C, and urine albumin-to-creatinine ratio and association with progression to end-stage renal disease and mortality. JAMA. 2011;305(15):1545–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Waikar SS, Sabbisetti VS, Bonventre JV. Normalization of urinary biomarkers to creatinine during changes in glomerular filtration rate. Kidney Int. 2010;78(5):486–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Nemmar A, Hoylaerts MF, Hoet PH, Vermylen J, Nemery B. Size effect of intratracheally instilled particles on pulmonary inflammation and vascular thrombosis. Toxicol Appl Pharmacol. 2003;186(1):38–45.

    Article  CAS  PubMed  Google Scholar 

  62. Heyder J, Gebhart J, Rudolf G, Schiller CF, Stahlhofen W. Deposition of particles in the human respiratory tract in the size range 0.005–15 μm. J Aerosol Sci. 1986;17(5):811–25.

    Article  Google Scholar 

  63. Hofmann W. Modelling inhaled particle deposition in the human lung—a review. J Aerosol Sci. 2011;42(10):693–724.

    Article  CAS  Google Scholar 

  64. Choi HS, Ashitate Y, Lee JH, Kim SH, Matsui A, Insin N, et al. Rapid translocation of nanoparticles from the lung airspaces to the body. Nat Biotechnol. 2010;28(12):1300–3.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Ulery BD, Petersen LK, Phanse Y, Kong CS, Broderick SR, Kumar D, et al. Rational design of pathogen-mimicking amphiphilic materials as nanoadjuvants. Sci Rep. 2011;1:198.

    Article  PubMed Central  PubMed  Google Scholar 

  66. Dailey LA, Jekel N, Fink L, Gessler T, Schmehl T, Wittmar M, et al. Investigation of the proinflammatory potential of biodegradable nanoparticle drug delivery systems in the lung. Toxicol Appl Pharmacol. 2006;215(1):100–8.

    Article  CAS  PubMed  Google Scholar 

  67. Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest. 1998;101(2):311–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Coelho AL, Hogaboam CM, Kunkel SL. Chemokines provide the sustained inflammatory bridge between innate and acquired immunity. Cytokine Growth Factor Rev. 2005;16(6):553–60.

    Article  CAS  PubMed  Google Scholar 

  69. Frevert CW, Huang S, Danaee H, Paulauskis JD, Kobzik L. Functional characterization of the rat chemokine KC and its importance in neutrophil recruitment in a rat model of pulmonary inflammation. J Immunol. 1995;154(1):335–44.

    CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS

The authors would like to acknowledge the financial support from NIH-NIAID (U19 AI-091031) and U.S. Army Medical Research and Materiel Command (grant no. W81XWH-10-1-0806). The authors would also like to thank Shawn Rigby of the ISU Flow Cytometry Facility for his expertise in flow cytometry.

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Authors and Affiliations

  1. Department of Chemical and Biological Engineering, Iowa State University, 2035 Sweeney Hall, Ames, Iowa, 50011, USA

    Julia E. Vela-Ramirez, Jonathan T. Goodman & Balaji Narasimhan

  2. Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, Iowa, 50011, USA

    Paola M. Boggiatto & Michael J. Wannemuehler

  3. Department of Chemistry, Indiana University, Bloomington, Indiana, 47405, USA

    Rajarshi Roychoudhury & Nicola L. B. Pohl

  4. Department of Veterinary Pathology, Iowa State University, Ames, Iowa, 50011, USA

    Jesse M. Hostetter

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  1. Julia E. Vela-Ramirez
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  2. Jonathan T. Goodman
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  7. Michael J. Wannemuehler
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Correspondence to Balaji Narasimhan.

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Vela-Ramirez, J.E., Goodman, J.T., Boggiatto, P.M. et al. Safety and Biocompatibility of Carbohydrate-Functionalized Polyanhydride Nanoparticles. AAPS J 17, 256–267 (2015). https://doi.org/10.1208/s12248-014-9699-z

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  • DOI: https://doi.org/10.1208/s12248-014-9699-z

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