Evaluating the Interactions Between Proteins and Components of the Immune System with Polymer Nanoparticles

  • Silvia Lorenzo-Abalde
  • Rosana Simón-Vázquez
  • Mercedes Peleteiro Olmedo
  • Tamara Lozano-Fernández
  • Olivia Estévez-Martínez
  • Andrea Fernández-Carrera
  • África González-FernándezEmail author


The use of polymer nanoparticles in biomedicine has increased in recent years because of their potential to improve a wide range of biomedical applications, particularly as drug-delivery systems. However, the use of these nanoparticles in biomedicine has been accompanied by significant concern regarding their biocompatibility. The success of the use of nanoparticles in biomedical applications will depend to some extent on their interactions with cells and other components of the immune system. The main focus of this chapter is the way in which the interactions between complement factors, antibodies and cells with nanoparticles can be studied. The main guidelines, protocols, and key issues to be considered in these assays will be discussed. Moreover, the potential immunogenicity induced by nanoparticles will be addressed. Immunostimulation can be beneficial for vaccine purposes as nanoparticles could activate the complement system, improve the antigenicity of weak antigens by serving as adjuvants, enhance antigen uptake, and stimulate antigen-presenting cells. In contrast, unwanted immune activation can lead to undesirable reactions in the host’s body, such as inflammation, allergic, or pseudoallergic reactions and autoimmune disorders.


Toxicity Immunogenicity Biocompatibility Immune response Complement Endocytic routes Nanotoxicology Nanomedicine Nanovaccines 



This work was financially supported by Xunta de Galicia (INBIOMED 2012/273, DXPCTSUG-FEDER and GPC, Potentially growing groups), Ministerio de Educación y Ciencia (Nanovac project SAF2011-30337-C02-02) and the BIOCAPS project (316265, FP7/REGPOT-2012-2013.1). We thank Isabel Pastoriza and Luis Liz for providing gold NPs, and Maria José Alonso for the protamine nanocapsules. The confocal and SEM-FIB images were taken in the University facilities of the Centre for Scientific and Technical Support (CACTI).

Conflict of interest

The authors declare no conflict of interest.


  1. Abu Lila AS, Kiwada H, Ishida T (2013) The accelerated blood clearance (ABC) phenomenon: clinical challenge and approaches to manage. J Control Release 172(1):38–47Google Scholar
  2. Aggarwal P, Hall JB, McLeland CB, Dobrovolskaia Ma, McNeil SE (2009) Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy. Adv Drug Deliver Rev 61(6):428–437Google Scholar
  3. Ahamed M, Akhtar MJ, Siddiqui MA, Ahmad J, Musarrat J, Al-Khedhairy AA et al (2011) Oxidative stress mediated apoptosis induced by nickel ferrite nanoparticles in cultured A549 cells. Toxicology 283(2–3):101–108PubMedCrossRefGoogle Scholar
  4. Aida Y, Pabst MJ (1990) Removal of endotoxin from protein solutions by phase separation using triton X-114. J Immunol Methods 132(2):191–195PubMedCrossRefGoogle Scholar
  5. Alexander C, Rietschel ET (2001) Bacterial lipopolysaccharides and innate immunity. J Endotoxin Res 7(3):167–202PubMedGoogle Scholar
  6. Alexis F, Pridgen E, Molnar LK, Farokhzad OC (2008) Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharmaceut 5(4):505–515CrossRefGoogle Scholar
  7. Almeida JP, Chen AL, Foster A, Drezek R (2011) In vivo biodistribution of nanoparticles. Nanomedicine 6(5):815–835PubMedCrossRefGoogle Scholar
  8. Alving CR, Swartz GM Jr, Wassef NM, Ribas JL, Herderick EE, Virmani R et al (1996) Immunization with cholesterol-rich liposomes induces anti-cholesterol antibodies and reduces diet-induced hypercholesterolemia and plaque formation. J Lab Clin Med 127(1):40–49PubMedCrossRefGoogle Scholar
  9. Aoyama Y, Kanamori T, Nakai T, Sasaki T, Horiuchi S, Sando S et al (2003) Artificial viruses and their application to gene delivery. Size-controlled gene coating with glycocluster nanoparticles. J Am Chem Soc 125(12):3455–3457PubMedCrossRefGoogle Scholar
  10. Areschoug T, Gordon S (2009) Scavenger receptors: role in innate immunity and microbial pathogenesis. Cell Microbiol 11(8):1160–1169PubMedCrossRefGoogle Scholar
  11. AshaRani PV, Low Kah Mun G, Hande MP, Valiyaveettil S (2008) Cytotoxicity and genotoxicity of silver nanoparticles in human cells. ACS Nano 3(2):279–290CrossRefGoogle Scholar
  12. Asharani PV, Sethu S, Vadukumpully S, Zhong S, Lim CT, Hande MP et al (2010) Investigations on the structural damage in human erythrocytes exposed to silver, gold, and platinum nanoparticles. Adv Funct Mater 20(8):1233–1242CrossRefGoogle Scholar
  13. Ballestrero A, Boy D, Moran E, Cirmena G, Brossart P, Nencioni A (2008) Immunotherapy with dendritic cells for cancer. Adv Drug Deliver Rev 60(2):173–183CrossRefGoogle Scholar
  14. Banerji B, Alving CR (1981) Anti-liposome antibodies induced by lipid A. I. Influence of ceramide, glycosphingolipids, and phosphocholine on complement damage. J Immunol 126(3):1080–1084PubMedGoogle Scholar
  15. Banerji B, Alving CR (1990) Antibodies to liposomal phosphatidylserine and phosphatidic acid. Biochem Cell Biol 68(1):96–101PubMedCrossRefGoogle Scholar
  16. Banerjee T, Mitra S, Kumar Singh A, Kumar Sharma R, Maitra A (2002) Preparation, characterization and biodistribution of ultrafine chitosan nanoparticles. Int J Pharm 243(1–2):93–105PubMedCrossRefGoogle Scholar
  17. Barauskas J, Cervin C, Jankunec M, Spandyreva M, Ribokaite K, Tiberg F et al (2010) Interactions of lipid-based liquid crystalline nanoparticles with model and cell membranes. Int J Pharm 391(1–2):284–291Google Scholar
  18. Barshtein G, Arbell D, Yedgar S (2011) Hemolytic effect of polymeric nanoparticles: role of albumin. IEEE Trans Nanobiosci 10(4):259–261CrossRefGoogle Scholar
  19. Bertram JP, Williams CA, Robinson R, Segal SS, Flynn NT, Lavik EB (2009) Intravenous hemostat: nanotechnology to halt bleeding. Sci Transl Med 1(11):11–22CrossRefGoogle Scholar
  20. Betts MR, Brenchley JM, Price DA, De Rosa SC, Douek DC, Roederer M et al (2003) Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J Immunol Methods 281(1–2):65–78PubMedCrossRefGoogle Scholar
  21. Beutler B (2004) Innate immunity: an overview. Mol Immunol 40(12):845–859PubMedCrossRefGoogle Scholar
  22. Binding N, Jaschinski S, Werlich S, Bletz S, Witting U (2004) Quantification of bacterial lipopolysaccharides (endotoxin) by GC-MS determination of 3-hydroxy fatty acids. J Environ Monit 6(1):65–70PubMedCrossRefGoogle Scholar
  23. Boess C, Bögl KW (1996) Influence of radiation treatment on pharmaceuticals—a review: alkaloids, morphine derivatives, and antibiotics. Drug Dev Ind Pharm 22(6):495–529CrossRefGoogle Scholar
  24. Bok K, Parra GI, Mitra T, Abente E, Shaver CK, Boon D et al (2011) Chimpanzees as an animal model for human norovirus infection and vaccine development. Proc Natl Acad Sci USA 108(1):325–330PubMedCrossRefGoogle Scholar
  25. Bousso P (2008) T-cell activation by dendritic cells in the lymph node: lessons from the movies. Nat Rev Immunol 8(9):675–684PubMedCrossRefGoogle Scholar
  26. Brady TC, Chang L-Y, Day BJ, Crapo JD (1997) Extracellular superoxide dismutase is upregulated with inducible nitric oxide synthase after NF-κB activation. Am J Physiol 273(5):L1002–L1006PubMedGoogle Scholar
  27. Brakha C, Arvers P, Villiers F, Marlu A, Buhot A, Livache T et al (2014) Relationship between humoral response against hepatitis C virus and disease overcome. SpringerPlus 3:56PubMedPubMedCentralCrossRefGoogle Scholar
  28. Bridget Wildt RAM, Brown RP (2013) The effects of engineered nanomaterials on erythrocytes. In: Marina A, Dobrovolskaia SEM (eds) Handbook of immunological properties of engineered nanomaterials. World Scientific, Singapore, pp 173–195Google Scholar
  29. Brown KJ, Formolo CA, Seol H, Marathi RL, Duguez S, An E et al (2012) Advances in the proteomic investigation of the cell secretome. Expert Rev Proteomics 9(3):337–345CrossRefGoogle Scholar
  30. Bryan NS, Grisham MB (2007) Methods to detect nitric oxide and its metabolites in biological samples. Free Radic Biol Med 43(5):645–657PubMedPubMedCentralCrossRefGoogle Scholar
  31. Burleson G, Burleson F, Dietert R (2010) The cytotoxic T lymphocyte assay for evaluating cell-mediated immune function. In: Dietert RR (ed) Immunotoxicity testing. Humana Press, New York, pp 195–205Google Scholar
  32. Canoa P, Simón-Vázquez R, Popplewell J, González-Fernández Á (2015) A quantitative binding study of fibrinogen and human serum albumin to metal oxide nanoparticles by Surface Plasmon Resonance. Biosens Bioelectron 74:376–383 Google Scholar
  33. Caron WP, Rawal S, Song G, Kumar P, Lay JC, Zamboni WC (2013) Bidirectional interaction between nanoparticles and cells of the mononuclear phagocytic system. Handbook of immunological properties of engineered nanomaterials. World Scientific, Singapore, pp 385–416Google Scholar
  34. Cavalli R, Caputo O, Carlotti ME, Trotta M, Scarnecchia C, Gasco MR (1997) Sterilization and freeze-drying of drug-free and drug-loaded solid lipid nanoparticles. Int J Pharm 148(1):47–54CrossRefGoogle Scholar
  35. Cedervall T, Lynch I, Lindman S, Berggard T, Thulin E, Nilsson H et al (2007) Understanding the nanoparticle-protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles. Proc Natl Acad Sci USA 104(7):2050–2055PubMedPubMedCentralCrossRefGoogle Scholar
  36. Chambers E, Mitragotri S (2007) Long circulating nanoparticles via adhesion on red blood cells: mechanism and extended circulation. Exp Biol Med 232(7):958–966Google Scholar
  37. Champion JA, Mitragotri S (2006) Role of target geometry in phagocytosis. Proc Natl Acad Sci USA 103(13):4930–4934PubMedPubMedCentralCrossRefGoogle Scholar
  38. Champion J, Mitragotri S (2009) Shape induced inhibition of phagocytosis of polymer particles. Pharm Res 26(1):244–249PubMedCrossRefGoogle Scholar
  39. Champion JA, Katare YK, Mitragotri S (2007) Particle shape: a new design parameter for micro- and nanoscale drug delivery carriers. J Control Release 121(1–2):3–9PubMedPubMedCentralCrossRefGoogle Scholar
  40. Chen C, Cheng YC, Yu CH, Chan SW, Cheung MK, Yu PHF (2008) In vitro cytotoxicity, hemolysis assay, and biodegradation behavior of biodegradable poly(3-hydroxybutyrate)–poly(ethylene glycol)–poly(3-hydroxybutyrate) nanoparticles as potential drug carriers. J Biomed Mater Res A 87A(2):290–298CrossRefGoogle Scholar
  41. Cho W-S, Thielbeer F, Duffin R, Johansson EMV, Megson IL, MacNee W et al (2014) Surface functionalization affects the zeta potential, coronal stability and membranolytic activity of polymeric nanoparticles. Nanotoxicology 8(2):202–211PubMedCrossRefGoogle Scholar
  42. Choi J, Reipa V, Hitchins VM, Goering PL, Malinauskas RA (2011) Physicochemical characterization and in vitro hemolysis evaluation of silver nanoparticles. Toxicol Sci 123(1):133–143PubMedCrossRefGoogle Scholar
  43. Chompoosor A, Saha K, Ghosh PS, Macarthy DJ, Miranda OR, Zhu Z-J et al (2010) The role of surface functionality on acute cytotoxicity, ROS generation and DNA damage by cationic gold nanoparticles. Small 6(20):2246–2249PubMedPubMedCentralCrossRefGoogle Scholar
  44. Chonn A, Cullis PR, Devine DV (1991) The role of surface charge in the activation of the classical and alternative pathways of complement by liposomes. J Immunol 146(12):4234–4241PubMedGoogle Scholar
  45. Chrastina A, Massey KA, Schnitzer JE (2011) Overcoming in vivo barriers to targeted nanodelivery. Wiley Interdisciplinary Rev Nanomed Nanobiotechnol 3(4):421–437CrossRefGoogle Scholar
  46. Chung S, Sudo R, Vickerman V, Zervantonakis I, Kamm R (2010) Microfluidic platforms for studies of angiogenesis, cell migration, and cell–cell interactions. Ann Biomed Eng 38(3):1164–1177PubMedCrossRefGoogle Scholar
  47. Çimen MYB (2008) Free radical metabolism in human erythrocytes. Clin Chim Acta 390(1–2):1–11PubMedCrossRefGoogle Scholar
  48. Climent N, Munier S, Piqué N, García F, Pavot V, Primard C et al (2014) Loading dendritic cells with PLA-p24 nanoparticles or MVA expressing HIV genes induces HIV-1-specific T cell responses. Vaccine 32(47):6266–6276PubMedCrossRefGoogle Scholar
  49. Cohavi O, Reichmann D, Abramovich R, Tesler AB, Bellapadrona G, Kokh DB et al (2011) A quantitative, real-time assessment of binding of peptides and proteins to gold surfaces. Chemistry 17(4):1327–1336PubMedCrossRefGoogle Scholar
  50. Colon J, Hsieh N, Ferguson A, Kupelian P, Seal S, Jenkins DW et al (2010) Cerium oxide nanoparticles protect gastrointestinal epithelium from radiation-induced damage by reduction of reactive oxygen species and upregulation of superoxide dismutase 2. Nanomedicine 6(5):698–705PubMedGoogle Scholar
  51. Constant SL, Bottomly K (1997) Induction of Th1 and Th2 CD4 + T cell responses: the alternative approaches. Annu Rev Immunol 15(1):297–322PubMedCrossRefGoogle Scholar
  52. Constantinescu I, Levin E, Gyongyossy-Issa M (2003) Liposomes and blood cells: a flow cytometric study. Artif Cells Blood Substit Biotechnol 31(4):395–424CrossRefGoogle Scholar
  53. Cui Z, Baizer L, Mumper RJ (2003) Intradermal immunization with novel plasmid DNA-coated nanoparticles via a needle-free injection device. J Biotechnol 102(2):105–115PubMedCrossRefGoogle Scholar
  54. Czerkinsky CC, Nilsson L-Å, Nygren H, Ouchterlony Ö, Tarkowski A (1983) A solid-phase enzyme-linked immunospot (ELISPOT) assay for enumeration of specific antibody-secreting cells. J Immunol Methods 65(1–2):109–121PubMedCrossRefGoogle Scholar
  55. Danhier F, Ansorena E, Silva JM, Coco R, Le Breton A, Préat V (2012) PLGA-based nanoparticles: an overview of biomedical applications. J Control Release 161(2):505–522PubMedCrossRefGoogle Scholar
  56. Daniel M, Kirchhoff F, Czajak S, Sehgal P, Desrosiers R (1992) Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science 258(5090):1938–1941PubMedCrossRefGoogle Scholar
  57. Das AP, Kumar PS, Swain S (2014) Recent advances in biosensor based endotoxin detection. Biosens Bioelectron 51:62–75PubMedCrossRefGoogle Scholar
  58. De Temmerman ML, Rejman J, Demeester J, Irvine DJ, Gander B, De Smedt SC (2011) Particulate vaccines: on the quest for optimal delivery and immune response. Drug Discov Today 16(13–14):569–582PubMedCrossRefGoogle Scholar
  59. Decuzzi P, Godin B, Tanaka T, Lee SY, Chiappini C, Liu X et al (2010) Size and shape effects in the biodistribution of intravascularly injected particles. J Control Release 141(3):320–327PubMedCrossRefGoogle Scholar
  60. Demento SL, Cui W, Criscione JM, Stern E, Tulipan J, Kaech SM et al (2012) Role of sustained antigen release from nanoparticle vaccines in shaping the T cell memory phenotype. Biomaterials 33(19):4957–4964PubMedCrossRefGoogle Scholar
  61. Deng ZJ, Liang M, Monteiro M, Toth I, Minchin RF (2011) Nanoparticle-induced unfolding of fibrinogen promotes Mac-1 receptor activation and inflammation. Nat Nanotechnol 6(1):39–44PubMedCrossRefGoogle Scholar
  62. Díaz B, Sánchez-Espinel C, Arruebo M, Faro J, de Miguel E, Magadán S et al (2008) Assessing methods for blood cell cytotoxic responses to inorganic nanoparticles and nanoparticle aggregates. Small 4(11):2025–2034PubMedCrossRefGoogle Scholar
  63. Ding JL, Ho B (2010) Endotoxin detection—from Limulus amebocyte lysate to recombinant Factor C. In: Wang X, Quinn PJ (eds) Endotoxins: structure, function and recognition. Springer Netherlands, Amsterdam, pp 187–208Google Scholar
  64. Dobrovolskaia MA (2013) Nanoparticles and antigenicity. In: Dobrovolskaia MA, McNeil SE (eds) Handbook of immunological properties of engineered nanomaterials. World Scientific, Singapore, pp 547–573Google Scholar
  65. Dobrovolskaia MA, McNeil SE (2007) Immunological properties of engineered nanomaterials. Nat Nanotechnol 2(8):469–478PubMedCrossRefGoogle Scholar
  66. Dobrovolskaia MA, McNeil SE (2013a) In vitro assays for monitoring nanoparticle interaction with components of the immune system. In: Dobrovolskaia MA, McNeil SE (eds) Handbook of immunological properties of engineered nanomaterials. World Scientific, Singapore, pp 581–634Google Scholar
  67. Dobrovolskaia MA, McNeil SE (2013b) Understanding the correlation between in vitro and in vivo immunotoxicity tests for nanomedicines. J Control Release 172(2):456–466PubMedCrossRefGoogle Scholar
  68. Dobrovolskaia MA, McNeil SE (2013c) Endotoxin and engineered nanomaterials. In: Dobrovolskaia MA, McNeil SE (eds) Handbook of immunological properties of engineered nanomaterials. World Scientific, Singapore, pp 77–116Google Scholar
  69. Dobrovolskaia MA, Vogel SN (2002) Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect 4(9):903–914PubMedCrossRefGoogle Scholar
  70. Dobrovolskaia MA, Aggarwal P, Hall JB, McNeil SE (2008a) Preclinical studies to understand nanoparticle interaction with the immune system and its potential effects on nanoparticle biodistribution. Mol Pharm 5(4):487–495CrossRefGoogle Scholar
  71. Dobrovolskaia MA, Clogston JD, Neun BW, Hall JB, Patri AK, McNeil SE (2008b) Method for analysis of nanoparticle hemolytic properties in vitro. Nano Lett 8(8):2180–2187PubMedPubMedCentralCrossRefGoogle Scholar
  72. Dobrovolskaia MA, Germolec DR, Weaver JL (2009) Evaluation of nanoparticle immunotoxicity. Nat Nanotechnol 4(7):411–414PubMedCrossRefGoogle Scholar
  73. Dobrovolskaia MA, Neun BW, Clogston JD, Ding H, Ljubimova J, McNeil SE (2010) Ambiguities in applying traditional Limulus Amebocyte Lysate tests to quantify endotoxin in nanoparticle formulations. Nanomedicine 5(4):555–562PubMedPubMedCentralCrossRefGoogle Scholar
  74. Dobrovolskaia MA, Patri AK, Simak J, Hall JB, Semberova J, De Paoli Lacerda SH et al (2011) Nanoparticle size and surface charge determine effects of PAMAM dendrimers on human platelets in vitro. Mol Pharmaceut 9(3):382–393CrossRefGoogle Scholar
  75. Dobrovolskaia MA, Patri AK, Potter TM, Rodriguez JC, Hall JB, McNeil SE (2012) Dendrimer-induced leukocyte procoagulant activity depends on particle size and surface charge. Nanomedicine 7(2):245–256PubMedCrossRefGoogle Scholar
  76. Doherty GJ, McMahon HT (2009) Mechanisms of endocytosis. Annu Rev Biochem 78(1):857–902PubMedCrossRefGoogle Scholar
  77. Dominska M, Dykxhoorn DM (2010) Breaking down the barriers: siRNA delivery and endosome escape. J Cell Sci 123(8):1183–1189PubMedCrossRefGoogle Scholar
  78. Du Y, Li X-J, Tan D-J (2011) Comparison of temperature rise interpretations in the rabbit pyrogen test among Chinese, Japanese, European, and United States pharmacopeias and 2-2-2 theoretical models proposed by S. Hoffmann. Innate Immun 17(5):486–495PubMedCrossRefGoogle Scholar
  79. Duan X, Li Y (2013) Physicochemical characteristics of nanoparticles affect circulation, biodistribution, cellular internalization, and trafficking. Small 9(9–10):1521–1532PubMedCrossRefGoogle Scholar
  80. Dube A, Reynolds JL, Law W-C, Maponga CC, Prasad PN, Morse GD (2014) Multimodal nanoparticles that provide immunomodulation and intracellular drug delivery for infectious diseases. Nanomedicine 10(4):831–838PubMedGoogle Scholar
  81. Duffin R, Mills NL, Donaldson K (2007) Nanoparticles-A thoracic toxicology perspective. Yonsei Med J 48(4):561–572PubMedPubMedCentralCrossRefGoogle Scholar
  82. Fadok VA, Bratton DL, Henson PM (2001) Phagocyte receptors for apoptotic cells: recognition, uptake, and consequences. J Clin Invest 108(7):957–962PubMedPubMedCentralCrossRefGoogle Scholar
  83. Fairley SJ, Singh SR, Yilma AN, Waffo AB, Subbarayan P, Dixit S et al (2013) Chlamydia trachomatis recombinant MOMP encapsulated in PLGA nanoparticles triggers primarily T helper 1 cellular and antibody immune responses in mice: a desirable candidate nanovaccine. Int J Nanomed 8:2085–2099PubMedPubMedCentralGoogle Scholar
  84. Fesenkova V (2013) The effects of nanoparticles on dendritic cells. In: Handbook of immunological properties of engineered nanomaterials. World Scientific, Singapore, pp 417–432Google Scholar
  85. Fifis T, Mottram P, Bogdanoska V, Hanley J, Plebanski M (2004a) Short peptide sequences containing MHC class I and/or class II epitopes linked to nano-beads induce strong immunity and inhibition of growth of antigen-specific tumour challenge in mice. Vaccine 23(2):258–266PubMedCrossRefGoogle Scholar
  86. Fifis T, Gamvrellis A, Crimeen-Irwin B, Pietersz GA, Li J, Mottram PL et al (2004b) Size-dependent immunogenicity: therapeutic and protective properties of nano-vaccines against tumors. J Immunol 173(5):3148–3154PubMedCrossRefGoogle Scholar
  87. Foged C, Brodin B, Frokjaer S, Sundblad A (2005) Particle size and surface charge affect particle uptake by human dendritic cells in an in vitro model. Int J Pharm 298(2):315–322PubMedCrossRefGoogle Scholar
  88. Fogler WE, Swartz GM Jr, Alving CR (1987) Antibodies to phospholipids and liposomes: binding of antibodies to cells. Biochim Biophys Acta (BBA) Biomembranes 903(2):265–272CrossRefGoogle Scholar
  89. Foucaud L, Wilson MR, Brown DM, Stone V (2007) Measurement of reactive species production by nanoparticles prepared in biologically relevant media. Toxicol Lett 174(1–3):1–9PubMedCrossRefGoogle Scholar
  90. França A, Pelaz B, Moros M, Sanchez-Espinel C, Hernandez A, Fernandez-Lopez C et al (2010) Sterilization matters: consequences of different sterilization techniques on gold nanoparticles. Small 6(1):89–95PubMedCrossRefGoogle Scholar
  91. França A, Aggarwal P, Barsov EV, Kozlov SV, Dobrovolskaia MA, González-Fernández Á (2011) Macrophage scavenger receptor A mediates the uptake of gold colloids by macrophages in vitro. Nanomedicine 6(7):1175–1188PubMedPubMedCentralCrossRefGoogle Scholar
  92. Friedl P, Sahai E, Weiss S, Yamada KM (2012) New dimensions in cell migration. Nat Rev Mol Cell Biol 13(11):743–747PubMedCrossRefGoogle Scholar
  93. Fruchon S, Poupot M, Martinet L, Turrin C-O, Majoral J-P, Fournié J-J et al (2009) Anti-inflammatory and immunosuppressive activation of human monocytes by a bioactive dendrimer. J Leukoc Biol 85(3):553–562PubMedCrossRefGoogle Scholar
  94. Gamucci O, Bertero A, Gagliardi M, Bardi G (2014) Biomedical nanoparticles: overview of their surface immune-compatibility. Coatings 4(1):139–159CrossRefGoogle Scholar
  95. Gardel ML, Schneider IC, Aratyn-Schaus Y, Waterman CM (2010) Mechanical integration of actin and adhesion dynamics in cell migration. Annu Rev Cell Dev Biol 26(1):315–333PubMedPubMedCentralCrossRefGoogle Scholar
  96. Goncalves DM, de Liz R, Girard D (2011) Activation of neutrophils by nanoparticles. Sci World J 11:1877–1885CrossRefGoogle Scholar
  97. González JRR, Larrea CL, Rodríguez SG, Naves EM (2006) Inmunología: Biología y patología del sistema inmune, 3rd ed. In: González JRR (ed) Editorial Panamericana, MadridGoogle Scholar
  98. Gopal NGS (1978) Radiation sterilization of pharmaceuticals and polymers. Radiat Phys Chem 12(1–2):35–50CrossRefGoogle Scholar
  99. Gorbet MB, Sefton MV (2004) Biomaterial-associated thrombosis: roles of coagulation factors, complement, platelets and leukocytes. Biomaterials 25(26):5681–5703PubMedCrossRefGoogle Scholar
  100. Gore ER, Gower J, Kurali E, Sui J-L, Bynum J, Ennulat D et al (2004) Primary antibody response to keyhole limpet hemocyanin in rat as a model for immunotoxicity evaluation. Toxicology 197(1):23–35PubMedCrossRefGoogle Scholar
  101. Groscurth P (1989) Cytotoxic effector cells of the immune system. Anat Embryol 180(2):109–119PubMedCrossRefGoogle Scholar
  102. Hajipour MJ, Fromm KM, Akbar Ashkarran A, Jimenez de Aberasturi D, Larramendi IRd, Rojo T et al (2012) Antibacterial properties of nanoparticles. Trends Biotechnol 30(10):499–511Google Scholar
  103. Hall JB, Dobrovolskaia MA, Patri AK, McNeil SE (2007) Characterization of nanoparticles for therapeutics. Nanomedicine 2(6):789–803PubMedCrossRefGoogle Scholar
  104. Halminen M, Sjöroos M, Mäkelä MJ, Waris M, Terho E, Lövgren T et al (1999) Simultaneous detection of IFN-γ and IL-4 mRNAS using RT-PCR and Time-Resolved Fluometry. Cytokine 11(1):87–93PubMedCrossRefGoogle Scholar
  105. Han HD, Mangala LS, Lee JW, Shahzad MMK, Kim HS, Shen D et al (2010) Targeted gene silencing using RGD-labeled chitosan nanoparticles. Clin Cancer Res 16(15):3910–3922PubMedPubMedCentralCrossRefGoogle Scholar
  106. Hancock J, Desikan R, Neill S (2001) Role of reactive oxygen species in cell signalling pathways. Biochem Soc Trans 29(2):345–349PubMedCrossRefGoogle Scholar
  107. Harboe M, Thorgersen EB, Mollnes TE (2011) Advances in assay of complement function and activation. Adv Drug Deliver Rev 63(12):976–987CrossRefGoogle Scholar
  108. Harding CV, Collins DS, Slot JW, Geuze HJ, Unanue ER (1991) Liposome-encapsulated antigens are processed in lysosomes, recycled, and presented to T cells. Cell 64(2):393–401PubMedCrossRefGoogle Scholar
  109. Harush-Frenkel O, Debotton N, Benita S, Altschuler Y (2007) Targeting of nanoparticles to the clathrin-mediated endocytic pathway. Biochem Biophys Res Commun 353(1):26–32PubMedCrossRefGoogle Scholar
  110. He C, Hu Y, Yin L, Tang C, Yin C (2010) Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials 31(13):3657–3666PubMedCrossRefGoogle Scholar
  111. Heiati H, Tawashi R, Phillips NC (1998) Drug retention and stability of solid lipid nanoparticles containing azidothymidine palmitate after autoclaving, storage and lyophilization. J Microencapsul 15(2):173–184PubMedCrossRefGoogle Scholar
  112. Herzyk DJ, Gore ER (2004) Adequate immunotoxicity testing in drug development. Toxicol Lett 149(1–3):115–122PubMedCrossRefGoogle Scholar
  113. Heusel JW, Wesselschmidt RL, Shresta S, Russell JH, Ley TJ (1994) Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells. Cell 76(6):977–987PubMedCrossRefGoogle Scholar
  114. Hirst SM, Karakoti AS, Tyler RD, Sriranganathan N, Seal S, Reilly CM (2009) Anti-inflammatory properties of cerium oxide nanoparticles. Small 5(24):2848–2856PubMedCrossRefGoogle Scholar
  115. Hoebe K, Janssen E, Beutler B (2004) The interface between innate and adaptive immunity. Nat Immunol 5(10):971–974PubMedCrossRefGoogle Scholar
  116. Hoffmann S, Luderitz-Puchel U, Montag T, Hartung T (2005a) Optimisation of pyrogen testing in parenterals according to different pharmacopoeias by probabilistic modelling. J Endotoxin Res 11(1):25–31PubMedCrossRefGoogle Scholar
  117. Hoffmann S, Peterbauer A, Schindler S, Fennrich S, Poole S, Mistry Y et al (2005b) International validation of novel pyrogen tests based on human monocytoid cells. J Immunol Methods 298(1–2):161–173PubMedCrossRefGoogle Scholar
  118. Hsu CL, Chang HT, Chen CT, Wei SC, Shiang YC, Huang CC (2011) Highly efficient control of thrombin activity by multivalent nanoparticles. Chemistry 17(39):10994–11000PubMedCrossRefGoogle Scholar
  119. Hubbell JA, Thomas SN, Swartz MA (2009) Materials engineering for immunomodulation. Nature 462(7272):449–460PubMedCrossRefGoogle Scholar
  120. Hudson SP, Padera RF, Langer R, Kohane DS (2008) The biocompatibility of mesoporous silicates. Biomaterials 29(30):4045–4055PubMedPubMedCentralCrossRefGoogle Scholar
  121. Humphries GK, McConnell HM (1974) Immune lysis of liposomes and erythrocyte ghosts loaded with spin label. Proc Natl Acad Sci USA 71(5):1691–1694PubMedPubMedCentralCrossRefGoogle Scholar
  122. Huttenlocher A, Horwitz AR (2011) Integrins in cell migration. Cold Spring Harb Perspect Biol 3(9):a005074PubMedPubMedCentralCrossRefGoogle Scholar
  123. ICH (2006) Topic S8 immunotoxicity studies for human pharmaceuticals note for guidance on immunotoxicity studies for human pharmaceuticals (CHMP/167235/2004). http://www.ichorg/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S8/Step4/S8_Guideline.pdf
  124. Idris NM, Li Z, Ye L, Wei Sim EK, Mahendran R, Ho PC-L et al (2009) Tracking transplanted cells in live animal using upconversion fluorescent nanoparticles. Biomaterials 30(28):5104–5113PubMedCrossRefGoogle Scholar
  125. Ilinskaya AN, Dobrovolskaia MA (2013) Nanoparticles and the blood coagulation system. Part I: benefits of nanotechnology. Nanomedicine 8(5):773–784PubMedCrossRefGoogle Scholar
  126. Inoue K (2011) Promoting effects of nanoparticles/materials on sensitive lung inflammatory diseases. Environ Health Prev Med 16(3):139–143PubMedCrossRefGoogle Scholar
  127. Ishida T, Kiwada H (2008) Accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes. Int J Pharm 354(1–2):56–62PubMedCrossRefGoogle Scholar
  128. Jain K, Kesharwani P, Gupta U, Jain NK (2010) Dendrimer toxicity: let’s meet the challenge. Int J Pharm 394(1–2):122–142PubMedCrossRefGoogle Scholar
  129. Janero DR (1990) Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med 9(6):515–540PubMedCrossRefGoogle Scholar
  130. Janeway CA, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20(1):197–216PubMedCrossRefGoogle Scholar
  131. Jenske R, Vetter W (2008) Gas chromatography/electron-capture negative ion mass spectrometry for the quantitative determination of 2- and 3-hydroxy fatty acids in bovine milk fat. J Agric Food Chem 56(14):5500–5505PubMedCrossRefGoogle Scholar
  132. Jerome KR, Sloan DD, Aubert M (2003) Measurement of CTL-induced cytotoxicity: the caspase 3 assay. Apoptosis 8(6):563–571PubMedCrossRefGoogle Scholar
  133. Jones CF, Grainger DW (2009) In vitro assessments of nanomaterial toxicity. Adv Drug Deliver Rev 61(6):438–456CrossRefGoogle Scholar
  134. Joos T, Bachmann J (2009) Protein microarrays: potentials and limitations. Front Biosci 14:4376–4385CrossRefGoogle Scholar
  135. Jorquera PA, Choi Y, Oakley KE, Powell TJ, Boyd JG, Palath N et al (2013) Nanoparticle vaccines encompassing the respiratory syncytial virus (RSV) G protein CX3C chemokine motif Induce robust immunity protecting from challenge and disease. PLoS ONE 8(9):e74905PubMedPubMedCentralCrossRefGoogle Scholar
  136. Kainthan RK, Gnanamani M, Ganguli M, Ghosh T, Brooks DE, Maiti S et al (2006) Blood compatibility of novel water soluble hyperbranched polyglycerol-based multivalent cationic polymers and their interaction with DNA. Biomaterials 27(31):5377–5390PubMedCrossRefGoogle Scholar
  137. Kasturi SP, Skountzou I, Albrecht RA, Koutsonanos D, Hua T, Nakaya HI et al (2011) Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470(7335):543–547PubMedPubMedCentralCrossRefGoogle Scholar
  138. Katial RK, Sachanandani D, Pinney C, Lieberman MM (1998) Cytokine production in cell culture by peripheral blood mononuclear cells from immunocompetent hosts. Clin Diagn Lab Immunol 5(1):78–81PubMedPubMedCentralGoogle Scholar
  139. Keston AS, Brandt R (1965) The fluorometric analysis of ultramicro quantities of hydrogen peroxide. Anal Biochem 11(1):1–5PubMedCrossRefGoogle Scholar
  140. Kiang T, Bright C, Cheung CY, Stayton PS, Hoffman AS, Leong KW (2014) Formulation of chitosan-DNA nanoparticles with poly(propyl acrylic acid) enhances gene expression. J Biomater Sci Polym Ed 15(11):1405–1421CrossRefGoogle Scholar
  141. Kim MJ, Shin S (2014) Toxic effects of silver nanoparticles and nanowires on erythrocyte rheology. Food Chem Toxicol 67:80–86PubMedCrossRefGoogle Scholar
  142. Kim D, El-Shall H, Dennis D, Morey T (2005) Interaction of PLGA nanoparticles with human blood constituents. Colloids Surf B Biointerfaces 40(2):83–91CrossRefGoogle Scholar
  143. Kim E, Okada K, Beeler JA, Crim RL, Piedra PA, Gilbert BE et al (2014a) Development of an adenovirus-based respiratory syncytial virus vaccine: preclinical evaluation of efficacy, immunogenicity, and enhanced disease in a cotton rat model. J Virol 88(9):5100–5108PubMedPubMedCentralCrossRefGoogle Scholar
  144. Kim D, Finkenstaedt-Quinn S, Hurley KR, Buchman JT, Haynes CL (2014b) On-chip evaluation of platelet adhesion and aggregation upon exposure to mesoporous silica nanoparticles. Analyst 139(5):906–913PubMedCrossRefGoogle Scholar
  145. Kirschfink M, Mollnes TE (2003) Modern complement analysis. Clin Diagn Lab Immunol 10(6):982–989PubMedPubMedCentralGoogle Scholar
  146. Klippstein R, Pozo D (2010) Nanotechnology-based manipulation of dendritic cells for enhanced immunotherapy strategies. Nanomedicine 6(4):523–529PubMedGoogle Scholar
  147. Knaapen AM, Schins RPF, Steinfartz Y, Borm PJA (2000) Ambient particulate matter induces oxidative DNA damage in lung epithelial cells. Inhal Toxicol 12(s3):125–132PubMedCrossRefGoogle Scholar
  148. Knight J (2001) When the chips are down. Nature 410(6831):860–861PubMedCrossRefGoogle Scholar
  149. Koh WCA, Chandra P, Kim D-M, Shim Y-B (2011) Electropolymerized self-assembled layer on gold nanoparticles: Detection of inducible nitric oxide synthase in neuronal cell culture. Anal Chem 83(16):6177–6183PubMedCrossRefGoogle Scholar
  150. Kosloski MP, Peng A, Varma PR, Fathallah AM, Miclea RD, Mager DE et al (2010) Immunogenicity and pharmacokinetic studies of recombinant Factor VIII containing lipid cochleates. Drug Deliv 18(4):246–254PubMedPubMedCentralCrossRefGoogle Scholar
  151. Kroll A, Pillukat MH, Hahn D, Schnekenburger J (2009) Current in vitro methods in nanoparticle risk assessment: limitations and challenges. Eur J Pharm Biopharm 72(2):370–377PubMedCrossRefGoogle Scholar
  152. Kuznetsov AV, Kehrer I, Kozlov A, Haller M, Redl H, Hermann M et al (2011) Mitochondrial ROS production under cellular stress: comparison of different detection methods. Anal Bioanal Chem 400(8):2383–2390PubMedCrossRefGoogle Scholar
  153. Lachmann PJ, Munn EA, Weissmann G (1970) Complement-mediated lysis of liposomes produced by the `reactive lysis’ procedure. Immunology 19(6):983–986PubMedPubMedCentralGoogle Scholar
  154. Ladics GS (2007) Primary immune response to sheep red blood cells (SRBC) as the conventional T-Cell dependent antibody response (TDAR) test. J Immunotoxicol 4(2):149–152PubMedCrossRefGoogle Scholar
  155. Lai ZW, Yan Y, Caruso F, Nice EC (2012) Emerging techniques in proteomics for probing nano–bio interactions. ACS Nano 6(12):10438–10448PubMedCrossRefGoogle Scholar
  156. Landsiedel R, Fabian E, Ma-Hock L, van Ravenzwaay B, Wohlleben W, Wiench K et al (2012) Toxico-/biokinetics of nanomaterials. Arch Toxicol 86(7):1021–1060PubMedCrossRefGoogle Scholar
  157. Lanier LL, Phillips JH (1992) Natural killer cells. Curr Opin Immunol 4(1):38–42PubMedCrossRefGoogle Scholar
  158. Laverman P, Carstens MG, Boerman OC, Dams ETM, Oyen WJ, van Rooijen N et al (2001) Factors affecting the accelerated blood clearance of polyethylene glycol-liposomes upon repeated injection. J Pharmacol Exp Ther 298(2):607–612PubMedGoogle Scholar
  159. Lebrec H, Molinier B, Boverhof D, Collinge M, Freebern W, Henson K et al (2014) The T-cell-dependent antibody response assay in nonclinical studies of pharmaceuticals and chemicals: study design, data analysis, interpretation. Regul Toxicol Pharmacol 69(1):7–21PubMedCrossRefGoogle Scholar
  160. Lee SC, Parthasarathy R, Duf TD, Botwin K, Zobel J, Beck T et al (2001) Recognition properties of antibodies to PAMAM dendrimers and their use in immune detection of dendrimers. Biomed Microdevices 3(1):53–59CrossRefGoogle Scholar
  161. Lee SC, Parthasarathy R, Botwin K, Kunneman D, Rowold E, Lange G et al (2004a) Regular Papers: biochemical and immunological properties of cytokines conjugated to dendritic polymers. Biomed Microdevices 6(3):191–202PubMedCrossRefGoogle Scholar
  162. Lee D, Powers K, Baney R (2004b) Physicochemical properties and blood compatibility of acylated chitosan nanoparticles. Carbohydr Polym 58(4):371–377CrossRefGoogle Scholar
  163. Lee S-H, Pumprueg S, Moudgil B, Sigmund W (2005) Inactivation of bacterial endospores by photocatalytic nanocomposites. Colloids Surf B Biointerfaces 40(2):93–98CrossRefGoogle Scholar
  164. Lee K, Lee H, Lee KW, Park TG (2011) Optical imaging of intracellular reactive oxygen species for the assessment of the cytotoxicity of nanoparticles. Biomaterials 32(10):2556–2565PubMedCrossRefGoogle Scholar
  165. Lee J, Lee SY, Won DI, Cha SI, Park JY, Kim CH (2013) Comparison of whole-blood interferon-γ assay and flow cytometry for the detection of tuberculosis infection. J Infect 66(4):338–345PubMedCrossRefGoogle Scholar
  166. Lee-MacAry AE, Ross EL, Davies D, Laylor R, Honeychurch J, Glennie MJ et al (2001) Development of a novel flow cytometric cell-mediated cytotoxicity assay using the fluorophores PKH-26 and TO-PRO-3 iodide. J Immunol Methods 252(1–2):83–92PubMedCrossRefGoogle Scholar
  167. Li J, Purves RW, Richards JC (2004) Coupling capillary electrophoresis and high-field asymmetric waveform ion mobility spectrometry mass spectrometry for the analysis of complex lipopolysaccharides. Anal Chem 76(16):4676–4683PubMedCrossRefGoogle Scholar
  168. Li J, Cox AD, Hood DW, Schweda EKH, Moxon ER, Richards JC (2005) Electrophoretic and mass spectrometric strategies for profiling bacterial lipopolysaccharides. Mol BioSyst 1(1):46–52PubMedCrossRefGoogle Scholar
  169. Li S-Q, Zhu R-R, Zhu H, Xue M, Sun X-Y, Yao S-D et al (2008) Nanotoxicity of TiO2 nanoparticles to erythrocyte in vitro. Food Chem Toxicol 46(12):3626–3631PubMedCrossRefGoogle Scholar
  170. Li X, Radomski A, Corrigan OI, Tajber L, De Sousa Menezes F, Endter S et al (2009) Platelet compatibility of PLGA, chitosan and PLGA–chitosan nanoparticles. Nanomedicine 4(7):735–746PubMedCrossRefGoogle Scholar
  171. Liebers V, Raulf-Heimsoth M, Brüning T (2008) Health effects due to endotoxin inhalation. Arch Toxicol 82(4):203–210PubMedCrossRefGoogle Scholar
  172. Lonez C, Bessodes M, Scherman D, Vandenbranden M, Escriou V, Ruysschaert J-M (2014) Cationic lipid nanocarriers activate Toll-like receptor 2 and NLRP3 inflammasome pathways. Nanomedicine 10(4):775–782PubMedGoogle Scholar
  173. Look M, Saltzman WM, Craft J, Fahmy TM (2014) The nanomaterial-dependent modulation of dendritic cells and its potential influence on therapeutic immunosuppression in lupus. Biomaterials 35(3):1089–1095PubMedCrossRefGoogle Scholar
  174. Lozano-Fernández T, Ballester-Antxordoki L, Pérez-Temprano N, Rojas E, Sanz D, Iglesias-Gaspar M et al (2014) Potential impact of metal oxide nanoparticles on the immune system: The role of integrins, L-selectin and the chemokine receptor CXCR4. Nanomedicine 10(6):1301–1310PubMedGoogle Scholar
  175. Lund FE (2008) Cytokine-producing B lymphocytes—key regulators of immunity. Curr Opin Immunol 20(3):332–338PubMedPubMedCentralCrossRefGoogle Scholar
  176. Lundqvist M, Stigler J, Elia G, Lynch I, Cedervall T, Dawson KA (2008) Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc Natl Acad Sci USA 105(38):14265–14270PubMedPubMedCentralCrossRefGoogle Scholar
  177. Lundqvist M, Stigler J, Cedervall T, Berggård T, Flanagan MB, Lynch I et al (2011) The evolution of the protein corona around nanoparticles: a test study. ACS Nano 5(9):7503–7509PubMedCrossRefGoogle Scholar
  178. Ma JS, Kim WJ, Kim JJ, Kim TJ, Ye SK, Song MD et al (2010) Gold nanoparticles attenuate LPS-induced NO production through the inhibition of NF-κB and IFN-β/STAT1 pathways in RAW264.7 cells. Nitric Oxide 23(3):214–219PubMedCrossRefGoogle Scholar
  179. Macho Fernandez E, Chang J, Fontaine J, Bialecki E, Rodriguez F, Werkmeister E et al (2012) Activation of invariant Natural Killer T lymphocytes in response to the α-galactosylceramide analogue KRN7000 encapsulated in PLGA-based nanoparticles and microparticles. Int J Pharm 423(1):45–54Google Scholar
  180. MacLean AG, Walker E, Sahu GK, Skowron G, Marx P, von Laer D et al (2014) A novel real-time CTL assay to measure designer T-cell function against HIV Env(+) cells. J Med Primatol 43(5):341–348PubMedPubMedCentralCrossRefGoogle Scholar
  181. Magalhaes PO, Lopes AM, Mazzola PG, Rangel-Yagui C, Penna TC, Pessoa A Jr (2007) Methods of endotoxin removal from biological preparations: a review. J Pharm Pharm Sci 10(3):388–404PubMedGoogle Scholar
  182. Mann M, Kelleher NL (2008) Precision proteomics: the case for high resolution and high mass accuracy. Proc Natl Acad Sci USA 105(47):18132–18138PubMedPubMedCentralCrossRefGoogle Scholar
  183. Manolova V, Flace A, Bauer M, Schwarz K, Saudan P, Bachmann MF (2008) Nanoparticles target distinct dendritic cell populations according to their size. Eur J Immunol 38(5):1404–1413PubMedCrossRefGoogle Scholar
  184. Martin RM, Brady JL, Lew AM (1998) The need for IgG2c specific antiserum when isotyping antibodies from C57BL/6 and NOD mice. J Immunol Methods 212(2):187–192PubMedCrossRefGoogle Scholar
  185. Marton Z, Kesmarky G, Vekasi J, Cser A, Russai R, Horvath B et al (2001) Red blood cell aggregation measurements in whole blood and in fibrinogen solutions by different methods. Clin Hemorheol Microcirc 24(2):75–83PubMedGoogle Scholar
  186. May C, Brosseron F, Chartowski P, Schumbrutzki C, Schoenebeck B, Marcus K (2011) Instruments and methods in proteomics. In: Hamacher M, Eisenacher M, Stephan C (eds) Data mining in proteomics. Humana Press, New York, pp 3–26Google Scholar
  187. Mayer A, Vadon M, Rinner B, Novak A, Wintersteiger R, Fröhlich E (2009) The role of nanoparticle size in hemocompatibility. Toxicology 258(2–3):139–147PubMedCrossRefGoogle Scholar
  188. Mbow ML, De Gregorio E, Valiante NM, Rappuoli R (2010) New adjuvants for human vaccines. Curr Opin Immunol 22(3):411–416PubMedCrossRefGoogle Scholar
  189. McGuinnes C, Duffin R, Brown SL, Mills N, Megson IL, MacNee W et al (2011) Surface derivatization state of polystyrene latex nanoparticles determines both their potency and their mechanism of causing human platelet aggregation in vitro. Toxicol Sci 119(2):359–368PubMedCrossRefGoogle Scholar
  190. Medzhitov R, Janeway CA (2002) Decoding the patterns of self and nonself by the innate immune system. Science 296(5566):298–300PubMedCrossRefGoogle Scholar
  191. Meerasa A, Huang JG, Gu FX (2011) CH(50): a revisited hemolytic complement consumption assay for evaluation of nanoparticles and blood plasma protein interaction. Curr Drug Deliv 8(3):290–298PubMedCrossRefGoogle Scholar
  192. Mehnert W, Mäder K (2001) Solid lipid nanoparticles: Production, characterization and applications. Adv Drug Deliv Rev 47(2–3):165–196CrossRefGoogle Scholar
  193. Memisoglu-Bilensoy E, Hincal AA (2006) Sterile, injectable cyclodextrin nanoparticles: effects of gamma irradiation and autoclaving. Int J Pharm 311(1–2):203–208PubMedCrossRefGoogle Scholar
  194. Miyamoto T, Okano S, Kasai N (2009) Inactivation of Escherichia coli endotoxin by soft hydrothermal processing. Appl Environ Microbiol 75(15):5058–5063PubMedPubMedCentralCrossRefGoogle Scholar
  195. Mocan T (2013) Hemolysis as expression of nanoparticles-induced cytotoxicity in red blood cells. BMBN 1(1):7–12Google Scholar
  196. Moghimi SM, Hunter AC (2000) Poloxamers and poloxamines in nanoparticle engineering and experimental medicine. Trends Biotechnol 18(10):412–420PubMedCrossRefGoogle Scholar
  197. Moghimi SM, Andersen AJ, Ahmadvand D, Wibroe PP, Andresen TL, Hunter AC (2011) Material properties in complement activation. Adv Drug Deliver Rev 63(12):1000–1007CrossRefGoogle Scholar
  198. Mollnes TE, Jokiranta TS, Truedsson L, Nilsson B, Rodriguez de Cordoba S, Kirschfink M (2007) Complement analysis in the 21st century. Mol Immunol 44(16):3838–3849PubMedCrossRefGoogle Scholar
  199. Moros M, Hernaez B, Garet E, Dias JT, Saez B, Grazu V et al (2012) Monosaccharides versus PEG-functionalized NPs: Influence in the cellular uptake. ACS Nano 6(2):1565–1577PubMedCrossRefGoogle Scholar
  200. Mottram PL, Leong D, Crimeen-Irwin B, Gloster S, Xiang SD, Meanger J et al (2006) Type 1 and 2 immunity following vaccination is influenced by nanoparticle size: formulation of a model vaccine for respiratory syncytial virus. Mol Pharmaceut 4(1):73–84CrossRefGoogle Scholar
  201. Muttil P, Prego C, Garcia-Contreras L, Pulliam B, Fallon J, Wang C et al (2010) Immunization of guinea pigs with novel hepatitis B antigen as nanoparticle aggregate powders administered by the pulmonary route. AAPS J 12(3):330–337PubMedPubMedCentralCrossRefGoogle Scholar
  202. Naahidi S, Jafari M, Edalat F, Raymond K, Khademhosseini A, Chen P (2013) Biocompatibility of engineered nanoparticles for drug delivery. J Control Release 166(2):182–194PubMedCrossRefGoogle Scholar
  203. Naeye B, Deschout H, Röding M, Rudemo M, Delanghe J, Devreese K et al (2011) Hemocompatibility of siRNA loaded dextran nanogels. Biomaterials 32(34):9120–9127PubMedCrossRefGoogle Scholar
  204. Nakai T, Kanamori T, Sando S, Aoyama Y (2003) Remarkably size-regulated cell invasion by artificial viruses. Saccharide-dependent self-aggregation of glycoviruses and its consequences in glycoviral gene delivery. J Am Chem Soc 125(28):8465–8475PubMedCrossRefGoogle Scholar
  205. Nam HY, Kwon SM, Chung H, Lee S-Y, Kwon S-H, Jeon H et al (2009) Cellular uptake mechanism and intracellular fate of hydrophobically modified glycol chitosan nanoparticles. J Control Release 135(3):259–267PubMedCrossRefGoogle Scholar
  206. Nayak AP, Tiyaboonchai W, Patankar S, Madhusudhan B, Souto EB (2010) Curcuminoids-loaded lipid nanoparticles: novel approach towards malaria treatment. Colloids Surf B Biointerfaces 81(1):263–273CrossRefGoogle Scholar
  207. Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TKA et al (2010) Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464(7293):1367–1370PubMedPubMedCentralCrossRefGoogle Scholar
  208. Nestle FO, Farkas A, Conrad C (2005) Dendritic-cell-based therapeutic vaccination against cancer. Curr Opin Immunol 17(2):163–169PubMedCrossRefGoogle Scholar
  209. Neu B, Meiselman HJ (2002) Depletion-mediated red blood cell aggregation in polymer solutions. Biophys J 83(5):2482–2490PubMedPubMedCentralCrossRefGoogle Scholar
  210. Nguyen TA, Yin T-I, Reyes D, Urban GA (2013) Microfluidic chip with integrated electrical cell-impedance sensing for monitoring single cancer cell migration in three-dimensional matrixes. Anal Chem 85(22):11068–11076PubMedCrossRefGoogle Scholar
  211. Oh N, Park JH (2014) Endocytosis and exocytosis of nanoparticles in mammalian cells. Int J Nanomed 9(Suppl. 1):51–63Google Scholar
  212. Okamoto S, Matsuura M, Akagi T, Akashi M, Tanimoto T, Ishikawa T et al (2009) Poly(gamma-glutamic acid) nano-particles combined with mucosal influenza virus hemagglutinin vaccine protects against influenza virus infection in mice. Vaccine 27(42):5896–5905PubMedCrossRefGoogle Scholar
  213. Okamura Y, Fukui Y, Kabata K, Suzuki H, Handa M, Ikeda Y et al (2009) Novel platelet substitutes: disk-shaped biodegradable nanosheets and their enhanced effects on platelet aggregation. Bioconjug Chem 20(10):1958–1965PubMedCrossRefGoogle Scholar
  214. Olsen MH, Hjortø GM, Hansen M, Met Ö, Svane IM, Larsen NB (2013) In-chip fabrication of free-form 3D constructs for directed cell migration analysis. Lab Chip 13(24):4800–4809PubMedCrossRefGoogle Scholar
  215. Omidi Y, Barar J, Heidari HR, Ahmadian S, Yazdi HA, Akhtar S (2008) Microarray analysis of the toxicogenomics and the genotoxic potential of a cationic lipid-based gene delivery nanosystem in human alveolar epithelial a549 cells. Toxicol Mech Methods 18(4):369–378PubMedCrossRefGoogle Scholar
  216. O’Shea JJ, Paul WE (2010) Mechanisms underlying lineage commitment and plasticity of helper CD4 + T cells. Science 327(5969):1098–1102PubMedPubMedCentralCrossRefGoogle Scholar
  217. Owens DE III, Peppas NA (2006) Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm 307(1):93–102Google Scholar
  218. Padmavathy N, Vijayaraghavan R (2008) Enhanced bioactivity of ZnO nanoparticles-an antimicrobial study. Sci Technol Adv Mat 9(3):035004Google Scholar
  219. Palazzolo-Ballance AM, Suquet C, Hurst JK (2007) Pathways for intracellular generation of oxidants and tyrosine nitration by a macrophage cell line. Biochemistry 46(25):7536–7548PubMedPubMedCentralCrossRefGoogle Scholar
  220. Park J, Gao W, Whiston R, Strom TB, Metcalfe S, Fahmy TM (2010) Modulation of CD4 + T lymphocyte lineage outcomes with targeted, nanoparticle-mediated cytokine delivery. Mol Pharmaceut 8(1):143–152CrossRefGoogle Scholar
  221. Parkin J, Cohen B (2001) An overview of the immune system. Lancet 357(9270):1777–1789PubMedCrossRefGoogle Scholar
  222. Parronchi P, De Carli M, Manetti R, Simonelli C, Sampognaro S, Piccinni MP et al (1992) IL-4 and IFN (alpha and gamma) exert opposite regulatory effects on the development of cytolytic potential by Th1 or Th2 human T cell clones. J Immunol 149(9):2977–2983PubMedGoogle Scholar
  223. Pascarelli NA, Moretti E, Terzuoli G, Lamboglia A, Renieri T, Fioravanti A et al (2013) Effects of gold and silver nanoparticles in cultured human osteoarthritic chondrocytes. J Appl Toxicol 33(12):1506–1513PubMedCrossRefGoogle Scholar
  224. Pastoriza I, Díaz-Freitas B, Sánchez-Espinel C, Faro JM, Magadán S, Liz Marzán L, González-Fernández A (2008) Visualización de nanopartículas por la técnica de SEM-FIB en el interior de los macrófagos (oral). XXXIV Congreso de la Sociedad Española de Inmunología; 2008; Palma de Mallorca (Spain)Google Scholar
  225. Patton LM, Pretzer D, Schulteis BS, Saggart BS, Tennant KD, Ahmed NK (1993) Activity assays for characterizing the thrombolytic protein fibrolase. J Biochem Biophys Methods 27(1):11–15PubMedCrossRefGoogle Scholar
  226. Pedersen MB, Zhou X, Larsen EK, Sorensen US, Kjems J, Nygaard JV et al (2010) Curvature of synthetic and natural surfaces is an important target feature in classical pathway complement activation. J Immunol 184(4):1931–1945PubMedCrossRefGoogle Scholar
  227. Pedersen GK, Hoschler K, Oie Solbak SM, Bredholt G, Pathirana RD, Afsar A et al (2014) Serum IgG titres, but not avidity, correlates with neutralizing antibody response after H5N1 vaccination. Vaccine 32(35):4550–4557PubMedCrossRefGoogle Scholar
  228. Pelkmans L (2005) Secrets of caveolae- and lipid raft-mediated endocytosis revealed by mammalian viruses. Biochim Biophys Acta (BBA) Mol Cell Res 1746(3):295–304CrossRefGoogle Scholar
  229. Peracchia MT, Harnisch S, Pinto-Alphandary H, Gulik A, Dedieu JC, Desmaële D et al (1999) Visualization of in vitro protein-rejecting properties of PEGylated stealth® polycyanoacrylate nanoparticles. Biomaterials 20(14):1269–1275PubMedCrossRefGoogle Scholar
  230. Perkins WR, Vaughan DE, Plavin SR, Daley WL, Rauch J, Lee L et al (1997) Streptokinase entrapment in interdigitation-fusion liposomes improves thrombolysis in an experimental rabbit model. Thromb Haemost 77(6):1174–1178PubMedGoogle Scholar
  231. Petsch D, Anspach FB (2000) Endotoxin removal from protein solutions. J Biotechnol 76(2–3):97–119PubMedCrossRefGoogle Scholar
  232. Pfaller T, Colognato R, Nelissen I, Favilli F, Casals E, Ooms D et al (2010) The suitability of different cellular in vitro immunotoxicity and genotoxicity methods for the analysis of nanoparticle-induced events. Nanotoxicology 4(1):52–72PubMedCrossRefGoogle Scholar
  233. Pham PV, Nguyen NT, Nguyen HM, Khuat LT, Le PM, Pham VQ et al (2014) A simple in vitro method for evaluating dendritic cell-based vaccinations. Onco Targets Ther 18(7):1455–1464CrossRefGoogle Scholar
  234. Pharmacopeia US (2010) Bacterial endotoxins test, Chap. 85. USP 33. United States Pharmacopeial Convention, Rockville, pp R65–R9Google Scholar
  235. Piao MJ, Kang KA, Lee IK, Kim HS, Kim S, Choi JY et al (2011) Silver nanoparticles induce oxidative cell damage in human liver cells through inhibition of reduced glutathione and induction of mitochondria-involved apoptosis. Toxicol Lett 201(1):92–100PubMedCrossRefGoogle Scholar
  236. Piccotti JR (2008) T cell-dependent antibody response tests. In: Bussiere DJHJL (ed) Immunotoxicology strategies for pharmaceutical safety assessment. Wiley, New York, pp 67–74Google Scholar
  237. Plitnick L, Herzyk D (2010) The T-Dependent antibody response to keyhole limpet hemocyanin in rodents. In: Dietert RR (ed) Immunotoxicity testing. Humana Press, New York, pp 159–171Google Scholar
  238. Poole S, Mussett MV (1989) The international standard for endotoxin: evaluation in an international collaborative study. J Biol Stand 17(2):161–171PubMedCrossRefGoogle Scholar
  239. Potter T, Neun B, Stern S (2011) Assay to detect lipid peroxidation upon exposure to nanoparticles. In: McNeil SE (ed) Characterization of nanoparticles intended for drug delivery. Humana Press, New York, pp 181–189Google Scholar
  240. Prach M, Stone V, Proudfoot L (2013) Zinc oxide nanoparticles and monocytes: Impact of size, charge and solubility on activation status. Toxicol Appl Pharmacol 266(1):19–26PubMedCrossRefGoogle Scholar
  241. Prasad GK, Agarwal GS, Singh B, Rai GP, Vijayaraghavan R (2009) Photocatalytic inactivation of Bacillus anthracis by titania nanomaterials. J Hazard Mater 165(1–3):506–510PubMedCrossRefGoogle Scholar
  242. Prego C, Paolicelli P, Díaz B, Vicente S, Sánchez A, González-Fernández A et al (2010) Chitosan-based nanoparticles for improving immunization against hepatitis B infection. Vaccine 28(14):2607–2614PubMedCrossRefGoogle Scholar
  243. Priano G, Pallarola D, Battaglini F (2007) Endotoxin detection in a competitive electrochemical assay: synthesis of a suitable endotoxin conjugate. Anal Biochem 362(1):108–116PubMedCrossRefGoogle Scholar
  244. Rabinovich N, McInnes P, Klein D, Hall B (1994) Vaccine technologies: view to the future. Science 265(5177):1401–1404PubMedCrossRefGoogle Scholar
  245. Rai M, Yadav A, Gade A (2009) Silver nanoparticles as a new generation of antimicrobials. Biotechnol Adv 27(1):76–83PubMedCrossRefGoogle Scholar
  246. Ramani K, Miclea RD, Purohit VS, Mager DE, Straubinger RM, Balu-Iyer SV (2008a) Phosphatidylserine containing liposomes reduce immunogenicity of recombinant human factor VIII (rFVIII) in a murine model of hemophilia A. J Pharm Sci 97(4):1386–1398PubMedPubMedCentralCrossRefGoogle Scholar
  247. Ramani K, Purohit V, Miclea R, Gaitonde P, Straubinger RM, Balu-Iyer SV (2008b) Passive transfer of polyethylene glycol to liposomal-recombinant human FVIII enhances its efficacy in a murine model for hemophilia A. J Pharm Sci 97(9):3753–3764PubMedPubMedCentralCrossRefGoogle Scholar
  248. Rangin M, Basu A (2004) Lipopolysaccharide identification with functionalized polydiacetylene liposome sensors. J Am Chem Soc 126(16):5038–5039PubMedCrossRefGoogle Scholar
  249. Reddy ST, Swartz MA, Hubbell JA (2006) Targeting dendritic cells with biomaterials: developing the next generation of vaccines. Trends Immunol 27(12):573–579PubMedCrossRefGoogle Scholar
  250. Rehman M, Yoshihisa Y, Miyamoto Y, Shimizu T (2012) The anti-inflammatory effects of platinum nanoparticles on the lipopolysaccharide-induced inflammatory response in RAW 264.7 macrophages. Inflamm Res 61(11):1177–1185PubMedCrossRefGoogle Scholar
  251. Richards RL, Aronson J, Schoenbechler M, Diggs CL, Alving CR (1983) Antibodies reactive with liposomal phospholipids are produced during experimental Trypanosoma rhodesiense infections in rabbits. J Immunol 130(3):1390–1394PubMedGoogle Scholar
  252. Rı́hová B (2002) Immunomodulating activities of soluble synthetic polymer-bound drugs. Adv Drug Deliver Rev 54(5):653–674Google Scholar
  253. Rocker C, Potzl M, Zhang F, Parak WJ, Nienhaus GU (2009) A quantitative fluorescence study of protein monolayer formation on colloidal nanoparticles. Nat Nanotechnol 4(9):577–580PubMedCrossRefGoogle Scholar
  254. Roesslein M, Hirsch C, Kaiser J-P, Krug HF, Wick P (2013) Comparability of in vitro tests for bioactive nanoparticles: A common assay to detect reactive oxygen species as an example. Int J Mol Sci 14(12):24320–24337PubMedPubMedCentralCrossRefGoogle Scholar
  255. Rohani R, de Chickera S, Willert C, Chen Y, Dekaban G, Foster P (2011) In vivo cellular MRI of dendritic cell migration using micrometer-sized iron oxide (MPIO) particles. Mol Imaging Biol 13(4):679–694PubMedCrossRefGoogle Scholar
  256. Romagnani S (2000) T-cell subsets (Th1 versus Th2). Ann Allergy Asthma Immunol 85(1):9–21PubMedCrossRefGoogle Scholar
  257. Ronzani C, Safar R, Diab R, Chevrier J, Paoli J, Abdel-Wahhab M et al (2014) Viability and gene expression responses to polymeric nanoparticles in human and rat cells. Cell Biol Toxicol 30(3):137–146PubMedCrossRefGoogle Scholar
  258. Rosalia R, Silva A, Camps M, Allam A, Jiskoot W, van der Burg S et al (2013) Efficient ex vivo induction of T cells with potent anti-tumor activity by protein antigen encapsulated in nanoparticles. Cancer Immunol Immunother 62(7):1161–1173PubMedCrossRefGoogle Scholar
  259. Rothen-Rutishauser BM, Schürch S, Haenni B, Kapp N, Gehr P (2006) Interaction of fine particles and nanoparticles with red blood cells visualized with advanced microscopic techniques. Environ Sci Technol 40(14):4353–4359PubMedCrossRefGoogle Scholar
  260. Sahay G, Alakhova DY, Kabanov AV (2010) Endocytosis of nanomedicines. J Control Release 145(3):182–195PubMedPubMedCentralCrossRefGoogle Scholar
  261. Salvador-Morales C, Sim RB (2013) Complement activation. Handbook of immunological properties of engineered nanomaterials. World Scientific, Singapore, pp 357–384Google Scholar
  262. Samama MM, Guinet C (2011) Laboratory assessment of new anticoagulants. Clin Chem Lab Med 49(5):761–772PubMedCrossRefGoogle Scholar
  263. Sanfins E, Augustsson C, Dahlbäck B, Linse S, Cedervall T (2014) Size-dependent effects of nanoparticles on enzymes in the blood coagulation cascade. Nano Lett 14(8):4736–4744PubMedCrossRefGoogle Scholar
  264. Schins RPF, Duffin R, Höhr D, Knaapen AM, Shi T, Weishaupt C et al (2002) Surface modification of quartz inhibits toxicity, particle uptake, and oxidative DNA damage in human lung epithelial cells. Chem Res Toxicol 15(9):1166–1173PubMedCrossRefGoogle Scholar
  265. Schlitzer A, McGovern N, Teo P, Zelante T, Atarashi K, Low D et al (2013) IRF4 transcription factor-dependent CD11b + dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 38(5):970–983PubMedPubMedCentralCrossRefGoogle Scholar
  266. Sebastià J, Cristòfol R, Martín M, Rodríguez-Farré E, Sanfeliu C (2003) Evaluation of fluorescent dyes for measuring intracellular glutathione content in primary cultures of human neurons and neuroblastoma SH-SY5Y. Cytometry Part A 51A(1):16–25CrossRefGoogle Scholar
  267. Sedgwick JD, Holt PG (1983) A solid-phase immunoenzymatic technique for the enumeration of specific antibody-secreting cells. J Immunol Methods 57(1–3):301–309PubMedCrossRefGoogle Scholar
  268. Sehgal K, Ragheb R, Fahmy TM, Dhodapkar MV, Dhodapkar KM (2014) Nanoparticle-mediated combinatorial targeting of multiple human dendritic cell (DC) subsets leads to enhanced T Cell activation via IL-15–dependent DC crosstalk. J Immunol 193(5):2297–2305PubMedCrossRefGoogle Scholar
  269. Shafer-Weaver K, Sayers T, Strobl S, Derby E, Ulderich T, Baseler M et al (2003) The granzyme B ELISPOT assay: an alternative to the (51)Cr-release assay for monitoring cell-mediated cytotoxicity. J Transl Med 1:14PubMedPubMedCentralCrossRefGoogle Scholar
  270. Sharma SK (1986) Endotoxin detection and elimination in biotechnology. Biotechnol Appl Biochem 8(1):5–22PubMedGoogle Scholar
  271. Sharma G, Valenta DT, Altman Y, Harvey S, Xie H, Mitragotri S et al (2010) Polymer particle shape independently influences binding and internalization by macrophages. J Control Release 147(3):408–412PubMedPubMedCentralCrossRefGoogle Scholar
  272. Sharma V, Anderson D, Dhawan A (2012) Zinc oxide nanoparticles induce oxidative DNA damage and ROS-triggered mitochondria mediated apoptosis in human liver cells (HepG2). Apoptosis 17(8):852–870PubMedCrossRefGoogle Scholar
  273. Shen H, Ackerman AL, Cody V, Giodini A, Hinson ER, Cresswell P et al (2006) Enhanced and prolonged cross-presentation following endosomal escape of exogenous antigens encapsulated in biodegradable nanoparticles. Immunology 117(1):78–88PubMedPubMedCentralCrossRefGoogle Scholar
  274. Shen Y, Zhang S, Zhang F, Loftis A, Pavía-Sanders A, Zou J et al (2013) Polyphosphoester-based cationic nanoparticles serendipitously release integral biologically-active components to serve as novel degradable inducible nitric oxide synthase inhibitors. Adv Mater 25(39):5609–5614PubMedPubMedCentralCrossRefGoogle Scholar
  275. Shenoy D, Little S, Langer R, Amiji M (2005) Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs. 1. In vitro evaluations. Mol Pharm 2(5):357–366PubMedPubMedCentralCrossRefGoogle Scholar
  276. Shiang Y-C, Hsu C-L, Huang C-C, Chang H-T (2011) Gold nanoparticles presenting hybridized self-assembled aptamers that exhibit enhanced inhibition of thrombin. Angew Chem Int Ed Engl 50(33):7660–7665PubMedCrossRefGoogle Scholar
  277. Shresta S, Pham CTN, Thomas DA, Graubert TA, Ley TJ (1998) How do cytotoxic lymphocytes kill their targets? Curr Opin Immunol 10(5):581–587PubMedCrossRefGoogle Scholar
  278. Simak J (2013a) The effects of enginereed nanomaterials on the plasma coagulation system. Handbook of immunological properties of engineered nanomaterials. World Scientific, Singapore, pp 263–285Google Scholar
  279. Simak J (2013b) The effects of enginereed nanomaterials on platelets. In: Marina A, Dobrovolskaia SEM (eds) Handbook of immunological properties of engineered nanomaterials. World Scientific, Singapore, pp 293–348Google Scholar
  280. Sintzel MB, Merkli A, Tabatabay C, Gurny R (1997) Influence of irradiation sterilization on polymers used as drug carriers—a review. Drug Dev Ind Pharm 23(9):857–878CrossRefGoogle Scholar
  281. Slowing II, Wu C-W, Vivero-Escoto JL, Lin VSY (2009) Mesoporous silica nanoparticles for reducing hemolytic activity towards mammalian red blood cells. Small 5(1):57–62PubMedCrossRefGoogle Scholar
  282. Socha M, Bartecki P, Passirani C, Sapin A, Damge C, Lecompte T et al (2009) Stealth nanoparticles coated with heparin as peptide or protein carriers. J Drug Target 17(8):575–585PubMedCrossRefGoogle Scholar
  283. Spira J, Plyushch O, Zozulya N, Yatuv R, Dayan I, Bleicher A et al (2010) Safety, pharmacokinetics and efficacy of factor VIIa formulated with PEGylated liposomes in haemophilia A patients with inhibitors to factor VIII—an open label, exploratory, cross-over, phase I/II study. Haemophilia Off J World Federation Hemophilia 16(6):910–918CrossRefGoogle Scholar
  284. Spira J, Plyushch O, Andreeva T, Zorenko V, Zozulya N, Velichkoi I et al (2012) Safety and efficacy of a long-acting liposomal formulation of plasma-derived factor VIII in haemophilia A patients. Br J Haematol 158(1):149–152PubMedCrossRefGoogle Scholar
  285. Stano A, van der Vlies AJ, Martino MM, Swartz MA, Hubbell JA, Simeoni E (2011) PPS nanoparticles as versatile delivery system to induce systemic and broad mucosal immunity after intranasal administration. Vaccine 29(4):804–812PubMedCrossRefGoogle Scholar
  286. Stano A, Scott EA, Dane KY, Swartz MA, Hubbell JA (2013) Tunable T cell immunity towards a protein antigen using polymersomes vs. solid-core nanoparticles. Biomaterials 34(17):4339–4346PubMedCrossRefGoogle Scholar
  287. Steinman RM, Hawiger D, Nussenzweig MC (2003) Tolerogenic dendritic cells. Annu Rev Immunol 21(1):685–711PubMedCrossRefGoogle Scholar
  288. Tafaghodi M, Saluja V, Kersten GF, Kraan H, Slutter B, Amorij JP et al (2012) Hepatitis B surface antigen nanoparticles coated with chitosan and trimethyl chitosan: impact of formulation on physicochemical and immunological characteristics. Vaccine 30(36):5341–5348PubMedCrossRefGoogle Scholar
  289. Tao L, Hu W, Liu Y, Huang G, Sumer BD, Gao J (2011) Shape-specific polymeric nanomedicine: emerging opportunities and challenges. Exp Biol Med 236(1):20–29CrossRefGoogle Scholar
  290. Tayel AA, El-Tras WF, Moussa S, El-Baz AF, Mahrous H, Salem MF et al (2011) Antibacterial action of zinc oxide nanoparticles against foodborne pathogens. J Food Safety 31(2):211–218CrossRefGoogle Scholar
  291. Thiele L, Merkle H, Walter E (2003) Phagocytosis and phagosomal fate of surface-modified microparticles in dendritic cells and macrophages. Pharm Res 20(2):221–228PubMedCrossRefGoogle Scholar
  292. Torres MP, Wilson-Welder JH, Lopac SK, Phanse Y, Carrillo-Conde B, Ramer-Tait AE et al (2011) Polyanhydride microparticles enhance dendritic cell antigen presentation and activation. Acta Biomater 7(7):2857–2864PubMedPubMedCentralCrossRefGoogle Scholar
  293. Triantafilou M, Triantafilou K (2005) The dynamics of LPS recognition: complex orchestration of multiple receptors. J Endotoxin Res 11(1):5–11PubMedGoogle Scholar
  294. Trojan A, Rajeswaran R, Montemurro M, Mütsch M, Steffen R (2007) Real time PCR for the assessment of CD8 + T cellular immune response after prophylactic vaccinia vaccination. J Clin Virol 40(1):80–83PubMedCrossRefGoogle Scholar
  295. Uto T, Akagi T, Hamasaki T, Akashi M, Baba M (2009) Modulation of innate and adaptive immunity by biodegradable nanoparticles. Immunol Lett 125(1):46–52PubMedCrossRefGoogle Scholar
  296. Vallhov H, Qin J, Johansson SM, Ahlborg N, Muhammed MA, Scheynius A et al (2006) The importance of an endotoxin-free environment during the production of nanoparticles used in medical applications. Nano Lett 6(8):1682–1686PubMedCrossRefGoogle Scholar
  297. VanGuilder HD, Vrana KE, Freeman WM (2008) Twenty-five years of quantitative PCR for gene expression analysis. Biotechniques 44(5):619–626PubMedCrossRefGoogle Scholar
  298. Verma A, Stellacci F (2010) Effect of surface properties on nanoparticle–cell interactions. Small 6(1):12–21PubMedCrossRefGoogle Scholar
  299. Vicente S, Peleteiro M, Díaz-Freitas B, Sanchez A, González-Fernández Á, Alonso MJ (2013a) Co-delivery of viral proteins and a TLR7 agonist from polysaccharide nanocapsules: a needle-free vaccination strategy. J Control Release 172(3):773–781PubMedCrossRefGoogle Scholar
  300. Vicente S, Diaz-Freitas B, Peleteiro M, Sanchez A, Pascual DW, Gonzalez-Fernandez A et al (2013b) A polymer/oil based nanovaccine as a single-dose immunization approach. PLos One 8(4):e62500–eGoogle Scholar
  301. Vicente S, Peleteiro M, Gonzalez-Aramundiz JV, Díaz-Freitas B, Martínez-Pulgarín S, Neissa JI et al (2014) Highly versatile immunostimulating nanocapsules for specific immune potentiation. Nanomedicine 9(15):2273–2289PubMedCrossRefGoogle Scholar
  302. Vicente-Manzanares M, Horwitz A (2011) Cell migration: an overview. In: Wells CM, Parsons M (eds) Cell migration. Humana Press, New York, pp 1–24Google Scholar
  303. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S (2008) Functions of natural killer cells. Nat Immunol 9(5):503–510PubMedCrossRefGoogle Scholar
  304. Walsh PN, Friedrich DP, Williams JA, Smith RJ, Stewart TL, Carter DK et al (2013) Optimization and qualification of a memory B-cell ELISpot for the detection of vaccine-induced memory responses in HIV vaccine trials. J Immunol Methods 394(1–2):84–93PubMedPubMedCentralCrossRefGoogle Scholar
  305. Wang H, Joseph JA (1999) Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. Free Radic Biol Med 27(5–6):612–616PubMedCrossRefGoogle Scholar
  306. Wang W, Xiong W, Zhu Y, Xu H, Yang X (2010) Protective effect of PEGylation against poly(amidoamine) dendrimer-induced hemolysis of human red blood cells. J Biomed Mater Res B Appl Biomater 93(1):59–64PubMedGoogle Scholar
  307. Wang H, Cai H-H, Zhang L, Cai J, Yang P-H, Chen ZW (2013) A novel gold nanoparticle-doped polyaniline nanofibers-based cytosensor confers simple and efficient evaluation of T-cell activation. Biosens Bioelectron 50:167–173PubMedCrossRefGoogle Scholar
  308. Wang Z, Li J, Cho J, Malik AB (2014a) Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils. Nat Nanotechnol 9(3):204–210PubMedPubMedCentralCrossRefGoogle Scholar
  309. Wang J, Zhu R, Gao B, Wu B, Li K, Sun X et al (2014b) The enhanced immune response of hepatitis B virus DNA vaccine using SiO2@LDH nanoparticles as an adjuvant. Biomaterials 35(1):466–478PubMedCrossRefGoogle Scholar
  310. Wason MS, Colon J, Das S, Seal S, Turkson J, Zhao J et al (2013) Sensitization of pancreatic cancer cells to radiation by cerium oxide nanoparticle-induced ROS production. Nanomedicine 9(4):558–569PubMedGoogle Scholar
  311. Wassef NM, Roerdink F, Swartz GM Jr, Lyon JA, Berson BJ, Alving CR (1984) Phosphate-binding specificities of monoclonal antibodies against phosphoinositides in liposomes. Mol Immunol 21(10):863–868PubMedCrossRefGoogle Scholar
  312. Wassef NM, Swartz GM Jr, Alving CR, Kates M (1990) Antibodies to liposomal phosphatidylcholine and phosphatidylsulfocholine. Biochem Cell Biol 68(1):54–64PubMedCrossRefGoogle Scholar
  313. Weber N, Ortega P, Clemente MI, Shcharbin D, Bryszewska M, de la Mata FJ et al (2008) Characterization of carbosilane dendrimers as effective carriers of siRNA to HIV-infected lymphocytes. J Control Release 132(1):55–64PubMedCrossRefGoogle Scholar
  314. Wonderlich J, Shearer G, Livingstone A, Brooks A (2006) Induction and measurement of cytotoxic T lymphocyte activity. Curr Protoc Immunol. John Wiley & Sons, Inc., New York, pp 1–23Google Scholar
  315. Wooldridge L, Lissina A, Cole DK, van den Berg HA, Price DA, Sewell AK (2009) Tricks with tetramers: how to get the most from multimeric peptide–MHC. Immunology 126(2):147–164PubMedPubMedCentralCrossRefGoogle Scholar
  316. Wyatt LS, Earl PL, Eller LA, Moss B (2004) Highly attenuated smallpox vaccine protects mice with and without immune deficiencies against pathogenic vaccinia virus challenge. Proc Natl Acad Sci USA 101(13):4590–4595PubMedPubMedCentralCrossRefGoogle Scholar
  317. Xia T, Kovochich M, Brant J, Hotze M, Sempf J, Oberley T et al (2006) Comparison of the abilities of ambient and manufactured nanoparticles to induce cellular toxicity according to an oxidative stress paradigm. Nano Lett 6(8):1794–1807PubMedCrossRefGoogle Scholar
  318. Xiang SD, Scholzen A, Minigo G, David C, Apostolopoulos V, Mottram PL et al (2006) Pathogen recognition and development of particulate vaccines: Does size matter? Methods 40(1):1–9PubMedCrossRefGoogle Scholar
  319. Xiang SD, Fuchsberger M, Karlson TDL, Hardy CL, Selomulya C, Plebanski M (2013) Nanoparticles, immunomodulation and vaccine delivery. In: Dobrovolskaia MA, McNeil SE (eds) Handbook of immunological properties of engineered nanomaterials. World Scientific, Singapore, pp 449–465Google Scholar
  320. Xu W, Shen Y, Jiang Z, Wang Y, Chu Y, Xiong S (2004) Intranasal delivery of chitosan–DNA vaccine generates mucosal SIgA and anti-CVB3 protection. Vaccine 22(27–28):3603–3612PubMedCrossRefGoogle Scholar
  321. Yagi H, Hashizume H, Horibe T, Yoshinari Y, Hata M, Ohshima A et al (2006) Induction of therapeutically relevant cytotoxic T lymphocytes in humans by percutaneous peptide immunization. Cancer Res 66(20):10136–10144PubMedCrossRefGoogle Scholar
  322. Yao J, Bechter C, Wiesneth M, Härter G, Götz M, Germeroth L et al (2008a) Multimer staining of cytomegalovirus phosphoprotein 65–specific T cells for diagnosis and therapeutic purposes: a comparative study. Clin Infect Dis 46(10):e96–e105PubMedCrossRefGoogle Scholar
  323. Yao Y, Ohko Y, Sekiguchi Y, Fujishima A, Kubota Y (2008b) Self-sterilization using silicone catheters coated with Ag and TiO2 nanocomposite thin film. J Biomed Mater Res B Appl Biomater 85(2):453–460CrossRefGoogle Scholar
  324. Yatuv R, Robinson M, Dayan-Tarshish I, Baru M (2010) The use of PEGylated liposomes in the development of drug delivery applications for the treatment of hemophilia. Int J Nanomedicine 5:581–591PubMedPubMedCentralGoogle Scholar
  325. Yoo D, Guk K, Kim H, Khang G, Wu D, Lee D (2013) Antioxidant polymeric nanoparticles as novel therapeutics for airway inflammatory diseases. Int J Pharm 450(1–2):87–94PubMedCrossRefGoogle Scholar
  326. Yoshikawa T, Okada N, Oda A, Matsuo K, Matsuo K, Kayamuro H et al (2008) Nanoparticles built by self-assembly of amphiphilic gamma-PGA can deliver antigens to antigen-presenting cells with high efficiency: a new tumor-vaccine carrier for eliciting effector T cells. Vaccine 26(10):1303–1313PubMedCrossRefGoogle Scholar
  327. Young KR, Nzula S, Burt DS, Ward BJ (2014) Immunologic characterization of a novel inactivated nasal mumps virus vaccine adjuvanted with Protollin. Vaccine 32(2):238–245PubMedCrossRefGoogle Scholar
  328. Yuseff M-I, Pierobon P, Reversat A, Lennon-Dumenil A-M (2013) How B cells capture, process and present antigens: a crucial role for cell polarity. Nat Rev Immunol 13(7):475–486PubMedCrossRefGoogle Scholar
  329. Zanivan S, Krueger M, Mann M (2012) In vivo quantitative proteomics: the SILAC Mouse. In: Shimaoka M (ed) Integrin and cell adhesion molecules. Humana Press, New York, pp 435–450Google Scholar
  330. Zhang G, Neubert TA (2009) Use of stable isotope labeling by amino acids in cell culture (SILAC) for phosphotyrosine protein identification and quantitation. Methods Mol Biol 527:79–92PubMedPubMedCentralCrossRefGoogle Scholar
  331. Zhang W, Wang L, Liu Y, Chen X, Liu Q, Jia J et al (2014) Immune responses to vaccines involving a combined antigen–nanoparticle mixture and nanoparticle-encapsulated antigen formulation. Biomaterials 35(23):6086–6097PubMedCrossRefGoogle Scholar
  332. Zhang Y, Luo W, Wang Y, Chen J, Liu Y, Zhang Y (2015) Enhanced antitumor immunity of nanoliposome-encapsulated heat shock protein 70 peptide complex derived from dendritic tumor fusion cells. Oncol Rep 33(6):2695–2702PubMedPubMedCentralGoogle Scholar
  333. Zhao F, Zhao Y, Liu Y, Chang X, Chen C, Zhao Y (2011a) Cellular uptake, intracellular trafficking, and cytotoxicity of nanomaterials. Small 7(10):1322–1337PubMedCrossRefGoogle Scholar
  334. Zhao Y, Sun X, Zhang G, Trewyn BG, Slowing II, Lin VSY (2011b) Interaction of mesoporous silica nanoparticles with human red blood cell membranes: size and surface effects. ACS Nano 5(2):1366–1375PubMedCrossRefGoogle Scholar
  335. Zhao L, Seth A, Wibowo N, Zhao C-X, Mitter N, Yu C et al (2014) Nanoparticle vaccines. Vaccine 32(3):327–337PubMedCrossRefGoogle Scholar
  336. Zhou HY, Zhang YP, Zhang WF, Chen XG (2011) Biocompatibility and characteristics of injectable chitosan-based thermosensitive hydrogel for drug delivery. Carbohydr Polym 83(4):1643–1651CrossRefGoogle Scholar
  337. Zolnik BS, González-Fernández Á, Sadrieh N, Dobrovolskaia MA (2010) Nanoparticles and the immune system. Endocrinology 151(2):458–465PubMedCrossRefGoogle Scholar
  338. Zook JM, MacCuspie RI, Locascio LE, Halter MD, Elliott JT (2010) Stable nanoparticle aggregates/agglomerates of different sizes and the effect of their size on hemolytic cytotoxicity. Nanotoxicology 5(4):517–530PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Silvia Lorenzo-Abalde
    • 1
  • Rosana Simón-Vázquez
    • 1
    • 2
  • Mercedes Peleteiro Olmedo
    • 1
  • Tamara Lozano-Fernández
    • 1
  • Olivia Estévez-Martínez
    • 1
  • Andrea Fernández-Carrera
    • 1
  • África González-Fernández
    • 1
    Email author
  1. 1.Immunology, Biomedical Research Center (CINBIO), Institute of Biomedical Research of Vigo (IBIV)Universidad de VigoVigoSpain
  2. 2.Institut Galien Paris Sud, Faculty of PharmacyCNRS, Univ. Paris-Sud, Université Paris SaclayChâtenay-MalabryFrance

Personalised recommendations