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Polyinosinic:polycytidylic acid loading onto different generations of PAMAM dendrimer-coated magnetic nanoparticles

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Abstract

Poly (I:C), which is a synthetic double-stranded RNA, have significant toxicity on tumor cells. The immobilization of Poly (I:C) onto nanoparticles is important for the fabrication of targeted delivery systems. In this study, different generations of newly synthesized PAMAM dendron-coated magnetic nanoparticles (DcMNP) which can be targeted to the tumor site under magnetic field were efficiently loaded for the first time with Poly (I:C). Different generations of DcMNPs (G2, G3, G4, G5, G6, and G7) were synthesized. Poly (I:C) activation was achieved in the presence of EDC and 1-methylimidazole. Loading of Poly (I:C) onto DcMNPs was followed by agarose gel electrophoresis. Acidic reaction conditions were found as superior to basic and neutral for binding of Poly (I:C). In addition, having more functional groups at the surface, higher generations (G7, G6, and G5) of PAMAM DcMNPs were found more suitable as a delivery system for Poly (I:C). Further in vitro and in vivo analyses of Poly (I:C)/PAMAM magnetic nanoparticles may provide new opportunities for the selective targeting and killing of tumor cells.

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References

  • Borges O, Silva M, de Sousa A, Borchard G, Junginger HE, Cordeiro-da-Silva A (2008) Alginate coated chitosan nanoparticles are an effective subcutaneous adjuvant for hepatitis B surface antigen. Int Immunopharmacol 8:1773–1780

    Article  CAS  Google Scholar 

  • Bosman AW, Janssen HM, Meijer EW (1999) About dendrimers: structure, physical properties and applications. Chem Rev 99:1665–1688

    Article  CAS  Google Scholar 

  • Butowski N, Lamborn KR, Lee BL, Prados MD, Cloughesy T, DeAngelis LM, Abrey L, Fink K, Lieberman F, Mehta M, Ian Robins H, Junck L, Salazar AM, Chang SM (2009) A North American brain tumor consortium phase II study of poly-ICLC for adult patients with recurrent anaplastic gliomas. J Neurooncol 91:183–189

    Article  CAS  Google Scholar 

  • Chen L, Ding Y, Wang Y, Liu X, Babu R, Ravis W, Yan W (2013) Codelivery of zoledronic acid and doublestranded RNA from core–shell nanoparticles. Int J Nanomed 8:137–145

    CAS  Google Scholar 

  • Colombo M, Carregal-Romero S, Casula MF, Gutiérrez L, Morales MP, Böhm IB, Heverhagen JT, Prosperi D, Parak WJ (2012) Biological applications of magnetic nanoparticles. Chem Soc Rev 41:4306–4334

    Article  CAS  Google Scholar 

  • Dobson J (2006) Magnetic nanoparticles for drug delivery. Drug Dev Res 67:55–60

    Article  CAS  Google Scholar 

  • Du X, Poltorak A, Wei Y, Beutler B (2000) Three novel mammalian toll-like receptors: gene structure, expression, and evolution. Eur Cytokine Netw 11:362–371

    CAS  Google Scholar 

  • Esfand R, Tomalia DA (2001) Poly(amidoamine) (PAMAM) dendrimers: from biomimicry to drug delivery and biomedical applications. Drug Discov Today 6:427–436

    Article  CAS  Google Scholar 

  • Fischer S, Schlosser E, Mueller M, Csaba N, Merkle HP, Groettrup M, Gander B (2009) Concomitant delivery of a CTL-restricted peptide antigen and CpG ODN by PLGA microparticles induces cellular immune response. J Drug Target 17:652–661

    Article  CAS  Google Scholar 

  • Friedman OM, Klass DL, Seligman AM (1954) N-phosphorylated derivatives of diethanolamine1. J Am Chem Soc 76:916–917

    Article  CAS  Google Scholar 

  • Gao F, Pan BF, Zheng WM, Ao LM, Gu HC (2005) Study of streptavidin coated onto PAMAM dendrimer modified magnetite nanoparticles. J Magn Magn Mater 293:48–54

    Article  CAS  Google Scholar 

  • Gomori G (1948, December) Histochemical demonstration of sites of phosphamidase activity. In Proceedings of the society for experimental biology and medicine, Vol. 69, No. 3. Society for Experimental Biology and Medicine, Royal Society of Medicine, New York, p 407–409

  • Hansson GK, Edfeldt K (2005) Toll to be paid at the gateway to the vessel wall. Arterioscler Thromb Vasc Biol 25:1085–1087

    Article  CAS  Google Scholar 

  • Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745

    Article  CAS  Google Scholar 

  • Ho KM, Li P (2008) Design and synthesis of novel magnetic core-shell polymeric particles. Langmuir 24:1801–1807

    Article  CAS  Google Scholar 

  • Jasani B, Navabi H, Adams M (2009) Ampligen: a potential toll-like 3 receptor adjuvant for immunotherapy of cancer. Vaccine 27:3401–3404

    Article  CAS  Google Scholar 

  • Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis e Sousa C, Matsuura Y, Fujita T, Akira S (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105

    Article  CAS  Google Scholar 

  • Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373–384

    Article  CAS  Google Scholar 

  • Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, Ishii KJ, Takeuchi O, Akira S (2005) IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 6:981–988

    Article  CAS  Google Scholar 

  • Khodadust R, Ünsoy G, Yalçın S, Gündüz G, Gündüz U (2013) PAMAM dendrimer-coated iron oxide nanoparticles:synthesis and characterization of different generations. J Nanopart Res 15:1488–1501

    Article  Google Scholar 

  • Khvalevsky E, Rivkin L, Rachmilewitz J, Galun E, Giladi H (2007) TLR3 signaling in a hepatoma cell line is skewed towards apoptosis. J Cell Biochem 100:1301–1312

    Article  CAS  Google Scholar 

  • Kohler N, Fryxell GE, Zhang M (2004) A bifunctional poly(ethylene glycol) silane immobilized on metallic oxide-based nanoparticles for conjugation with cell targeting agents. J Am Chem Soc 126:7206–7211

    Article  CAS  Google Scholar 

  • Kumar H, Kawai T, Kato H, Sato S, Takahashi K, Coban C, Yamamoto M, Uematsu S, Ishii KJ, Takeuchi O, Akira S (2006) Essential role of IPS-1 in innate immune responses against RNA viruses. J Exp Med 203:1795–1803

    Article  CAS  Google Scholar 

  • Liu Y, Bryantsev VS, Diallo MS, Goddard WA (2009) PAMAM dendrimers undergo pH responsive conformational changes without swelling. J Am Chem Soc 131:2798–2799

    Article  CAS  Google Scholar 

  • Ludeman SM (1999) The chemistry of the metabolites of cyclophosphamide. Curr Pharm Des 5:627–644

    CAS  Google Scholar 

  • Maiti PK, Çağın T, Lin ST, Goddard WA (2005) Effect of solvent and pH on the structure of PAMAM dendrimers. Macromolecules 38:979–991

    Article  CAS  Google Scholar 

  • Matsumoto M, Funami K, Oshiumi H, Seya T (2004) Toll-like receptor 3: a link between toll-like receptor, interferon and viruses. Microbiol Immunol 48:147–154

    CAS  Google Scholar 

  • McBain SC, Yiu HHP, Haj AE, Dobson J (2007) Polyethyleneimine functionalized iron oxide nanoparticles as agents for DNA delivery and transfection. J Mater Chem 17:2561–2565

    Article  CAS  Google Scholar 

  • Meyer J, Weinmann JP (1957) Occurrence of phosphamidase activity in keratinizing epithelia1. J Investig Dermatol 29:393–405

    CAS  Google Scholar 

  • Milhaud PG, Machy P, Lebleu B, Leserman L (1989) Antibody targeted liposomes containing poly(rI).poly(rC) exert a specific antiviral and toxic effect on cells primed with interferons alpha/beta or gamma. Biochim Biophys Acta 987:15–20

    Article  CAS  Google Scholar 

  • Milhaud PG, Compagnon B, Bienvenue A, Philippot JR (1992) Interferon production of 1929 and hela cells, enhanced by polyriboinosinic acid-polyribocytidylic acid pH-sensitive liposomes. Bioconjug Chem 3:402–407

    Article  CAS  Google Scholar 

  • Mornet S, Vasseur S, Grasset F, Duguet E (2004) Magnetic nanoparticle design for medical diagnosis and therapy. J Mater Chem 14:2161–2175

    Article  CAS  Google Scholar 

  • Okada H (2009) Brain tumor immunotherapy with type-1 polarizing strategies. Ann NY Acad Sci 1174:18–23

    Article  CAS  Google Scholar 

  • Pan B, Cui D, Sheng Y, Ozkan C, Gao F, He R, Li Q, Xu P, Huang T (2007) Dendrimer-modified magnetic nanoparticles enhance efficiency of gene delivery system. Cancer Res 67:8156–8163

    Article  CAS  Google Scholar 

  • Patri AK, István JM, Baker JR (2002) Dendritic polymer macromolecular carriers for drug delivery. Curr Opin Chem Biol 6:466–471

    Article  CAS  Google Scholar 

  • Salaun B, Greutert M, Romero P (2009) Toll-like receptor 3 is necessary for dsRNA adjuvant effects. Vaccine 27:1841–1847

    Article  CAS  Google Scholar 

  • Salem ML, El-Naggar SA, Kadima A, Gillanders WE, Cole DJ (2006) The adjuvant effects of the toll-like receptor 3 ligand polyinosinic-cytidylic acid poly (I:C) on antigen-specific CD8 + T cell responses are partially dependent on NK cells with the induction of a beneficial cytokine milieu. Vaccine 24:5119–5132

    Article  CAS  Google Scholar 

  • Salvador A, Igartua M, Hernandez RM, Pedraz JL (2012) Combination of immune stimulating adjuvants with poly(lactide-co-glycolide) microspheres enhances the immune response of vaccines. Vaccine 30:589–596

    Article  CAS  Google Scholar 

  • Sanz V, Conde J, Hernandez Y, Baptista PV, Ibarra MR, Fuente JM (2012) Effect of PEG biofunctional spacers and TAT peptide on dsRNA loading on gold nanoparticles. J Nanopart Res 14:917–925

    Article  CAS  Google Scholar 

  • Schaffert D, Kiss M, Rödl W, Shir A, Levitzki A, Ogris M, Wagner E (2011) Poly(I:C)-mediated tumor growth suppression in EGF-receptor overexpressing tumors using EGF-polyethylene glycol-linear polyethylenimine as carrier. Pharm Res 28:731–741

    Article  CAS  Google Scholar 

  • Schlosser E, Mueller M, Fischer S, Basta S, Busch DH, Gander B, Groettrup M (2008) TLR ligands and antigen need to be coencapsulated into the same biodegradable microsphere for the generation of potent cytotoxic T lymphocyte responses. Vaccine 26:1626–1637

    Article  CAS  Google Scholar 

  • Schulz O, Diebold SS, Chen M, Näslund TI, Nolte MA, Alexopoulou L, Azuma YT, Flavell RA, Liljeström P, Reis e Sousa C (2005) Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature 433:887–892

    Article  CAS  Google Scholar 

  • Seib FP, Jones AT, Duncan R (2007) Comparison of the endocytic properties of linear and branched PEIs, and cationic PAMAM dendrimers in B16f10 melanoma cells. J Control Release 117:291–300

    Article  CAS  Google Scholar 

  • Sheehan J, Cruickshank P, Boshart G (1961) A convenient synthesis of water-soluble carbodiimides. J Org Chem 26:2525

    Article  CAS  Google Scholar 

  • Shen T, Weissleder R, Papisov M, Bogdanov A, Brady TJ (1993) Monocrystalline iron oxide nanocompounds (MION): physicochemical properties. Magn Reson Med 29:599–604

    Article  CAS  Google Scholar 

  • Shir A, Ogris M, Wagner E, Levitzki A (2006) EGF receptor-targeted synthetic double-stranded RNA eliminates glioblastoma, breast cancer, and adenocarcinoma tumors in mice. PLoS Med 3(1):e6

    Article  Google Scholar 

  • Shukoor MI, Natalio F, Ksenofontov V, Tahir MN, Eberhardt M, Theato P, Schröder HC, Müller WE, Tremel W (2007) Double-stranded RNA polyinosinic-polycytidylic acid immobilized onto gamma-Fe2O3 nanoparticles by using a multifunctional polymeric linker. Small 3:1374–1378

    Article  CAS  Google Scholar 

  • Shukoor MI, Natalio F, Metz N, Glube N, Tahir MN, Therese HA, Ksenofontov V, Theato P, Langguth P, Boissel JP, Schröder HC, Müller WE, Tremel W (2008) dsRNA-functionalized multifunctional gamma-Fe2O3 nanocrystals: a tool for targeting cell surface receptors. Angew Chem Int Ed Engl 47:4748–4752

    Article  CAS  Google Scholar 

  • Sun C, Lee JS, Zhang M (2008) Magnetic nanoparticles in MR imaging and drug delivery. Adv Drug Deliv Rev 60:1252–1265

    Article  CAS  Google Scholar 

  • Svenson S, Tomalia DA (2005) Dendrimers in biomedical applications-reflections on the field. Adv Drug Deliv Rev 57:2106–2129

    Article  CAS  Google Scholar 

  • Tabeta K, Georgel P, Janssen E, Du X, Hoebe K, Crozat K, Mudd S, Shamel L, Sovath S, Goode J, Alexopoulou L, Flavell RA, Beutler B (2004) Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc Natl Acad Sci USA 101:3516–3521

    Article  CAS  Google Scholar 

  • Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376

    Article  CAS  Google Scholar 

  • Tincer G, Yerlikaya S, Yagci FC, Kahraman T, Atanur OM, Erbatur O, Gursel I (2011) Immunostimulatory activity of polysaccharide-poly(I:C) nanoparticles. Biomaterials 32:4275–4282

    Article  CAS  Google Scholar 

  • Tomalia DA, Baker H, Dewald J, Hall M, Kallos G, Martin S, Roeck J, Ryder J, Smith P (1986) Dendritic macromolecules: synthesis of starburst dendrimers. Macromolecules 19:2466–2468

    Article  CAS  Google Scholar 

  • Unsoy G, Yalcin S, Khodadust R, Gunduz G, Gunduz U (2012) Synthesis optimization and characterization of chitosan-coated iron oxide nanoparticles produced for biomedical applications. J Nanopart Res 14:964–977

    Article  Google Scholar 

  • Veiseh O, Gunn JW, Zhang M (2010) Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. Adv Drug Deliv Rev 62:284–304

    Article  CAS  Google Scholar 

  • Weber A, Kirejczyk Z, Besch R, Potthoff S, Leverkus M, Häcker G (2010) Proapoptotic signalling through Toll-like receptor-3 involves TRIF-dependent activation of caspase-8 and is under the control of inhibitor of apoptosis proteins in melanoma cells. Cell Death Differ 17:942–951

    Article  CAS  Google Scholar 

  • Whitesides GM (2003) The ‘right’ size in nanobiotechnology. Nat Biotechnol 21:1161–1165

    Article  CAS  Google Scholar 

  • Widder KJ, Senyei AE, Ranney DF (1979) Magnetically responsive microspheres and other carriers for the biophysical targeting of antitumor agents. Adv Pharmacol Chemother 16:213–271

    Article  CAS  Google Scholar 

  • Xiangzhong Z, Miao A, Yuqi G, Xianbin Z, Li W, Xia L, Chengfang Y (2012) Poly I:C-ınduced tumor cell apoptosis mediated by pattern-recognition receptors. Cancer Biother Radiopharm 27:530–534

    Article  Google Scholar 

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Acknowledgments

This study was supported by TÜBİTAK (TBAG-109T949 and TBAG-2215), and Middle East Technical University (BAP-07-02-2010-06).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biotechnology, Middle East Technical University, 06800, Ankara, Turkey

    Rouhollah Khodadust, Gozde Unsoy & Ufuk Gunduz

  2. Central Laboratory, Molecular Biology and Biotechnology R&D Center, Middle East Technical University, 06800, Ankara, Turkey

    Pelin Mutlu

  3. Department of Food Engineering, Ahi Evran University, 40000, Kırşehir, Turkey

    Serap Yalcın

  4. Department of Biological Sciences, Middle East Technical University, 06800, Ankara, Turkey

    Rouhollah Khodadust & Ufuk Gunduz

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  1. Rouhollah Khodadust
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  2. Pelin Mutlu
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  4. Gozde Unsoy
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  5. Ufuk Gunduz
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Correspondence to Rouhollah Khodadust or Ufuk Gunduz.

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Khodadust, R., Mutlu, P., Yalcın, S. et al. Polyinosinic:polycytidylic acid loading onto different generations of PAMAM dendrimer-coated magnetic nanoparticles. J Nanopart Res 15, 1860 (2013). https://doi.org/10.1007/s11051-013-1860-6

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  • DOI: https://doi.org/10.1007/s11051-013-1860-6

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