Riboflavin-Conjugated Multivalent Dendrimer Platform for Cancer-Targeted Drug and Gene Delivery

  • Pamela T. WongEmail author
  • Kumar SinniahEmail author
  • Seok Ki ChoiEmail author
Part of the Nanomedicine and Nanotoxicology book series (NANOMED)


Riboflavin receptors (RFRs) are overexpressed in several malignant cells, and have been characterized as an emerging tumor surface biomarker. In this article, we discuss the design principles of a RFR-targeted nanoparticle system and illustrate its applications with studies performed in our laboratories. This system is based on a poly(amidoamine) (PAMAM) dendritic polymer which is modified on the surface by conjugation with riboflavin (RF) as the targeting ligand. First, we discuss the application of this system for targeted drug delivery by its conjugation with methotrexate as an antitumor payload. In cell-based experiments performed in vitro, this drug conjugate displayed RF-dependent, potent inhibition of cell growth in RFR(+) KB carcinoma cells. Second, the use of the RF-conjugated dendrimer for gene delivery applications through the formation of polyplexes with plasmid DNA is described. The ability of this targeted system to significantly enhance gene transfection in epithelial cells points to its potential as a promising new class of nonviral vectors. Third, the tunability of the functional properties of the dendrimer through modular integration is illustrated with an optically active gold nanoparticle (AuNP). The resultant dendrimer-coated AuNPs have a unique capability for tumor cell imaging via surface plasmon resonance scattering. Finally, we discuss the biophysical basis of the multivalent mechanism involved in the tight and specific binding of a RF-conjugated multivalent dendrimer to RFRs on the cell surface. The design principles and proof of concept studies presented here are strongly supportive of the promising potential of RF-conjugated nanoparticles for delivery and imaging applications in tumors.


Riboflavin Tumor surface marker PAMAM dendrimer Targeted delivery Multivalent avidity Surface plasmon resonance Imaging cavity 



Atomic force microscopy


Bovine serum albumin




Dynamic light scattering


Enhanced permeation and retention


Epidermal growth factor receptor


Fibroblast growth factor receptor


Flavin adenine dinucleotide


Flavin mononucleotide


Fluorescein isothiocyanate


Folate receptor


Generation 5


Gold nanoparticle




Isothermal titration calorimetry






Plasmid DNA




Prostate-specific membrane antigen




Riboflavin binding protein


Riboflavin receptor


Surface plasmon resonance



The authors wish to acknowledge the support from the Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School. SKC acknowledges partial support from the British Council and Department for Business Innovation and Skills through Global Innovation Initiative. KS acknowledges partial support from a Calvin College Research Fellowship.


  1. 1.
    Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R (2007) Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol 2(12):751–760CrossRefGoogle Scholar
  2. 2.
    Wong PT, Choi SK (2015) Mechanisms of drug release in nanotherapeutic delivery systems. Chem Rev (Washington, DC, US) 115(9):3388–3432CrossRefGoogle Scholar
  3. 3.
    Kamaly N, Xiao Z, Valencia PM, Radovic-Moreno AF, Farokhzad OC (2012) Targeted polymeric therapeutic nanoparticles: design, development and clinical translation. Chem Soc Rev 41(7):2971–3010CrossRefGoogle Scholar
  4. 4.
    Maeda H (2001) The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul 41(1):189–207CrossRefGoogle Scholar
  5. 5.
    Zhu J, Shi X (2013) Dendrimer-based nanodevices for targeted drug delivery applications. J Mater Chem B 1(34):4199–4211CrossRefGoogle Scholar
  6. 6.
    Esmaeili F, Ghahremani MH, Ostad SN, Atyabi F, Seyedabadi M, Malekshahi MR, Amini M, Dinarvand R (2008) Folate-receptor-targeted delivery of docetaxel nanoparticles prepared by PLGA–PEG–folate conjugate. J Drug Targ 16(5):415–423CrossRefGoogle Scholar
  7. 7.
    Kelemen LE (2006) The role of folate receptor α in cancer development, progression and treatment: cause, consequence or innocent bystander? Int J Cancer 119(2):243–250CrossRefGoogle Scholar
  8. 8.
    Yang W, Cheng Y, Xu T, Wang X, Wen L-P (2008) Targeting cancer cells with biotin-dendrimer conjugates. Eur J Med Chem 44:862–868CrossRefGoogle Scholar
  9. 9.
    Yellepeddi VK, Kumar A, Palakurthi S (2009) Biotinylated poly(amido)amine (PAMAM) dendrimers as carriers for drug delivery to ovarian cancer cells in vitro. Anticancer Res 29(8):2933–2943Google Scholar
  10. 10.
    Kok RJ, Schraa AJ, Bos EJ, Moorlag HE, Asgeirsdottir SA, Everts M, Meijer DKF, Molema G (2002) Preparation and functional evaluation of RGD-modified proteins as αvβ3 integrin directed therapeutics. Bioconj Chem 13(1):128–135CrossRefGoogle Scholar
  11. 11.
    Pinto JT, Suffoletto BP, Berzin TM, Qiao CH, Lin S, Tong WP, May F, Mukherjee B, Heston WD (1996) Prostate-specific membrane antigen: a novel folate hydrolase in human prostatic carcinoma cells. Clin Cancer Res 2(9):1445–1451Google Scholar
  12. 12.
    Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C (1997) Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res 3(1):81–85Google Scholar
  13. 13.
    Ross JS, Fletcher JA (1998) The HER2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Oncologist 3:237–252Google Scholar
  14. 14.
    Arteaga CL (2002) Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist 7(suppl 4):31–39CrossRefGoogle Scholar
  15. 15.
    Haugsten EM, Wiedlocha A, Olsnes S, Wesche J (2010) Roles of fibroblast growth factor receptors in carcinogenesis. Mol Cancer Res 8(11):1439–1452CrossRefGoogle Scholar
  16. 16.
    Pollak M (2012) The insulin receptor/insulin-like growth factor receptor family as a therapeutic target in oncology. Clin Cancer Res 18(1):40–50CrossRefGoogle Scholar
  17. 17.
    Herbison CE, Thorstensen K, Chua ACG, Graham RM, Leedman P, Olynyk JK, Trinder D (2009) The role of transferrin receptor 1 and 2 in transferrin-bound iron uptake in human hepatoma cells. Am J Physiol Cell Physiol 297(6):C1567–C1575CrossRefGoogle Scholar
  18. 18.
    Bareford LM, Swaan PW (2007) Endocytic mechanisms for targeted drug delivery. Adv Drug Deliv Rev 59(8):748–758CrossRefGoogle Scholar
  19. 19.
    Karande AA, Sridhar L, Gopinath KS, Adiga PR (2001) Riboflavin carrier protein: a serum and tissue marker for breast carcinoma. Int J Cancer 95:277–281CrossRefGoogle Scholar
  20. 20.
    Johnson T, Ouhtit A, Gaur R, Fernando A, Schwarzenberger P, Su J, Ismail MF, El-Sayyad HI, Karande A, Elmageed ZA, Rao P, Raj M (2009) Biochemical characterization of riboflavin carrier protein (RCP) in prostate cancer. Front Biosci Landmark Ed 14:3634–3640CrossRefGoogle Scholar
  21. 21.
    Holladay SR, Yang Z-F, Kennedy MD, Leamon CP, Lee RJ, Jayamani M, Mason T, Low PS (1999) Riboflavin-mediated delivery of a macromolecule into cultured human cells. Biochim Biophys Acta Gen Subj 1426(1):195–204CrossRefGoogle Scholar
  22. 22.
    Phelps MA, Foraker AB, Gao W, Dalton JT, Swaan PW (2004) A novel rhodamine-riboflavin conjugate probe exhibits distinct fluorescence resonance energy transfer that enables riboflavin trafficking and subcellular localization studies. Mol Pharm 1(4):257–266CrossRefGoogle Scholar
  23. 23.
    Huang S-N, Swaan PW (2000) Involvement of a receptor-mediated component in cellular translocation of riboflavin. J Pharmacol Exp Ther 294(1):117–125Google Scholar
  24. 24.
    Leistra AN, Han JH, Tang S, Orr BG, Banaszak Holl MM, Choi SK, Sinniah K (2015) Force spectroscopy of multivalent binding of riboflavin-conjugated dendrimers to riboflavin binding protein. J Phys Chem B 119(18):5785–5792CrossRefGoogle Scholar
  25. 25.
    Plantinga A, Witte A, Li M-H, Harmon A, Choi SK, Banaszak Holl MM, Orr BG, Baker JR Jr, Sinniah K (2011) Bioanalytical screening of riboflavin antagonists for targeted drug delivery: a thermodynamic and kinetic study. ACS Med Chem Lett 2(5):363–367CrossRefGoogle Scholar
  26. 26.
    Thomas TP, Choi SK, Li M-H, Kotlyar A, Baker JR Jr (2010) Design of riboflavin-presenting PAMAM dendrimers as a new nanoplatform for cancer-targeted delivery. Bioorg Med Chem Lett 20:5191–5194CrossRefGoogle Scholar
  27. 27.
    Witte AB, Leistra AN, Wong PT, Bharathi S, Refior K, Smith P, Kaso O, Sinniah K, Choi SK (2014) Atomic force microscopy probing of receptor-nanoparticle interactions for riboflavin receptor targeted gold-dendrimer nanocomposites. J Phys Chem B 118(11):2872–2882CrossRefGoogle Scholar
  28. 28.
    Witte AB, Timmer CM, Gam JJ, Choi SK, Banaszak Holl MM, Orr BG, Baker JR, Sinniah K (2012) Biophysical characterization of a riboflavin-conjugated dendrimer platform for targeted drug delivery. Biomacromol 13:507–516CrossRefGoogle Scholar
  29. 29.
    Beztsinna N, Solé M, Taib N, Bestel I (2016) Bioengineered riboflavin in nanotechnology. Biomaterials 80:121–133CrossRefGoogle Scholar
  30. 30.
    Marlin F, Simon P, Bonneau S, Alberti P, Cordier C, Boix C, Perrouault L, Fossey A, Saison-Behmoaras T, Fontecave M, Giovannangeli C (2012) Flavin conjugates for delivery of peptide nucleic acids. ChemBioChem 13(17):2593–2598CrossRefGoogle Scholar
  31. 31.
    Bareford LM, Avaritt BR, Ghandehari H, Nan A, Swaan PW (2013) Riboflavin-targeted polymer conjugates for breast tumor delivery. Pharm Res 30(7):1799–1812CrossRefGoogle Scholar
  32. 32.
    Jayapaul J, Arns S, Bunker M, Weiler M, Rutherford S, Comba P, Kiessling F (2016) In vivo evaluation of riboflavin receptor targeted fluorescent USPIO in mice with prostate cancer xenografts. Nano Res 9(5):1319–1333CrossRefGoogle Scholar
  33. 33.
    Lu Y, Low PS (2002) Folate-mediated delivery of macromolecular anticancer therapeutic agents. Adv Drug Deliv Rev 54(5):675–693CrossRefGoogle Scholar
  34. 34.
    Low PS, Henne WA, Doorneweerd DD (2008) Discovery and development of folic-acid-based receptor targeting for imaging and therapy of cancer and inflammatory diseases. Acc Chem Res 41(1):120–129CrossRefGoogle Scholar
  35. 35.
    Wang H-L, Wang S-S, Song W-H, Pan Y, Yu H-P, Si T-G, Liu Y, Cui X-N, Guo Z (2015) Expression of prostate-specific membrane antigen in lung cancer cells and tumor neovasculature endothelial cells and its clinical significance. PLoS ONE 10(5):e0125924CrossRefGoogle Scholar
  36. 36.
    Shukla R, Thomas TP, Peters JL, Desai AM, Kukowska-Latallo J, Patri AK, Kotlyar A, Baker JR (2006) HER2 specific tumor targeting with dendrimer conjugated anti-HER2 mAb. Bioconj Chem 17(5):1109–1115CrossRefGoogle Scholar
  37. 37.
    Mamot C, Drummond DC, Greiser U, Hong K, Kirpotin DB, Marks JD, Park JW (2003) Epidermal growth factor receptor (EGFR)-targeted immunoliposomes mediate specific and efficient drug delivery to EGFR- and EGFRvIII-overexpressing tumor cells. Cancer Res 63(12):3154–3161Google Scholar
  38. 38.
    Foraker AB, Khantwal CM, Swaan PW (2003) Current perspectives on the cellular uptake and trafficking of riboflavin. Adv Drug Deliv Rev 55(11):1467–1483CrossRefGoogle Scholar
  39. 39.
    Wu AML, Dedina L, Dalvi P, Yang M, Leon-Cheon J, Earl B, Harper PA, Ito S (2016) Riboflavin uptake transporter Slc52a2 (RFVT2) is upregulated in the mouse mammary gland during lactation. Am J Physiol Regul Integr Comp Physiol 310(7):R578–R585CrossRefGoogle Scholar
  40. 40.
    Yonezawa A, Inui K-I (2013) Novel riboflavin transporter family RFVT/SLC52: identification, nomenclature, functional characterization and genetic diseases of RFVT/SLC52. Mol Aspects Med 34(2–3):693–701CrossRefGoogle Scholar
  41. 41.
    White HB, Merrill AH (1988) Riboflavin-binding proteins. Annu Rev Nutr 8(1):279–299CrossRefGoogle Scholar
  42. 42.
    Wong PT, Tang K, Coulter A, Tang S, Baker JR, Choi SK (2014) Multivalent dendrimer vectors with DNA intercalation motifs for gene delivery. Biomacromol 15(11):4134–4145CrossRefGoogle Scholar
  43. 43.
    Miranda-Lorenzo I, Dorado J, Lonardo E, Alcala S, Serrano AG, Clausell-Tormos J, Cioffi M, Megias D, Zagorac S, Balic A, Hidalgo M, Erkan M, Kleeff J, Scarpa A, Sainz B Jr, Heeschen C (2014) Intracellular autofluorescence: a biomarker for epithelial cancer stem cells. Nat Methods 11(11):1161–1169CrossRefGoogle Scholar
  44. 44.
    Zheng DB, Lim HM, Pène JJ, White HB (1988) Chicken riboflavin-binding protein. cDNA sequence and homology with milk folate-binding protein. J Biol Chem 263(23):11126–11129Google Scholar
  45. 45.
    Monaco HL (1997) Crystal structure of chicken riboflavin-binding protein. EMBO J 16(7):1475–1483CrossRefGoogle Scholar
  46. 46.
    Huang S-N, Phelps MA, Swaan PW (2003) Involvement of endocytic organelles in the subcellular trafficking and localization of riboflavin. J Pharmacol Exp Ther 306(2):681–687CrossRefGoogle Scholar
  47. 47.
    Mack M, Grill S (2006) Riboflavin analogs and inhibitors of riboflavin biosynthesis. Appl Microbiol Biotechnol 71(3):265–275CrossRefGoogle Scholar
  48. 48.
    Chu CK, Bardos TJ (1977) Synthesis and inhibition analysis of 2(4)-imino-4(2)-amino-2,4-dideoxyriboflavin, a dual antagonist of riboflavin and folinic acid. J Med Chem 20(2):312–314CrossRefGoogle Scholar
  49. 49.
    Musser EA, Heinle RW (1958) The effect of a riboflavin antagonist upon leukocytes of normal and shay myeloid chloroleukemic rats. Blood 13(5):464–474Google Scholar
  50. 50.
    Choi S-K (2004) Synthetic multivalent molecules: concepts and biomedical applications. Wiley, New JerseyCrossRefGoogle Scholar
  51. 51.
    Mammen M, Choi SK, Whitesides GM (1998) Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors. Angew Chem Int Ed 37:2754–2794CrossRefGoogle Scholar
  52. 52.
    Fasting C, Schalley CA, Weber M, Seitz O, Hecht S, Koksch B, Dernedde J, Graf C, Knapp E-W, Haag R (2012) Multivalency as a chemical organization and action principle. Angew Chem Int Ed 51(42):10472–10498CrossRefGoogle Scholar
  53. 53.
    Caelen I, Kalman A, Wahlstrom L (2003) Biosensor-based determination of riboflavin in milk samples. Anal Chem 76(1):137–143CrossRefGoogle Scholar
  54. 54.
    Wu FYH, MacKenzie RE, McCormick DB (1970) Kinetics and mechanism of oxidation-reduction reactions between pyridine nucleotides and flavins. Biochemistry 9(11):2219–2224CrossRefGoogle Scholar
  55. 55.
    Tomalia DA, Naylor AM, Goddard WA (1990) Starburst dendrimers: molecular-level control of size, shape, surface chemistry, topology, and flexibility from atoms to macroscopic matter. Angew Chem Int Ed 29(2):138–175CrossRefGoogle Scholar
  56. 56.
    Wong P, Tang S, Mukherjee J, Tang K, Gam K, Isham D, Murat C, Sun R, Baker JR, Choi SK (2016) Light-controlled active release of photocaged ciprofloxacin for lipopolysaccharide-targeted drug delivery using dendrimer conjugates. Chem Commun (Cambridge UK) 52:10357–10360CrossRefGoogle Scholar
  57. 57.
    Wong PT, Chen D, Tang S, Yanik S, Payne M, Mukherjee J, Coulter A, Tang K, Tao K, Sun K, Baker JR Jr, Choi SK (2015) Modular integration of upconversion nanocrystal-dendrimer composites for folate receptor-specific near infrared imaging and light triggered drug release. Small 11(45):6078–6090CrossRefGoogle Scholar
  58. 58.
    Cloninger MJ (2002) Biological applications of dendrimers. Curr Opin Chem Biol 6(6):742–748CrossRefGoogle Scholar
  59. 59.
    Esfand R, Tomalia DA (2001) Poly(amidoamine) (PAMAM) dendrimers: from biomimicry to drug delivery and biomedical applications. Drug Discov Today 6(8):427–436CrossRefGoogle Scholar
  60. 60.
    Majoros I, Baker J Jr (eds) (2008) Dendrimer-based nanomedicine. Pan Stanford, HackensackGoogle Scholar
  61. 61.
    Medina SH, El-Sayed MEH (2009) Dendrimers as carriers for delivery of chemotherapeutic agents. Chem Rev (Washington, DC, US) 109(7):3141–3157CrossRefGoogle Scholar
  62. 62.
    Rosowsky A, Forsch RA, Wright JE (2004) Synthesis and in vitro antifolate activity of rotationally restricted aminopterin and methotrexate analogues. J Med Chem 47(27):6958–6963CrossRefGoogle Scholar
  63. 63.
    Kiessling LL, Gestwicki JE, Strong LE (2000) Synthetic multivalent ligands in the exploration of cell-surface interactions. Curr Opin Chem Biol 4(6):696–703CrossRefGoogle Scholar
  64. 64.
    Horowitz ED, Hud NV (2006) Ethidium and proflavine binding to a 2′,5′-Linked RNA duplex. J Am Chem Soc 128(48):15380–15381CrossRefGoogle Scholar
  65. 65.
    Sankaran NB, Nishizawa S, Seino T, Yoshimoto K, Teramae N (2006) Abasic-site-containing oligodeoxynucleotides as aptamers for riboflavin. Angew Chem Int Ed 45(10):1563–1568CrossRefGoogle Scholar
  66. 66.
    Luo D, Saltzman WM (2000) Synthetic DNA delivery systems. Nat Biotechnol 18(1):33–37CrossRefGoogle Scholar
  67. 67.
    Herd H, Daum N, Jones AT, Huwer H, Ghandehari H, Lehr C-M (2013) Nanoparticle geometry and surface orientation influence mode of cellular uptake. ACS Nano 7(3):1961–1973CrossRefGoogle Scholar
  68. 68.
    Giljohann DA, Seferos DS, Daniel WL, Massich MD, Patel PC, Mirkin CA (2010) Gold nanoparticles for biology and medicine. Angew Chem Int Ed 49(19):3280–3294CrossRefGoogle Scholar
  69. 69.
    Daniel M-C, Astruc D (2004) Gold nanoparticles; assembly, supramolecular chemistry, quantum-size-related properties, and applications toward biology, catalysis, and nanotechnology. Chem Rev (Washington, DC, US) 104(1):293–346CrossRefGoogle Scholar
  70. 70.
    El-Sayed IH, Huang X, El-Sayed MA (2005) Surface plasmon resonance scattering and absorption of anti-EGFR antibody conjugated gold nanoparticles in cancer diagnostics: applications in oral cancer. Nano Lett 5(5):829–834CrossRefGoogle Scholar
  71. 71.
    El-Sayed IH, Huang X, El-Sayed MA (2006) Selective laser photo-thermal therapy of epithelial carcinoma using anti-EGFR antibody conjugated gold nanoparticles. Cancer Lett (NY, NY, US) 239(1):129–135CrossRefGoogle Scholar
  72. 72.
    Qian W, Huang X, Kang B, El-Sayed MA (2010) Dark-field light scattering imaging of living cancer cell component from birth through division using bioconjugated gold nanoprobes. J Biomed Opt 15(4):46025–46029CrossRefGoogle Scholar
  73. 73.
    Klein S, Petersen S, Taylor U, Barcikowski S, Rath D (2010) Quantitative visualization of colloidal and intracellular gold nanoparticles by confocal microscopy. J Biomed Opt 15(3):36015CrossRefGoogle Scholar
  74. 74.
    Lee YC, Lee RT (1995) Carbohydrate-protein interactions: basis of glycobiology. Acc Chem Res 28(8):321–327CrossRefGoogle Scholar
  75. 75.
    Choi S-K, Mammen M, Whitesides GM (1997) Generation and in situ evaluation of libraries of poly(acrylic acid) presenting sialosides as side chains as polyvalent inhibitors of influenza-mediated hemagglutination. J Am Chem Soc 119(18):4103–4111CrossRefGoogle Scholar
  76. 76.
    Jayaraman N (2009) Multivalent ligand presentation as a central concept to study intricate carbohydrate-protein interactions. Chem Soc Rev 38(12):3463–3483CrossRefGoogle Scholar
  77. 77.
    Hong S, Leroueil PR, Majoros IJ, Orr BG, Baker JR Jr, Banaszak Holl MM (2007) The binding avidity of a nanoparticle-based multivalent targeted drug delivery platform. Chem Biol (Oxford UK) 14(1):107–115Google Scholar
  78. 78.
    Li X, Zhou H, Yang L, Du G, Pai-Panandiker AS, Huang X, Yan B (2011) Enhancement of cell recognition in vitro by dual-ligand cancer targeting gold nanoparticles. Biomaterials 32(10):2540–2545CrossRefGoogle Scholar
  79. 79.
    Silpe JE, Sumit M, Thomas TP, Huang B, Kotlyar A, van Dongen MA, Banaszak Holl MM, Orr BG, Choi SK (2013) Avidity modulation of folate-targeted multivalent dendrimers for evaluating biophysical models of cancer targeting nanoparticles. ACS Chem Biol 8(9):2063–2071CrossRefGoogle Scholar
  80. 80.
    Li M-H, Choi SK, Thomas TP, Desai A, Lee K-H, Kotlyar A, Banaszak Holl MM, Baker JR Jr (2012) Dendrimer-based multivalent methotrexates as dual acting nanoconjugates for cancer cell targeting. Eur J Med Chem 47:560–572CrossRefGoogle Scholar
  81. 81.
    Thomas TP, Huang B, Choi SK, Silpe JE, Kotlyar A, Desai AM, Gam J, Joice M Jr (2012) Polyvalent PAMAM-methotrexate dendrimer as a folate receptor-targeted therapeutic. Mol Pharm 9(9):2669–2676CrossRefGoogle Scholar
  82. 82.
    Thomas TP, Joice M, Sumit M, Silpe JE, Kotlyar A, Bharathi S, Kukowska-Latallo J, Baker JR, Choi SK (2013) Design and in vitro validation of multivalent dendrimer methotrexates as a folate-targeting anticancer therapeutic. Curr Pharm Des 19(37):6594–6605CrossRefGoogle Scholar
  83. 83.
    Wong P, Choi SK (2015) Mechanisms and implications of dual-acting methotrexate in folate-targeted nanotherapeutic delivery. Int J Mol Sci 16(1):1772–1790CrossRefGoogle Scholar
  84. 84.
    Choi SK, Myc A, Silpe JE, Sumit M, Wong PT, McCarthy K, Desai AM, Thomas TP, Kotlyar A, Banaszak Holl MM, Orr BG, Baker JR (2013) Dendrimer-based multivalent vancomycin nanoplatform for targeting the drug-resistant bacterial surface. ACS Nano 7(1):214–228CrossRefGoogle Scholar
  85. 85.
    Krishnamurthy VM, Quinton LJ, Estroff LA, Metallo SJ, Isaacs JM, Mizgerd JP, Whitesides GM (2006) Promotion of opsonization by antibodies and phagocytosis of gram-positive bacteria by a bifunctional polyacrylamide. Biomaterials 27(19):3663–3674Google Scholar
  86. 86.
    Qi G, Li L, Yu F, Wang H (2013) Vancomycin-modified mesoporous silica nanoparticles for selective recognition and killing of pathogenic gram-positive bacteria over macrophage-like cells. ACS Appl Mater Interfaces 5(21):10874–10881CrossRefGoogle Scholar
  87. 87.
    Kell AJ, Stewart G, Ryan S, Peytavi R, Boissinot M, Huletsky A, Bergeron MG, Simard B (2008) Vancomycin-modified nanoparticles for efficient targeting and preconcentration of gram-positive and gram-negative bacteria. ACS Nano 2(9):1777–1788CrossRefGoogle Scholar
  88. 88.
    Li M-H, Choi SK, Leroueil PR, Baker JR (2014) Evaluating binding avidities of populations of heterogeneous multivalent ligand-functionalized nanoparticles. ACS Nano 8(6):5600–5609CrossRefGoogle Scholar
  89. 89.
    Choi S-K, Mammen M, Whitesides GM (1996) Monomeric inhibitors of influenza neuraminidase enhance the hemagglutination inhibition activities of polyacrylamides presenting multiple C-sialoside groups. Chem Biol (Oxford UK) 3:97–104Google Scholar
  90. 90.
    Bhatia S, Dimde M, Haag R (2014) Multivalent glycoconjugates as vaccines and potential drug candidates. MedChemComm 5(7):862–878CrossRefGoogle Scholar
  91. 91.
    Zhou H, Jiao P, Yang L, Li X, Yan B (2010) Enhancing cell recognition by scrutinizing cell surfaces with a nanoparticle array. J Am Chem Soc 133(4):680–682CrossRefGoogle Scholar
  92. 92.
    Mintzer MA, Dane EL, O’Toole GA, Grinstaff MW (2011) Exploiting dendrimer multivalency to combat emerging and re-emerging infectious diseases. Mol Pharm 9(3):342–354CrossRefGoogle Scholar
  93. 93.
    Bromfield SM, Posocco P, Fermeglia M, Tolosa J, Herreros-López A, Pricl S, Rodríguez-López J, Smith DK (2014) Shape-persistent and adaptive multivalency: rigid transgeden (TGD) and flexible PAMAM dendrimers for heparin binding. Chem Eur J 20(31):9666–9674CrossRefGoogle Scholar
  94. 94.
    Bhatia S, Camacho LC, Haag R (2016) Pathogen inhibition by multivalent ligand architectures. J Am Chem Soc 138(28):8654–8666CrossRefGoogle Scholar
  95. 95.
    Hlavacek WS, Posner RG, Perelson AS (1999) Steric effects on multivalent ligand-receptor binding: exclusion of ligand sites by bound cell surface receptors. Biophys J 76(6):3031–3043CrossRefGoogle Scholar
  96. 96.
    Howard M, Zern BJ, Anselmo AC, Shuvaev VV, Mitragotri S, Muzykantov V (2014) Vascular targeting of nanocarriers: perplexing aspects of the seemingly straightforward paradigm. ACS Nano 8(5):4100–4132CrossRefGoogle Scholar
  97. 97.
    Choi SK, Leroueil P, Li M-H, Desai A, Zong H, Van Der Spek AFL, Baker JR Jr (2011) Specificity and negative cooperativity in dendrimer-oxime drug complexation. Macromolecules 44(11):4026–4029CrossRefGoogle Scholar
  98. 98.
    Gomez-Casado A, Dam HH, Yilmaz MD, Florea D, Jonkheijm P, Huskens J (2011) Probing multivalent interactions in a synthetic host-guest complex by dynamic force spectroscopy. J Am Chem Soc 133(28):10849–10857CrossRefGoogle Scholar
  99. 99.
    Roy R (1996) Syntheses and some applications of chemically defined multivalent glycoconjugates. Curr Opin Struct Biol 6(5):692–702CrossRefGoogle Scholar
  100. 100.
    Mullen DG, Fang M, Desai A, Baker JR Jr, Orr BG, Banaszak Holl MM (2010) A quantitative assessment of nanoparticle-ligand distributions: implications for targeted drug and imaging delivery in dendrimer conjugates. ACS Nano 4(2):657–670CrossRefGoogle Scholar
  101. 101.
    Teulon J-M, Delcuze Y, Odorico M, S-wW Chen, Parot P, Pellequer J-L (2011) Single and multiple bonds in (strept)avidin-biotin interactions. J Mol Recognit 24(3):490–502CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Michigan Nanotechnology Institute for Medicine and Biological Sciences, and Department of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborUSA
  2. 2.Department of Chemistry and BiochemistryCalvin CollegeGrand RapidsUSA

Personalised recommendations