Skip to main content

Influence of dendrimers on red blood cells

Abstract

Dendrimers, highly branched macromolecules with a specific size and shape, provide many exciting opportunities for biomedical applications. However, most dendrimers demonstrate toxic and haemolytic activity because of their positively charged surface. Masking the peripheral cationic groups by coating them with biocompatible molecules is a method to reduce it. It was proven that modified dendrimers can even diminish haemolytic activity of encapsulated drugs. Experiments confirmed that anionic dendrimers are less haemotoxic than cationic ones. Due to the high affinity of dendrimers for serum proteins, presence of these components in an incubation buffer might also influence red blood cell (RBC)-dendrimer interactions and decrease the haemolysis level. Generally, haemotoxicity of dendrimers is concentration-, generation-, and time-dependent. Various changes in the RBCs’ shape in response to interactions with dendrimers have been observed, from echinocytic transformations through cell aggregation to cluster formation, depending on the dendrimer’s type and concentration. Understanding the physical and chemical origins of dendrimers’ influences on RBCs might advance scientists’ ability to construct dendrimers more suitable for medical applications.

Abbreviations

AFM:

atomic force microscopy

CSi:

carbosilane dendrimers

DOX:

doxorubicin

FA:

folic acid

HSA:

human serum albumin

MRI:

magnetic resonance imaging

PAD-PPI:

dextran conjugated PPI dendrimers

PAMAM:

polyamidoamine dendrimers

PEG:

poly(ethylene glycol)

PEO:

poly(ethylene oxide)

PPI:

poly(propyleneimine) dendrimers

PPI-DAB:

PPI dendrimers with diaminobutane core

PPI-DAE:

PPI dendrimers with diaminoethane core

RBCs:

red blood cells

Rms:

AFM roughness values

References

  1. 1.

    Tomalia, D.A., Baker, H., Dewald, J.R., Hall, M., Kallos, G., Martin, S., Roeck, S., Ryder, J. and Smith, P. A new class of polymers: Starburstdendric macromolecules. Polym. J. 17 (1985) 117–132.

    CAS  Article  Google Scholar 

  2. 2.

    Newkome, G.R., Yao, Z.Q., Baker, G.R. and Gupta, V.K. Cascade molecules: A new approach to micelles, A[27]-arborol. J. Org. Chem. 50 (1985) 2003–2006.

    CAS  Article  Google Scholar 

  3. 3.

    Tomalia, D.A., Naylor, A.M. and Goddard III, W.A. Starburst Dendrimers: Molecular-Level Control of Size, Shape, Surface Chemistry, Topology, and Flexibility from Atoms to Macroscopic Matter. Angew. Chem. Int. Ed. Engl. 29 (1990) 138–175.

    Article  Google Scholar 

  4. 4.

    Dykes, G.M., Brierley, L.J., Smith, D.K., McGrail, P.T. and Seeley, G.J. Supramolecular solubilisation of hydrophilic dyes by using individual dendritic branches. Chemistry 7(21) (2001) 4730–4739.

    PubMed  CAS  Article  Google Scholar 

  5. 5.

    Frechet, J.M.J. Dendrimers and supramolecular chemistry. Proc. Natl. Acad. Sci. U. S. A. 99 (2002) 4782–4787.

    PubMed  CAS  Article  Google Scholar 

  6. 6.

    Lee, C.C., MacKay, J.A., Fréchet, J.M. and Szoka, F.C. Designing dendrimers for biological applications. Nat. Biotechnol. 23 (2005) 1517–1526.

    PubMed  CAS  Article  Google Scholar 

  7. 7.

    Domanski, D.M., Klajnert, B. and Bryszewska, M. Influence of PAMAM dendrimers on human red blood cells. Bioelectrochemistry 63 (2004) 189–191.

    PubMed  CAS  Article  Google Scholar 

  8. 8.

    Dykes, G.M. Dendrimers: a review of their appeal and applications. J. Chem. Technol. Biotechnol. 79 (2001) 903–918.

    Article  Google Scholar 

  9. 9.

    Bumb, A., Brechbiel, M.W. and Choyke, P. Macromolecular and dendrimerbased magnetic resonance contrast agents. Acta Radiol. 51 (2010) 751–767.

    PubMed  Article  Google Scholar 

  10. 10.

    Bourne, M. W., Margerun, L., Hylton, N., Campion, B., Lai, J. J., Derugin, N. and Higgins, C.B. Evaluation of the effects of intravascular MR contrast media (gadolinium dendrimer) on 3D time of flight magnetic resonance angiography of the body. J. Magn. Reson. Imaging 6 (1996) 305–310.

    Article  Google Scholar 

  11. 11.

    Boas, U. and Heegaard, P.M. Dendrimers in drug research. Chem. Soc. Rev. 33 (2004) 43–63.

    PubMed  CAS  Article  Google Scholar 

  12. 12.

    Malik, N., Wiwattanapatapee, R., Klopsch, R., Lorenz, K., Frey, H., Weener, J.W., Meijer, E.W., Paulus, W. and Duncan, R. Dendrimers: relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I-labelled polyamidoamine dendrimers in vivo. J. Control Release 65 (2000) 133–148.

    PubMed  CAS  Article  Google Scholar 

  13. 13.

    Bhadra, D., Yadav, A.K., Bandra, S. and Jain, N.K. Glycodendrimeric nanoparticulate carriers of primaquine phosphate for liver targeting. Int. J. Pharm. 295 (2005) 221–223.

    PubMed  CAS  Article  Google Scholar 

  14. 14.

    Bhadra, D., Bhadra, S. and Jain, N.K. PEGylated peptide dendrimeric carriers for the delivery of antimalarial drug chloroquine phosphate. Pharm. Res. 23 (2006) 623–633.

    PubMed  CAS  Article  Google Scholar 

  15. 15.

    Lee, H. and Larson, R.G. Lipid bilayer curvature and pore formation induced by charged linear polymers and dendrimers: the effect of molecular shape. J. Phys. Chem. B 112 (2008) 12279–12285.

    PubMed  CAS  Article  Google Scholar 

  16. 16.

    Choi, S.H., Lee, S.H. and Park, T.G., Temperature-sensitive pluronic/poly(ethylenimine) nanocapsules for thermally triggered disruption of intracellular endosomal compartment. Biomacromolecules 7 (2006) 1864–1870.

    PubMed  CAS  Article  Google Scholar 

  17. 17.

    Dutta, T., Jain, N.K., McMillan, N.A. and Parekh, H.S. Dendrimer nanocarriers as versatile vectors in gene delivery. Nanomedicine 6 (2010) 25–34.

    PubMed  CAS  Article  Google Scholar 

  18. 18.

    Pedziwiatr-Werbicka, E., Ferenc, M., Zaborski, M., Gabara, B., Klajnert, B. and Bryszewska, M. Characterization of complexes formed by polypropylene imine dendrimers and anti-HIV oligonucleotides. Colloids Surf. B. Biointerfaces 83 (2011) 360–366.

    PubMed  CAS  Article  Google Scholar 

  19. 19.

    Wilbur, D., Pathare, P., Hamlin, D., Bhular, K. and Vessela, R. Biotin reagents for antibody pretargeting: Synthesis, radioiodination, and evaluation of biotinylated starburst dendrimers. Bioconj. Chem. 9 (1998) 813–825.

    CAS  Article  Google Scholar 

  20. 20.

    Singh, P., Gupta, U., Asthana, A. and Jain, N.K. Folate and Folate-PEGPAMAM Dendrimers: Synthesis, Characterization, and Targeted Anticancer Drug Delivery Potential in Tumor Bearing Mice. Bioconjug. Chem. 19 (2008) 2239–2252.

    PubMed  CAS  Article  Google Scholar 

  21. 21.

    Wang, Y., Guo, R., Cao, X., Shen, M., and Shi, X. Encapsulation of 2-methoxyestradiol within multifunctional poly(amidoamine) dendrimers for targeted cancer therapy. Biomaterials 32 (2011) 3322–3329

    PubMed  CAS  Article  Google Scholar 

  22. 22.

    Zhang, T.L., Gao, Y.X., Lu, J.F. and Wang, K. Arsenite, arsenate and vanadate affect human erythrocyte membrane. J. Inorg. Biochem. 79 (2000) 195–203.

    PubMed  CAS  Article  Google Scholar 

  23. 23.

    Zhang, Z.-Y. and Smith, B.D. High-generation polycationic dendrimers are unusually effective at disrupting anionic vesicles: membrane bending model. Bioconjug. Chem. 11 (2000) 805–814.

    PubMed  CAS  Article  Google Scholar 

  24. 24.

    Klajnert, B. and Bryszewska, M. Fluorescence studies on PAMAM dendrimers interactions with bovine serum albumin. Bioelectrochemistry 55 (2002) 33–35.

    PubMed  CAS  Article  Google Scholar 

  25. 25.

    Klajnert, B., Sadowska, M. and Bryszewska, M. The effect of polyamidoamine dendrimers on human erythrocyte membrane acetylcholinesterase activity. Bioelectrochemistry 65 (2004) 23–26.

    PubMed  CAS  Article  Google Scholar 

  26. 26.

    Ottaviani, M.F., Matteini, P., Brustolon, M., Turro, N.J., Jockusch, S. and Tomalia, D.A. Characterization of starburst dendrimers and vesicle solutions and their interactions by CW- and Pulsed-EPR, TEM, and dynamic light scattering. J. Phys. Chem. B 102 (1998) 6029–6039.

    CAS  Article  Google Scholar 

  27. 27.

    Ottaviani, M.F., Daddi, R., Brustolon, M., Turro, N.J. and Tomalia, D.A. Structural modifications of DMPC vesicles upon interaction with polyamidoamine dendrimers studied by CW-electron paramagnetic resonance and electron spin-echo techniques. Langmuir 15 (1999) 1973–1980.

    CAS  Article  Google Scholar 

  28. 28.

    Ottaviani, M.F., Favuzza, P., Sacchi, B., Turro, N.J., Jockusch, S. and Tomalia, D.A. Interactions between starburst dendrimers and mixed DMPC/DMPA-Na vesicles studied by spin label and spin probe techniques, supported by transmission electron microscopy. Langmuir 18 (2002) 2347–2357.

    CAS  Article  Google Scholar 

  29. 29.

    Zhang, Z.-Y. and Smith, B.D. High-generation polycationic dendrimers are unusually effective at disrupting anionic vesicles: membrane bending model. Bioconjug. Chem. 11 (2000) 805–814.

    PubMed  CAS  Article  Google Scholar 

  30. 30.

    Karoonuthaisiri, N., Titiyevskiy, K. and Thomas, J.L. Destabilization of fatty acid-containing liposomes by polyamidoamine dendrimers. Colloids Surf. B: Biointerfaces 27 (2003) 365–375.

    CAS  Article  Google Scholar 

  31. 31.

    Hong, S., Bielinska, A.U., Mecke, A., Keszler, B., Beals, J., Shi, X., Balogh, L., Orr, B.G., Baker Jr., J.R. and Banaszak Holl, M.M. Interactions of poly(amidoamine) dendrimers with supported lipid bilayer and cells: Hole formation and the relation to transport. Boconjug. Chem. 15 (2004) 774–782.

    CAS  Article  Google Scholar 

  32. 32.

    Klajnert, B. and Epand, R. M. PAMAM dendrimers and model membranes: Differential scanning calorimetry studies. Int. J. Pharm. 305 (2005) 154–166.

    PubMed  CAS  Article  Google Scholar 

  33. 33.

    Gardikis, K., Hatziantoniou, S., Viras, K., Wagner, M. and Demetzos, C. A DSC and Raman spectroscopy study on the effect of PAMAM dendrimer on DPPC model lipid membranes. Int. J. Phar. 318 (2006) 118–123.

    CAS  Article  Google Scholar 

  34. 34.

    Mecke, A., Uppuluri, S., Sassanella, T.J., Lee, D.K., Ramamoorthy, A., Baker, J.R., Orr, B.G. and Banaszak Holl, M.M. Direct observation of lipid bilayer disruption by poly(amidoamine) dendrimers. Chem. Phys. Lipids 132 (2004) 3–14.

    PubMed  CAS  Article  Google Scholar 

  35. 35.

    Fischer, D., Li, Y., Ahlemeyer, B., Krieglstein, J. and Kissel, T. In vitro cytotoxicity testing of polycations: influence of polymer structure on cell viability and haemolysis. Biomaterials 24 (2003) 1121–1131.

    PubMed  CAS  Article  Google Scholar 

  36. 36.

    Mecke, A., Uppuluri, S., Sassanella, T.M., Lee, D.K., Ramamoorthy, A., Baker, J.R. Jr, Orr, B.G. and Banaszak Holl, M.M. Direct observation of lipid bilayer disruption by poly(amidoamine) dendrimers. Chem. Phys. Lipids 132 (2004) 3–14.

    PubMed  CAS  Article  Google Scholar 

  37. 37.

    Duncan, R. and Izzo, L., Dendrimer biocompatibility and toxicity. Adv. Drug Deliv. Rev. 57 (2005) 2215–2237.

    PubMed  CAS  Article  Google Scholar 

  38. 38.

    Klajnert, B. and Bryszewska, M. Synthesis and structure. in Dendrimers in medicine, 1st edition, Nova Science Pub. Inc., 2007, 7–18.

  39. 39.

    Janiszewska, J., Swieton, J., Lipkowski, A.W. and Urbanczyk-Lipkowska, Z. Low molecular mass peptide dendrimers that express antimicrobial properties. Bioorg. Med. Chem. Lett. 13 (2003) 3711–3713.

    PubMed  CAS  Article  Google Scholar 

  40. 40.

    Klajnert, B., Janiszewska, J., Urbanczyk-Lipkowska, Z., Bryszewska, M., Shcharbin, D. and Labieniec, M. Biological properties of low molecular mass peptide dendrimers. Int. J. Pharm. 309 (2006) 208–217.

    PubMed  CAS  Article  Google Scholar 

  41. 41.

    Domanski, D.M., Bryszewska, M. and Salamończyk, G. Preliminary evaluation of the behavior of fifth-generation thiophosphate dendrimer in biological systems. Biomacromolecules 5 (2004) 2007–2012.

    PubMed  CAS  Article  Google Scholar 

  42. 42.

    Wang, W., Xiong, W., Zhu, Y., Xu, H. and Yang, X. Protective effect of PEGylation against poly(amidoamine) dendrimer-induced haemolysis of human red blood cells. J. Biomed. Mater. Res. B. Appl. Biomater. 93 (2010) 59–64.

    PubMed  Google Scholar 

  43. 43.

    Mao, S., Neu, M., Germershaus, O., Merkel, O., Sitterberg, J., Bakowsky, U. and Kissel, T. Influence of polyethylene glycol chain length on the physicochemical and biological properties of poly(ethylene imine)-graftpoly( ethylene glycol) block copolymer/SiRNA polyplexes. Bioconj. Chem. 17 (2006) 1209–1218.

    CAS  Article  Google Scholar 

  44. 44.

    Wang, W., Xiong, W., Wan, J., Sun, X., Xu, H. and Yang, X. The decrease of PAMAM dendrimer-induced cytotoxicity by PEGylation via attenuation of oxidative stress. Nanotechnology 20 (2009) 105103.

    PubMed  Article  Google Scholar 

  45. 45.

    Jevprasesphant, R., Penny, J., Jalal, R., Attwood, D., McKeown, N.B. and D’Emanuele, A. The influence of surface modification on the cytotoxicity of PAMAM dendrimers. Int. J. Pharm. 252 (2003) 263–266.

    PubMed  CAS  Article  Google Scholar 

  46. 46.

    Chen, H.T., Neerman, M.F., Parrish, A.R. and Simanek, E.E. Cytotoxicity, haemolysis, and acute in vivo toxicity of dendrimers based on melamine, candidate vehicles for drug delivery. J. Am. Chem. Soc. 126 (2006) 10044–10048.

    Article  Google Scholar 

  47. 47.

    Klajnert, B., Appelhans, D., Komber, H., Morgner, N., Schwarz, S., Richter, S., Brutschy, B., Ionov, M., Tonkikh, A.K., Bryszewska, M. and Voit, B. The influence of densely organized maltose shells on the biological properties of poly(propylene imine) dendrimers: new effects dependent on hydrogen bonding. Chemistry 14 (2008) 7030–7041.

    PubMed  CAS  Article  Google Scholar 

  48. 48.

    Navath, R.S., Menjoge, A.R., Wang, B., Romero, R., Kannan, S., Kannan, R.M. Amino acid-functionalized dendrimers with heterobifunctional chemoselective peripheral groups for drug delivery applications. Biomacromolecules 11 (2010) 1544–1563.

    PubMed  CAS  Article  Google Scholar 

  49. 49.

    Wang, P., Zhao, X.H., Wang, Z.Y., Meng, M., Li, X. and Ning, Q. Generation 4 polyamidoamine dendrimers is a novel candidate of nanocarrier for gene delivery agents in breast cancer treatment. Cancer Lett. 298 (2010) 34–49.

    PubMed  CAS  Article  Google Scholar 

  50. 50.

    Gupta, U., Dwivedi, S.K., Bid, H.K., Konwar, R. and Jain, N.K. Ligand anchored dendrimers based nanoconstructs for effective targeting to cancer cells. Int. J. Pharm. 393 (2010) 185–196.

    PubMed  CAS  Article  Google Scholar 

  51. 51.

    Agarwal, A., Gupta, U., Asthana, A. and Jain, N.K. Dextran conjugated dendritic nanoconstructs as potential vectors for anti-cancer agent. Biomaterials 30 (2009) 3588–3596.

    PubMed  CAS  Article  Google Scholar 

  52. 52.

    Bhadra, D., Bhadra, S., Jain, S. and Jain, N.K. A PEGylated dendritic nanoparticulate carrier of fluorouracil. Int. J. Pharm. 257 (2003) 111–124.

    PubMed  CAS  Article  Google Scholar 

  53. 53.

    Agrawal, P., Gupta, U. and Jain, N.K. Glycoconjugated peptide dendrimersbased nanoparticulate system for the delivery of chloroquine phosphate. Biomaterials 28 (2007) 3349–3359.

    PubMed  CAS  Article  Google Scholar 

  54. 54.

    Klajnert, B., Pikala, S. and Bryszewska, M., Haemolytic activity of polyamidoamine dendrimers and the protective role of human serum albumin. Proc. R. Soc. A 466 (2010) 1527–1534.

    CAS  Article  Google Scholar 

  55. 55.

    Shcharbin, D., Janicka, M., Wasiak, M., Palecz, B., Przybyszewska, M., Zaborski, M. and Bryszewska, M. Serum albumins have five sites for binding of cationic dendrimers, Biochim. Biophys. Acta 1774 (2007) 946–961.

    PubMed  CAS  Google Scholar 

  56. 56.

    Bessis, M. Red cell shapes: an illustrated classification and its rationale. In: Bessis M., Wed, R.I., LeBond P.F. (Eds), Red Cell Shapes, Springer, New York, 1973, pp. 1–23.

    Google Scholar 

  57. 57.

    Sheetz, P. and Singer, S.J. Biological membranes as bilayer couples. A molecular mechanism of drug-erythrocyte interactions. Proc. Natl. Acad. Sci. U. S. A. 71 (1974) 4457–4461.

    PubMed  CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Barbara Ziemba.

Additional information

Paper authored by participants of the international conference: 18th Meeting, European Association for Red Cell Research, Wrocław — Piechowice, Poland, May 12–15th, 2011. Publication cost was covered by the organizers of this meeting.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ziemba, B., Matuszko, G., Bryszewska, M. et al. Influence of dendrimers on red blood cells. Cell Mol Biol Lett 17, 21–35 (2012). https://doi.org/10.2478/s11658-011-0033-9

Download citation

Key words

  • Dendrimer
  • Erythrocytes
  • Haemolysis
  • Red blood cell
  • Red blood cell morphology
  • Toxicity