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Influence of dendrimers on red blood cells
Cellular & Molecular Biology Letters volume 17, pages 21–35 (2012)
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
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.
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.
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.
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.
Frechet, J.M.J. Dendrimers and supramolecular chemistry. Proc. Natl. Acad. Sci. U. S. A. 99 (2002) 4782–4787.
Lee, C.C., MacKay, J.A., Fréchet, J.M. and Szoka, F.C. Designing dendrimers for biological applications. Nat. Biotechnol. 23 (2005) 1517–1526.
Domanski, D.M., Klajnert, B. and Bryszewska, M. Influence of PAMAM dendrimers on human red blood cells. Bioelectrochemistry 63 (2004) 189–191.
Dykes, G.M. Dendrimers: a review of their appeal and applications. J. Chem. Technol. Biotechnol. 79 (2001) 903–918.
Bumb, A., Brechbiel, M.W. and Choyke, P. Macromolecular and dendrimerbased magnetic resonance contrast agents. Acta Radiol. 51 (2010) 751–767.
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.
Boas, U. and Heegaard, P.M. Dendrimers in drug research. Chem. Soc. Rev. 33 (2004) 43–63.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
Klajnert, B. and Bryszewska, M. Fluorescence studies on PAMAM dendrimers interactions with bovine serum albumin. Bioelectrochemistry 55 (2002) 33–35.
Klajnert, B., Sadowska, M. and Bryszewska, M. The effect of polyamidoamine dendrimers on human erythrocyte membrane acetylcholinesterase activity. Bioelectrochemistry 65 (2004) 23–26.
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.
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.
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.
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.
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.
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.
Klajnert, B. and Epand, R. M. PAMAM dendrimers and model membranes: Differential scanning calorimetry studies. Int. J. Pharm. 305 (2005) 154–166.
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.
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.
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.
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.
Duncan, R. and Izzo, L., Dendrimer biocompatibility and toxicity. Adv. Drug Deliv. Rev. 57 (2005) 2215–2237.
Klajnert, B. and Bryszewska, M. Synthesis and structure. in Dendrimers in medicine, 1st edition, Nova Science Pub. Inc., 2007, 7–18.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Bhadra, D., Bhadra, S., Jain, S. and Jain, N.K. A PEGylated dendritic nanoparticulate carrier of fluorouracil. Int. J. Pharm. 257 (2003) 111–124.
Agrawal, P., Gupta, U. and Jain, N.K. Glycoconjugated peptide dendrimersbased nanoparticulate system for the delivery of chloroquine phosphate. Biomaterials 28 (2007) 3349–3359.
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.
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.
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.
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.
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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.
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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
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DOI: https://doi.org/10.2478/s11658-011-0033-9