Skip to main content
SpringerLink
Log in

Self-assembling chitosan/poly-γ-glutamic acid nanoparticles for targeted drug delivery

  • Original Contribution
  • Published:
Colloid and Polymer Science Aims and scope Submit manuscript

Abstract

For the purpose of targeted drug delivery, composite biodegradable nanoparticles were prepared from chitosan and the poly-γ-glutamic acid via an ionotropic gelation process. These stable self-assembled nanoparticles were characterized by dynamic light scattering, transmission electron microscopy, and atomic force microscopy, which demonstrated that the nanosystem consists of spherical particles with a smooth surface both in aqueous environment and in dried state. Toxicity measurements showed that the composition is nontoxic when tested either on cell cultures or in animal feeding experiments. To evaluate the potential of the nanosystem for intracellular drug delivery, the nanoparticles were fluorescently labeled and folic acid was attached as a cancer cell-specific targeting moiety. The ability of the particles to be internalized was tested using confocal microscopic imaging on cultured A2780/AD ovarian cancer cells, which overexpress folate receptors. The quantitative data obtained by digital processing of the intensity of green color of each pixel in the pictures inside the cell boundaries and total intensity of fluorescence inside the cells showed that “targeted” particles internalized into the cells significantly faster and the total accumulation of these particles was substantially higher in the cancer cells when compared with “nontargeted” particles, which may facilitate effective and specific cytoplasmic delivery of anticancer agents loaded into such nanoparticles.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. McNeil SE (2005) Nanotechnology for the biologists. J Leukocyte Biol 78:585–594

    Article  CAS  Google Scholar 

  2. Majoros IJ, Thomas T, Baker JR Jr (2006) Molecular engineering in nanotechnology: engineered drug delivery. In: Reith M, Schommers W (eds) Handbook of theoretical and computational nanotechnology, vol 6. American Scientific, Stevenson Ranch, CA, pp 673–717

    Google Scholar 

  3. Vicent MJ, Duncan R (2006) Polymer conjugates: nanosized medicines for treating cancer. Trends Biotech 24:39–47

    Article  CAS  Google Scholar 

  4. Duncan R (2003) The dawning era of polymer therapeutics. Nat Rev Drug Discover 2:347–360

    Article  CAS  Google Scholar 

  5. Nobs L, Buchegger F, Gurny R, Allémann E (2006) Biodegradable nanoparticles for direct and two-step tumor immunotargeting. Bioconj Chem 17:139–145

    Article  CAS  Google Scholar 

  6. Torchilin VP (2006) Multifunctional nanocarriers. Adv Drug Del Rev 58:1532–1555

    Article  CAS  Google Scholar 

  7. Ulbrich K, Subr V (2004) Polymeric anticancer drugs with pH-controlled activation. Adv Drug Deliv Rev 56:123–1050

    Article  Google Scholar 

  8. Sawant RM, Hurley JP, Salmaso S, Kale A, Tolcheva E, Levchenko TS, Torchilin VP (2006) “SMART” drug delivery systems: double-targeted pH-responsive pharmaceutical nanocarriers. Bioconj Chem 17:943–949

    Article  CAS  Google Scholar 

  9. Grodzinsky P, Silver M, Molnar LM (2006) Nanotechnology for cancer diagnostics: promises and challenges. Expert Rev Mol Diagn 6:307–318

    Article  Google Scholar 

  10. Khan MK, Nigavekar SS, Minc LD, Kariapper MST, Nair BM, Lesniak WG, Balogh LP (2005) In vivo biodistribution of dendrimers and dendrimer nanocomposites—implications for cancer imaging and therapy. Technol Cancer Res Threat 4:603–613

    CAS  Google Scholar 

  11. Hajdu I, Bodnar M, Filipcsei G, Hartmann JF, Daroczi L, Zrinyi M, Borbely J (2008) Nanoparticles prepared by self-assembly of chitosan and poly-γ-glutamic acid. Coll Polym Sci 286:343–350

    Article  CAS  Google Scholar 

  12. Berger J, Reist M, Mayer JM, Felt O, Gurny R (2004) Structure and interactions in chitosan hydrogels formed by complexation or aggregation for biomedical applications. Eur J Pharm Biopharm 57:35–52

    Article  CAS  Google Scholar 

  13. Hsieh C-Y, Tsai S-P, Wang D-M, Chang Y-N, Hsieh H-J (2005) Preparation of γ-PGA/chitosan composite tissue engineering matrices. Biomaterials 26:5617–5623

    Article  CAS  Google Scholar 

  14. Lin Y-H, Chung CK, Chen C-T, Liang H-F, Chen S-C, Sung H-W (2005) Preparation of nanoparticles composed of chitosan/poly-g-glutamic acid and evaluation of their permeability through caco-2 cells. Biomacromolecules 6:1104–1112

    Article  CAS  Google Scholar 

  15. Lin Y-H, Mi F-L, Chen C-T, Chang W-C, Peng S-F, Liang H-F, Sung H-W (2007) Preparation and characterization of nanoparticles shelled with chitosan for oral insulin delivery. Biomacromolecules 8:146–152

    Article  CAS  Google Scholar 

  16. Lin WC, Yu DG, Yang MC (2006) Blood compatibility of novel poly(γ-glutamic acid)/polyvinyl alcohol hydrogels. Colloid Surface B 47:43–49

    Article  CAS  Google Scholar 

  17. Krecz A, Pocsi I, Borbely J (2001) Preparation and chemical modification of poly-gamma-L-glutamic acid. Folia Microbiol 46:183–186

    Article  CAS  Google Scholar 

  18. Borbely M, Nagasaki Y, Borbely J, Fan K, Bhogle A, Sevoian M (1994) Biosynthesis and chemical modification of poly(gamma-glutamic acid). Polym Bull 32:127–132

    Article  CAS  Google Scholar 

  19. Bodnár M, Hartmann JF, Borbély J (2005) Preparation and characterization of chitosan-based nanoparticles. Biomacromolecules 6:2521–2527

    Article  Google Scholar 

  20. Bodnár M, Hartmann JF, Borbély J (2006) Synthesis and study of cross-linked chitosan-N-poly(ethylene glycol) nanoparticles. Biomacromolecules 7:3030–3036

    Article  Google Scholar 

  21. Minko T, Kopeckova P, Pozharov V, Kopecek J (1998) HPMA copolymer bound adriamycin overcomes MDR1 gene encoded resistance in a human ovarian carcinoma cell line. J Controlled Release 54:223–233

    Article  CAS  Google Scholar 

  22. Minko T, Kopeckova P, Kopecek J (1999) Chronic exposure to HPMA copolymer-bound adriamycin does not induce multidrug resistance in a human ovarian carcinoma cell line. J Controlled Release 59:133–148

    Article  CAS  Google Scholar 

  23. Pakunlu RI, Cook TJ, Minko T (2003) Simultaneous modulation of multidrug resistance and antiapoptotic cellular defense by MDR1 and BCL-2 targeted antisense oligonucleotides enhances the anticancer efficacy of doxorubicin. Pharm Res 20:351–359

    Article  CAS  Google Scholar 

  24. Dharap SS, Chandna P, Wang Y, Khandare JJ, Qiu B, Stein S, Minko T (2006) Molecular targeting of BCL2 and BCLXL proteins by synthetic BH3 peptide enhances the efficacy of chemotherapy. J Pharmacol Exp Ther 316:992–998

    Article  CAS  Google Scholar 

  25. Khandare JJ, Chandna P, Wang Y, Pozharov VP, Minko T (2006) Novel polymeric prodrug with multivalent components for cancer therapy. J Pharmacol Exp Ther 317:929–937

    Article  CAS  Google Scholar 

  26. Khandare JJ, Jayant S, Singh S, Chandna P, Wang Y, Vorsa N, Minko T (2006) Dendrimer versus linear conjugate: influence of polymeric architecture on the delivery and anticancer effect of Paclitaxel. Bioconjug Chem 17:1464–1472

    Article  CAS  Google Scholar 

  27. Dharap SS, Wang Y, Chandna P, Khandare JJ, Qiu B, Gunaseelan S, Sinko PJ, Stein S, Farmanfarmaian A, Minko T (2005) Tumor-specific targeting of an anticancer drug delivery system by LHRH peptide. Proc Natl Acad Sci USA 102:12962–12967

    Article  CAS  Google Scholar 

  28. Pakunlu RI, Wang Y, Saad M, Khandare JJ, Starovoytov V, Minko T (2006) In vitro and in vivo intracellular liposomal delivery of antisense oligonucleotides and anticancer drug. J Controlled Release 114:153–162

    Article  CAS  Google Scholar 

  29. Hong S, Leroueil PR, Majoros IJ, Orr BG, Baker JR Jr, Banasak Holl MM (2007) The binding avidity of a nanoparticle-based multivalent targeted drug delivery platform. Chem Biol 14:P107–P115

    Article  Google Scholar 

  30. Kang HS, Park SH, Lee YG, Son TI (2007) Polyelectrolyte complex hydrogel composed of chitosan and poly(γ-glutamic acid) for biological application: preparation, physical properties, and cytocompatibility. J Appl Polym Sci 103(1):386–394

    Article  CAS  Google Scholar 

  31. Bhumkar DR, Pokharkar VB (2006) Studies on effect of pH on cross-linking of chitosan with sodium tripolyphosphate: a technical note. AAPS PharmSciTech 7(2):138–143

    Article  Google Scholar 

  32. Novak L, Banyai I, Fleischer-Radu JE, Borbely J (2007) Direct amidation of poly(γ-glutamic acid) with benzylamine in dimethyl sulfoxide. Biomacromolecules 8:1624–1632

    Article  CAS  Google Scholar 

Download references

Acknowledgment

This research was supported by the grant of Regional University Knowledge Center of Debrecen (Genomnanotech Debrecen, contract number RET-06/432/2004) and a grant from the New Jersey Commission on Science and Technology.

Author information

Authors and Affiliations

  1. Department of Colloid and Environmental Chemistry, University of Debrecen, Egyetem tér 1., Debrecen, 4032, Hungary

    Zsolt Keresztessy, Magdolna Bodnár, István Hajdu & János Borbély

  2. Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA

    Elizabeth Ber, Min Zhang & Tamara Minko

  3. ElizaNor Polymer LLC, Princeton Junction, NJ, 08550, USA

    John F. Hartmann

  4. BBS Nanotechnology Ltd., Debrecen 16, P.O. Box 12, 4225, Hungary

    János Borbély

Authors
  1. Zsolt Keresztessy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Magdolna Bodnár
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elizabeth Ber
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. István Hajdu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Min Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John F. Hartmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tamara Minko
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. János Borbély
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to János Borbély.

Additional information

Zsolt Keresztessy and Magdolna Bodnár contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Keresztessy, Z., Bodnár, M., Ber, E. et al. Self-assembling chitosan/poly-γ-glutamic acid nanoparticles for targeted drug delivery. Colloid Polym Sci 287, 759–765 (2009). https://doi.org/10.1007/s00396-009-2022-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00396-009-2022-3

Keywords

Search

Navigation