Skip to main content
SpringerLink
Log in

Preparation, characterisation and preliminary antitumour activity evaluation of a novel nanoparticulate system based on a cisplatin-hyaluronate complex and N-trimethyl chitosan

  • PRECLINICAL STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

In this work, nanoparticles with a positive surface charge were prepared through the electrostatic interaction of a new cisplatin-hyaluronate complex with N-trimethyl chitosan (substitution degree of 85%). Mean particle diameter was approximately 195 nm. Drug loading of nanoparticles, which had a zeta potential of about 27 mV, was equal to 6% w/w. After 24 h, while the cisplatin-hyaluronate complex released approximately 60% w/w drug in phosphate buffered saline at pH 7.4, approximately 40% w/w of total cisplatin was released from nanoparticles. The same cumulative amounts of released drug were found after 48 h. These nanoparticles, as well as the starting cisplatin-hyaluronate complex, were active on all cell lines tested (P388, A2780, A549), with an antiproliferative activity similar to that of cisplatin. Apoptosis was markedly induced in A2780 cells by nanoparticles. In a preliminary in vivo experiment, the antitumour activity against a murine tumour (P388 cells) subcutaneously implanted in mice, resulted similar to that of cisplatin for nanoparticles whereas the starting complex showed a non-significant activity at the cisplatin dose tested. Body weight change of treated mice suggested a significantly better tolerance of the nanoparticles compared to cisplatin, after an initial brief period of acute toxicity higher than the parent drug. These results indicate that such a particulate system could be useful as a carrier for cisplatin delivery.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Gandara DR, Perez EA, Phillips WA, Lawrence HJ, DeGregorio M (1989) Evaluation of cisplatin dose intensity: current status and future prospects. Anticancer Res 9:1121–1128

    PubMed  CAS  Google Scholar 

  2. Gianasi E, Wasil M, Evagorou EG, Keddle A, Wilson G, Duncan R (1999) Hpma copolymer platinates as novel antitumour agents: in vitro properties, pharmacokinetics and antitumour activity in vivo. Eur J Cancer 35:994–1002

    Article  PubMed  CAS  Google Scholar 

  3. Malik N, Evagorou EG, Duncan R (1999) Dendrimer-platinate: a novel approach to cancer chemotherapy. Anticancer Drugs 10:767–776

    Article  PubMed  CAS  Google Scholar 

  4. Ye H, Jin L, Hu R, Yi Z, Li J, Wu Y, Xi X, Wu Z (2006) Poly-(γ, l-glutamic acid)-cisplatin conjugate effectively inhibits human breast tumor xenografted in nude mice. Biomaterials 27:5958–5965

    Article  PubMed  CAS  Google Scholar 

  5. Schlechter B, Neumann A, Wilchek M, Arnon R (1989) Soluble polymers as carriers of cis-platinum. J Controll Release 10:75–87

    Article  Google Scholar 

  6. Imai T, Fujii K, Shiraishi S, Otagiri M (1997) Alteration of pharmacokinetics and nephrotoxicity of cisplatin by alginates. J Pharm Sci 86:244–247

    Article  PubMed  CAS  Google Scholar 

  7. Cafaggi S, Russo E, Stefani R, Leardi R, Caviglioli G, Parodi B, Bignardi G, De Totero D, Aiello C, Viale M (2007) Preparation and evaluation of nanoparticles made of chitosan or n-trimethyl chitosan and a cisplatin-alginate complex. J Controll Release 121:110–123

    Article  CAS  Google Scholar 

  8. Avichezer D, Schechter B, Arnon R (1998) Functional polymers in drug delivery: carrier-supported cddp (cis-platin) complexes of polycarboxylates—effect on human ovarian carcinoma. Reactive Funct Polymers 36:59–69

    Article  CAS  Google Scholar 

  9. Sugahara KN, Hirata T, Hayasaka H, Stern R, Murai T, Miyasaka M (2006) Tumor cells enhance their own cd44 cleavage and motility by generating hyaluronan fragments. J Biol Chem 281:5861–5868

    Article  PubMed  CAS  Google Scholar 

  10. Yip GW, Smollich M, Gotte M (2006) Therapeutic value of glycosaminoglycans in cancer. Mol Cancer Therap 5:2139–2148

    Article  CAS  Google Scholar 

  11. Ravi Kumar MNV (2001) A review of chitin and chitosan applications. Reactive Funct Polymers 46:1–27

    Article  Google Scholar 

  12. Calvo P, Remunan-Lopez C, Vila-jato JL, Alonso MJ (1997) Novel hydrophilic chitosan-polyethylene oxide nanoparticles as protein carriers. J Appl Polym Sci 63:125–132

    Article  CAS  Google Scholar 

  13. Mi FL, Sung HW, Shyu SS (2001) Release of indomethacin from a novel chitosan microsphere prepared by naturally occurring crosslinker: examination of crosslinking and polycation/anionic drug interaction. J Appl Polym Sci 81:1700–1711

    Article  CAS  Google Scholar 

  14. Amidi M, Romeijn SG, Borchard G, Junginger HE, Hennink WE, Jiskoot W (2006) Preparation and characterization of protein-loaded n-trimethyl chitosan nanoparticles as nasal delivery system. J Controll Release 111:107–116

    Article  CAS  Google Scholar 

  15. Hamman JH, Stander M, Kotzé AF (2002) Effect of the degree of quaternization of n-trimethyl chitosan chloride on absorption enhancement: in vivo evaluation in rat nasal epithelia. Int J Pharm 232:235–242

    Article  PubMed  CAS  Google Scholar 

  16. Lee J-K, Lim H-S, Kim J-H (2002) Cytotoxic activity of aminoderivatized cationic chitosan derivatives. Bioorg Med Chem Lett 12:2949–2951

    Article  PubMed  CAS  Google Scholar 

  17. Kean T, Roth S, Thanou M (2005) Trimethylated chitosans as non-viral gene delivery vectors: cytotoxicity and transfection efficiency. J Controll Release 103:643–653

    Article  CAS  Google Scholar 

  18. Haas J, Kumar MNVR, Borchard G, Bakowsky U, Lehr C-M (2005) Preparation and characterization of chitosan and trimethyl-chitosan modified poly-(ε-caprolactone) nanoparticles as DNA carriers. AAPS PharmSciTech 6:E22–E30

    Article  PubMed  Google Scholar 

  19. Russo E, Stefani R, Parodi B, Caviglioli G, Aiello C, Viale M, Cafaggi S, Bignardi G (2008) Cisplatin delivery: a study on a cisplatin-hyaluronate complex and nanoparticles formed by its interaction with n-trimethyl chitosan. 6th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology. Barcelona

  20. Jeong Y-I, Kim S-T, Jin S-G, Ryu H-H, Jin Y-H, Jung T-Y, Kim I-Y, Jung S (2008) Cisplatin-incorporated hyaluronic acid nanoparticles based on ion-complex formation. J Pharm Sci 97:1268–1276

    Article  PubMed  CAS  Google Scholar 

  21. Cai S, Xie Y, Bagby TR, Cohen MS, Forrest ML (2008) Intralymphatic chemotherapy using a hyaluronan-cisplatin conjugate. J Surg Res 147:247–252

    Article  PubMed  CAS  Google Scholar 

  22. Peer D, Margalit R (2004) Tumor-targeted hyaluronan nanoliposomes increase the antitumor activity of liposomal doxorubicin in syngeneic and human xenograft mouse tumor models. Neoplasia 6:343–353

    Article  PubMed  CAS  Google Scholar 

  23. Lorenz MR, Holzapfel V, Musyanovych A, Nothelfer K, Walther P, Frank H, Landfester K, Schrezenmeier H, Mailander V (2006) Uptake of functionalized, fluorescent-labeled polymeric particles in different cell lines and stem cells. Biomaterials 27:2820–2828

    Article  PubMed  CAS  Google Scholar 

  24. Lewis GA, Mathieu D, Phan-Tan-Luu R (1999) Pharmaceutical experimental design. Dekker, New York

    Google Scholar 

  25. Hussain RF, Nouri AME, Oliver RTD (1993) A new approach for measurement of cytotoxicity using colorimetric assay. J Immunol Methods 160:89–96

    Article  PubMed  CAS  Google Scholar 

  26. Coradini D, Pellizzaro C, Scarlata I, Zorzet S, Garrovo C, Abolafio G, Speranza A, Fedeli M, Cantoni S, Sava G, Daidone MG, Perbellini A (2006) A novel retinoic/butyric hyaluronan ester for the treatment of acute promyelocytic leukemia: preliminary preclinical results. Leukemia 20:785–792

    Article  PubMed  CAS  Google Scholar 

  27. Drímalová E, Velebný V, Sasinková V, Hromádková Z, Ebringerová A (2005) Degradation of hyaluronan by ultrasonication in comparison to microwave and conventional heating. Carbohydr Polym 61:420–426

    Article  Google Scholar 

  28. Cowman MK, Matsuoka S (2005) Experimental approaches to hyaluronan structure. Carbohydr Res 340:791–809

    Article  PubMed  CAS  Google Scholar 

  29. Hargittai I, Hargittai M (2008) Molecular structure of hyaluronan: an introduction. Struct Chem 19:697–717

    Article  CAS  Google Scholar 

  30. Mao HQ, Roy K, Troung-Le VL, Janes KA, Lin KY, Wang Y, August JT, Leong KW (2001) Chitosan-DNA nanoparticles as gene carriers: synthesis, characterization and transfection efficiency. J Controll Release 70:399–421

    Article  CAS  Google Scholar 

  31. Verheul RJ, Amidi M, van Steenbergen MJ, van Riet E, Jiskoot W, Hennink WE (2009) Influence of the degree of acetylation on the enzymatic degradation and in vitro biological properties of trimethylated chitosans. Biomaterials 30:3129–3135

    Article  PubMed  CAS  Google Scholar 

  32. Furth G, Knierim R, Buss V, Mayer C (2008) Binding of bivalent cations by hyaluronate in aqueous solution. Int J Biol Macromol 42:33–40

    Article  PubMed  CAS  Google Scholar 

  33. Haxton KJ, Burt HM (2009) Polymeric drug delivery of platinum-based anticancer agents. J Pharm Sci 98:2299–2316

    Article  PubMed  CAS  Google Scholar 

  34. Kim JH, Kim YS, Park K, Lee S, Nam HY, Min KH, Jo HG, Park JH, Choi K, Jeong SY, Park RW, Kim IS, Kim K, Kwon IC (2008) Antitumor efficacy of cisplatin-loaded glycol chitosan nanoparticles in tumor-bearing mice. J Controll Release 127:41–49

    Article  CAS  Google Scholar 

  35. Kruczynski A, Hill BT (2001) Classic in vivo cancer models: Three examples of mouse models used in experimental therapeutics. Curr Protoc Pharmacol Unit 5.24:5.24.1–5.24.16

  36. Couvreur P, Reddy LH, Mangenot S, Poupaert JH, Desmaele D, Lepetre-Mouelhi S, Pili B, Bourgaux C, Amenitsch H, Ollivon M (2008) Discovery of new hexagonal supramolecular nanostructures formed by squalenoylation of an anticancer nucleoside analogue. Small 4:247–253

    Article  PubMed  CAS  Google Scholar 

  37. Nishioka Y, Yoshino H (2001) Lymphatic targeting with nanoparticulate system. Adv Drug Deliv Rev 47:55–64

    Article  PubMed  CAS  Google Scholar 

  38. Bankhead C (2006) Intraperitoneal therapy for advanced ovarian cancer: will it become standard care? J Natl Cancer Inst 98:510–512

    Article  PubMed  Google Scholar 

  39. Auzenne E, Ghosh SC, Khodadadian M, Rivera B, Farquhar D, Price RE, Ravoori M, Kundra V, Freedman RS, Klostergaard J (2007) Hyaluronic acid-paclitaxel: antitumor efficacy against cd44(+) human ovarian carcinoma xenografts. Neoplasia 9:479–486

    Article  PubMed  CAS  Google Scholar 

  40. Lee H, Lee K, Park TG (2008) Hyaluronic acid-paclitaxel conjugate micelles: synthesis, characterization, and antitumor activity. Bioconjug Chem 19:1319–1325

    Article  PubMed  CAS  Google Scholar 

  41. Toole BP, Ghatak S, Misra S (2008) Hyaluronan oligosaccharides as a potential anticancer therapeutic. Curr Pharm Biotechnol 9:249–252

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from Ministero dell’Istruzione, Universita` e Ricerca, (MIUR), Rome, Italy.

Author information

Authors and Affiliations

  1. Dipartimento di Chimica e Tecnologie Farmaceutiche ed Alimentari, Via Brigata Salerno 13, 16147, Genoa, Italy

    Sergio Cafaggi, Eleonora Russo, Rossana Stefani, Brunella Parodi, Gabriele Caviglioli, Greta Sillo & Angela Bisio

  2. Istituto Nazionale per la Ricerca sul Cancro, S.C. Terapia Immunologica, Largo R. Benzi 10, 16132, Genoa, Italy

    Cinzia Aiello & Maurizio Viale

Authors
  1. Sergio Cafaggi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eleonora Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rossana Stefani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brunella Parodi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gabriele Caviglioli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Greta Sillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Angela Bisio
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cinzia Aiello
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maurizio Viale
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sergio Cafaggi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cafaggi, S., Russo, E., Stefani, R. et al. Preparation, characterisation and preliminary antitumour activity evaluation of a novel nanoparticulate system based on a cisplatin-hyaluronate complex and N-trimethyl chitosan. Invest New Drugs 29, 443–455 (2011). https://doi.org/10.1007/s10637-009-9373-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-009-9373-y

Keywords

Search

Navigation