Advertisement

Journal of Nanoparticle Research

, Volume 13, Issue 9, pp 4311–4323 | Cite as

Multifunctional antitumor magnetite/chitosan-l-glutamic acid (core/shell) nanocomposites

  • Daniela P. Santos
  • M. Adolfina Ruiz
  • Visitación Gallardo
  • Maria Valnice B. Zanoni
  • José L. Arias
Research Paper

Abstract

The development of anticancer drug delivery systems based on biodegradable nanoparticles has been intended to maximize the localization of chemotherapy agents within tumor interstitium, along with negligible drug distribution into healthy tissues. Interestingly, passive and active drug targeting strategies to cancer have led to improved nanomedicines with great tumor specificity and efficient chemotherapy effect. One of the most promising areas in the formulation of such nanoplatforms is the engineering of magnetically responsive nanoparticles. In this way, we have followed a chemical modification method for the synthesis of magnetite/chitosan-l-glutamic acid (core/shell) nanostructures. These magnetic nanocomposites (average size ≈340 nm) exhibited multifunctional properties based on its capability to load the antitumor drug doxorubicin (along with an adequate sustained release) and its potential for hyperthermia applications. Compared to drug surface adsorption, doxorubicin entrapment into the nanocomposites matrix yielded a higher drug loading and a slower drug release profile. Heating characteristics of the magnetic nanocomposites were investigated in a high-frequency alternating magnetic gradient: a stable maximum temperature of 46 °C was successfully achieved within 40 min. To our knowledge, this is the first time that such kind of stimuli-sensitive nanoformulation with very important properties (i.e., magnetic targeting capabilities, hyperthermia, high drug loading, and little burst drug release) has been formulated for combined antitumor therapy against cancer.

Keywords

Biodegradable nanoparticle Cancer Doxorubicin Hyperthermia Magnetically responsive drug nanocarrier Multifunctional nanoformulation Nanomedicine 

Notes

Acknowledgments

Financial support from project PE2008-FQM-3993 (Junta de Andalucía) is acknowledged. D.P. Santos also gratefully acknowledges the financial support of FAPESP (research fellowship: process no. 2007/07914-7).

References

  1. Ang KL, Venkatraman S, Ramanujan RV (2007) Magnetic PNIPA hydrogels for hyperthermia applications in cancer therapy. Mater Sci Eng C 27:347–351. doi: 10.1016/j.msec.2006.05.027 CrossRefGoogle Scholar
  2. Arias JL (2008) Novel strategies to improve the anticancer action of 5-fluorouracil by using drug delivery systems. Molecules 13:2340–2369. doi: 10.3390/molecules13102340 CrossRefGoogle Scholar
  3. Arias JL (2011) Drug targeting strategies in cancer treatment: an overview. Mini Rev Med Chem 11:1–17. doi: 10.2174/138955711793564024 CrossRefGoogle Scholar
  4. Arias JL, Gallardo V, Gómez-Lopera SA, Plaza RC, Delgado AV (2001) Synthesis and characterization of poly(ethyl-2-cyanoacrylate) nanoparticles with a magnetic core. J Control Release 77:309–321. doi: 10.1016/S0168-3659(01)00519-3 CrossRefGoogle Scholar
  5. Arias JL, Gallardo V, Linares-Molinero F, Delgado AV (2006) Preparation and characterization of carbonyl iron/poly(butylcyanoacrylate) core/shell nanoparticles. J Colloid Interface Sci 299:599–607. doi: 10.1016/j.jcis.2006.03.005 CrossRefGoogle Scholar
  6. Arias JL, Gallardo V, Ruiz MA, Delgado AV (2007) Ftorafur loading and controlled release from poly(ethyl-2-cyanoacrylate) and poly(butylcyanoacrylate) nanospheres. Int J Pharm 337:282–290. doi: 10.1016/j.ijpharm.2006.12.023 CrossRefGoogle Scholar
  7. Arias JL, Reddy LH, Couvreur P (2008) Magnetoresponsive squalenoyl gemcitabine composite nanoparticles for cancer active targeting. Langmuir 24:7512–7519. doi: 10.1021/la800547s CrossRefGoogle Scholar
  8. Arias JL, Reddy LH, Couvreur P (2009) Polymeric nanoparticulate system augmented the anticancer therapeutic efficacy of gemcitabine. J Drug Target 17:586–598. doi: 10.1080/10611860903105739 CrossRefGoogle Scholar
  9. Arias JL, Martínez-Soler GI, López-Viota M, Ruiz MA (2010a) Formulation of chitosan nanoparticles loaded with metronidazole for the treatment of infectious diseases. Lett Drug Des Discov 7:70–78. doi: 10.2174/157018010790225831 CrossRefGoogle Scholar
  10. Arias JL, López-Viota M, Gallardo V, Ruiz MA (2010b) Chitosan nanoparticles as a new delivery system for the chemotherapy agent tegafur. Drug Dev Ind Pharm 36:744–750. doi: 10.3109/03639040903517914 CrossRefGoogle Scholar
  11. Bodnar M, Hartmann JF, Borbely J (2005) Preparation and characterization of chitosan-based nanoparticles. Biomacromolecules 6:2521–2527. doi: 10.1021/bm0502258 CrossRefGoogle Scholar
  12. Campbell RB (2007) Battling tumors with magnetic nanotherapeutics and hyperthermia: turning up the heat. Nanomedicine 2:649–652. doi: 10.2217/17435889.2.5.649 CrossRefGoogle Scholar
  13. Gaihre B, Khil MS, Lee DR, Kim HY (2009) Gelatin-coated magnetic iron oxide nanoparticles as carrier system: drug loading and in vitro drug release study. Int J Pharm 365:180–189. doi: 10.1016/j.ijpharm.2008.08.020 CrossRefGoogle Scholar
  14. Huber DL (2005) Synthesis, properties, and applications of iron nanoparticles. Small 1:482–501. doi: 10.1002/smll.200500006 CrossRefGoogle Scholar
  15. Iannone A, Magin RL, Walczack T, Federico M, Swartz HM, Tomasi A, Vannini V (1991) Blood clearance of dextran magnetite particles determined by a noninvasive in vivo ESR method. Magn Reson Med 22:435–442. doi: 10.1002/mrm.1910220251 CrossRefGoogle Scholar
  16. Illum L (1998) Chitosan and its use as a pharmaceutical excipient. Pharm Res 15:1326–1331. doi: 10.1023/A:1011929016601 CrossRefGoogle Scholar
  17. Ito A, Shinkai M, Honda H, Kobayashi T (2005) Medical application of functionalized magnetic nanoparticles. J Biosci Bioeng 100:1–11. doi: 10.1263/jbb.100.1 CrossRefGoogle Scholar
  18. Jordan A, Scholz R, Maier-Hauff K, Johannsen M, Wust P, Nadobny J, Schirra H, Schmidt H, Deger S, Loening S, Lanksch W, Felix R (2001) Presentation of a new magnetic field therapy system for the treatment of human solid tumors with magnetic fluid hyperthermia. J Magn Magn Mater 225:118–126. doi: 10.1016/S0304-8853(00)01239-7 CrossRefGoogle Scholar
  19. Kalele S, Narain R, Krishnan KM (2009) Probing temperature-sensitive behavior of pNIPAAm-coated iron oxide nanoparticles using frequency-dependent magnetic measurements. J Magn Magn Mater 321:1377–1380. doi: 10.1016/j.jmmm.2009.02.134 CrossRefGoogle Scholar
  20. Kallay N, Torbić Ž, Golić M, Matijević E (1991) Determination of the isoelectric points of several metals by an adhesion method. J Phys Chem 95:7028–7032. doi: 10.1021/j100171a056 CrossRefGoogle Scholar
  21. Lao LL, Ramanujan RV (2004) Magnetic and hydrogel composite materials for hyperthermia applications. J Mater Sci Mater Med 15:1061–1064. doi: 10.1023/B:JMSM.0000046386.78633.e5 CrossRefGoogle Scholar
  22. Laurent S, Forge D, Port M, Roch A, Robic C, Elst LV, Muller RN (2008) Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem Rev 108:2064–2110. doi: 10.1021/cr068445e CrossRefGoogle Scholar
  23. Llovet MI, Egea MA, Valero J, Alsina MA, García ML, Chauvet A (1995) Methotrexate-loaded nanoparticles: analysis of drug content and study of the matrix structure. Drug Dev Ind Pharm 21:1761–1771. doi: 10.3109/03639049509069263 CrossRefGoogle Scholar
  24. Lyklema J (2002) The role of surface conduction in the development of electrokinetics. In: Delgado AV (ed) Interfacial electrokinetics and electrophoresis. Marcel Dekker, New York, pp 87–98Google Scholar
  25. Lyon RJP (1967) Infrared absorption spectroscopy. In: Zussman J (ed) Physical methods in determinative mineralogy. Academic Press, London/New York, pp 371–399Google Scholar
  26. Massart R (1981) Preparation of aqueous magnetic liquids in alkaline and acidic media. IEEE Trans Magn 17:1247–1248. doi: 10.1109/TMAG.1981.1061188 CrossRefGoogle Scholar
  27. Meers P (2001) Enzyme-activated targeting of liposomes. Adv Drug Deliv Rev 53:265–272. doi: 10.1016/S0169-409X(01)00205-8 CrossRefGoogle Scholar
  28. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229. doi: 10.1124/pr.56.2.6 CrossRefGoogle Scholar
  29. Müller RH, Maaßen S, Weyhers H, Specht F, Lucks JS (1996) Cytotoxicity of magnetite-loaded polylactide, polylactide/glycolide particles and solid lipid nanoparticles. Int J Pharm 138:85–94. doi: 10.1016/0378-5173(96)04539-5 CrossRefGoogle Scholar
  30. Needham D, Dewhirst MW (2001) The development and testing of a new temperature-sensitive drug delivery system for the treatment of solid tumors. Adv Drug Deliv Rev 53:285–305. doi: 10.1016/S0169-409X(01)00233-2 CrossRefGoogle Scholar
  31. Needham D, Anyarambhatla G, Kong G, Dewhirst MW (2000) A new temperature-sensitive liposome for use with mild hyperthermia: characterization and testing in a human tumor xenograft model. Cancer Res 60:1197–1201Google Scholar
  32. Nordtveit RJ, Vårum KM, Smidsrød O (1994) Degradation of fully water-soluble, partially N-acetylated chitosans with lysozyme. Carbohydr Polym 23:253–260. doi: 10.1016/0144-8617(94)90187-2 CrossRefGoogle Scholar
  33. O’Brien RW, White LR (1978) Electrophoretic mobility of a spherical colloidal particle. J Chem Soc Faraday Trans 2:1607–1626. doi: 10.1039/F29787401607 Google Scholar
  34. Okon E, Pouliquen D, Okon P, Kovaleva ZV, Stepanova TP, Lavit SG, Kudryavtsev BN, Jallet P (1994) Biodegradation of magnetite dextran nanoparticles in the rat: a histologic and biophysical study. Lab Invest 71:895–903Google Scholar
  35. Papadimitriou S, Bikiaris D, Avgoustakis K, Karavas E, Georgarakis M (2008) Chitosan nanoparticles loaded with dorzolamide and pramipexole. Carbohydr Polym 73:44–54. doi: 10.1016/j.carbpol.2007.11.007 CrossRefGoogle Scholar
  36. Pitt CG (1990) The controlled parenteral delivery of polypeptides and proteins. Int J Pharm 59:173–196. doi: 10.1016/0378-5173(90)90108-G CrossRefGoogle Scholar
  37. Plaza RC, Arias JL, Espín M, Jiménez ML, Delgado AV (2002) Aging effects in the electrokinetics of colloidal iron oxides. J Colloid Interface Sci 245:86–90. doi: 10.1006/jcis.2001.7964 CrossRefGoogle Scholar
  38. Purushotham S, Ramanujan RV (2010) Thermoresponsive magnetic composite nanomaterials for multimodal cancer therapy. Acta Biomater 6:502–510. doi: 10.1016/j.actbio.2009.07.004 CrossRefGoogle Scholar
  39. Rapoport N (2004) Combined cancer therapy by micellar-encapsulated drug and ultrasound. Int J Pharm 277:155–162. doi: 10.1016/j.ijpharm.2003.09.048 CrossRefGoogle Scholar
  40. Regazzoni AE, Blesa MA, Maroto AJG (1983) Interfacial properties of zirconium dioxide and magnetite in water. J Colloid Interface Sci 91(2):560–570. doi: 10.1016/0021-9797(83)90370-3 CrossRefGoogle Scholar
  41. Ruiz MA, Gallardo V, Arias JL, Delgado A (2003) Effect of latex and plasticizer concentration on glucocorticoid release from ointments. Pharm Ind 65:454–457Google Scholar
  42. Singh J, Dutta PK, Dutta J, Hunt AJ, Macquarrie DJ, Clark JH (2009) Preparation and properties of highly soluble chitosan-l-glutamic acid aerogel derivative. Carbohydr Polym 76:188–195. doi: 10.1016/j.carbpol.2008.10.011 CrossRefGoogle Scholar
  43. Sinha VR, Singla AK, Wadhawan S, Kaushik R, Kumria R, Bansal K, Dhawan S (2004) Chitosan microspheres as a potential carrier for drugs. Int J Pharm 274:1–33. doi: 10.1016/j.ijpharm.2003.12.026 CrossRefGoogle Scholar
  44. Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE (2001) Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release 70:1–20. doi: 10.1016/S0168-3659(00)00339-4 CrossRefGoogle Scholar
  45. Sun JB, Duan JH, Dai SL, Ren J, Zhang YD, Tian JS, Li Y (2007) In vitro and in vivo antitumor effects of doxorubicin loaded with bacterial magnetosomes (DBMs) on H22 cells: the magnetic bio-nanoparticles as drug carriers. Cancer Lett 258:109–117. doi: 10.1016/j.canlet.2007.08.018 CrossRefGoogle Scholar
  46. Tanaka K, Ito A, Kobayashi T, Kawamura T, Shimada S, Matsumoto K, Saida T, Honda H (2005) Heat immunotherapy using magnetic nanoparticles and dendritic cells for T-lymphoma. J Biosci Bioeng 100:112–115. doi: 10.1263/jbb.100.112 CrossRefGoogle Scholar
  47. Tashjian JA, Dewhirst MW, Needham D, Viglianti BL (2008) Rationale for and measurement of liposomal drug delivery with hyperthermia using non-invasive imaging techniques. Int J Hyperth 24:79–90. doi: 10.1080/02656730701840147 CrossRefGoogle Scholar
  48. Thanoo BC, Sunny MC, Jayakrishnan A (1992) Cross-linked chitosan microspheres: preparation and evaluation as a matrix for the controlled release of pharmaceuticals. J Pharm Pharmacol 44:283–286CrossRefGoogle Scholar
  49. Torchilin VP (2006) Multifunctional nanocarriers. Adv Drug Deliv Rev 58:1532–1555. doi: 10.1016/j.addr.2006.09.009 CrossRefGoogle Scholar
  50. van Oss CJ (2006) Interfacial forces in aqueous media, 2nd edn. CRC Press, Boca Raton, FLGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Daniela P. Santos
    • 1
  • M. Adolfina Ruiz
    • 2
  • Visitación Gallardo
    • 2
  • Maria Valnice B. Zanoni
    • 1
  • José L. Arias
    • 2
  1. 1.Institute of ChemistryUniversity of São Paulo State, UNESPAraraquaraBrazil
  2. 2.Department of Pharmacy and Pharmaceutical Technology, Faculty of PharmacyUniversity of GranadaGranadaSpain

Personalised recommendations