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Folic acid conjugated magnetic drug delivery system for controlled release of doxorubicin

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Abstract

Targeting tumors by means of their vascular endothelium is a promising strategy, which utilizes targets that are easily accessible, stable, and do not develop resistance against therapeutic agents. Folate receptor is a highly specific tumor marker, frequently over expressed in cancer tumors. In the present study, an active drug delivery system, which can effectively target cancer cells by means of folate receptor-mediated endocytosis, have ability to escape from opsonization and capability of magnetic targeting to withstand the drag force of the body fluid have been designed and synthesized. The core of the drug delivery system is of mono-domain magnetic particles of magnetite. Magnetite nanoparticles are shielded with PEG, which prevents their phagocytosis by reticuloendothelial system. These PEG shielded magnetite nanoparticles are further decorated with an antitumor receptor—folic acid and loaded with an antineoplastic agent doxorubicin. An in vitro drug loading and release kinetics study reveals that the drug delivery system can take 52 % of drug load and can release doxorubicin over a sustained period of 7 days. The control and sustained release over a period of several days may find its practical utilities in chemotherapy where frequent dosing is not possible.

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References

  • Barrera C, Herrera A, Zayas Y, Rinaldi C (2009) Surface modification of magnetite nanoparticles for biomedical applications. J Magn Magn Mater 321:1397–1399

    Article  CAS  Google Scholar 

  • Brannon-Peppas L, Blanchette J (2004) Nanoparticles and targeted systems for cancer therapy. Adv Drug Del Rev 56:1649–1659

    Article  CAS  Google Scholar 

  • Caliceti P, Salmaso S, Semenzato A, Carofiglio T, Fornasier R, Fermeqlia M, Ferrone M, Pricl S (2003) Synthesis and physicochemical characterization of folate: cyclodextrin bioconjugate for active drug delivery. Bioconjugate Chem 14:899–908

    Article  CAS  Google Scholar 

  • Cascante M, Centelles J, Veech R, Lee W, Boros L (2000) Role of thiamin (Vitamin B1) and transketolase in tumor cell proliferation. Nutr Cancer 36:150–154

    Article  CAS  Google Scholar 

  • Dreborg S, Akerblom E (1990) Immunotherapy with monomethoxypolyethelene glycol modified allergens. Crit Rev Ther Drug Carrier Sys 63:15–365

    Google Scholar 

  • Fornari F, Randolph J, Yalowich J, Ritke M, Gewirtz D (1994) Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells. Mol Pharmacol 45:649–656

    CAS  Google Scholar 

  • Gupta A, Gupta M (2005) Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials 26:3995–4021

    Article  CAS  Google Scholar 

  • Harris J (1985) Laboratory synthesis of polyethelene glycol derivatives. J Macromol Sci, Rev Macromol Chem Phys C25:325–373

    Article  CAS  Google Scholar 

  • Kaul G, Amiji M (2002) Long-circulating poly (ethylene glycol)-modified gelatin nanoparticles for intracellular delivery. Pharm Res 19:1061–1067

    Article  CAS  Google Scholar 

  • Kiessling L, Gestwicki J, Strong L (2000) Synthetic multivalent ligands in the exploration of cell-surface interactions. Curr Opin Chem Biol 4:696–703

    Article  CAS  Google Scholar 

  • Koda J, Venook A, Walser E, Goodwin S (2002) Phase I/II trial of hepatic intraarterial delivery of doxorubicin hydrochloride adsorbed to magnetic targeted carriers in patients with hepatocarcinoma. Eur J Cancer 38:S18

    Google Scholar 

  • Komaki R, Putnam J, Cox J (1997) Thymic neoplasms. Curr Opin Oncol 9:156–160

    Article  CAS  Google Scholar 

  • Lee K (2005) Stability of Ionic complexes prepared from plasmid DNA and self-aggregated chitosan nanoparticles. Macromol Res 13:542–544

    Article  CAS  Google Scholar 

  • Li Y, Afzaal M, Brien P (2006) The synthesis of ammine-capped magnetic (Fe, Mn, Co., Ni) oxide nanocrystals and their surface modification for aquous dispersibility. J Mater Chem 16:2175–2180

    Article  CAS  Google Scholar 

  • Lin C, Chiang RJ, Sung T (2006) Magnetic nanoproperties of monodispersed iron oxide nanoparticles. J App Phys 99: 08N710

  • Lopez-Quintela M, Rivas J (1993) Chemical reactions in microemulsions: a powerful method to obtain ultrafine particles. J Coll Interface Sci 158:446–451

    Article  CAS  Google Scholar 

  • Luangtana-anan M, Nunthanid J, Limmatvapirat S (2010) Effect of molecular weight and concentration of polyethylene glycol on physicochemical properties and stability of shellac film. J Agric Food Chem 58:12934–12940

    Article  CAS  Google Scholar 

  • Lübbe AS, Bergemann C, Huhnt W, Fricke T, Riess H, Brock JW, Huhn D (1996) Preclinical experiences with magnetic drug targeting: tolerance and efficacy. Cancer Res 56:4694–4701

    Google Scholar 

  • Lübbe A, Alexiou C, Bergmann C (2001) Clinical applications of magnetic drug targeting. J Surg Res 95:200–206

    Article  Google Scholar 

  • Ma M, Zhang Y, Yu W, Shen H, Zhang H, Gu N (2003) Preparation and characterization of magnetite nanoparticles coated by amino silane. J Colloids surf A: 212–219

  • Maed H, Wu J, Sawa T, Matsumura Y, Hori K (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 65:271–284

    Article  Google Scholar 

  • Mohapatra S, Mallick S, Maiti T, Ghosh S, Pramanik P (2007) Synthesis of highly stable folic acid conjugate magnetite nanoparticles for targeting cancer cells. Nanotechnology 18:385102

    Article  Google Scholar 

  • Pankhurst Q, Connolly J, Jones S, Dobson J (2003) Applications of magnetic nanoparticles in biomedicine. J Phys D 36:R167–R181

    Article  CAS  Google Scholar 

  • Park J, An K, Hwang Y, Park J, Noh H, Kim J, Park J, Hwang N, Hyeon T (2004) Ultra-large-scale syntheses of monodisperse nanocrystals. Nature Mater 3:891–895

    Article  CAS  Google Scholar 

  • Plank C (2009) Nanomedicine: silence the target. Nat Nanotechnol 4:544–545

    Article  CAS  Google Scholar 

  • Prozorov T, Prozorov R, Koltypin Yu, Felner I, Gedanken A (1998) Sonochemistry under an applied magnertic field: determining the shape of a magnetic particle. J Phys Chem B 102:10165–10168

    Article  CAS  Google Scholar 

  • Reddy J, Allagadda V, Leamon C (2005) Targeting therapeutics and imaging agents to folate receptor positive tumors. Curr Pharm Biotechnol 6:131–150

    Article  CAS  Google Scholar 

  • Sahoo S, Labhasetwar V (2003) Nanotech approaches to drug delivery and imaging. Drug Discov Today 8:1112–1120

    Article  CAS  Google Scholar 

  • Sugimoto T, Matijevic E (1980) Formation of uniform spherical magnetite particles by crystalization from ferrus hydroxyde gels. J Coll Interface Sci 74:227–243

    Article  CAS  Google Scholar 

  • Sun S, Zeng H (2002) Size controlled synthesis of magnetite nanoparticles. J Am Chem Soc 124:8204–8205

    Article  CAS  Google Scholar 

  • Sun S, Zeng H, Robinson D, Raoux S, Rice P, Wang S, Li G (2004) Monodispersed MFe2O4 (M = Fe, Co., Mn)nanoparticles. J Am Chem Soc 126:273–279

    Article  CAS  Google Scholar 

  • Sun C, Sze R, Zhang M (2006) Folic acid-PEG conjugated superparamagnetic nanoparticles for targeted cellular uptake and detection by MIR. J Biomed Mater Res, Part A 78A:550–557

    Article  CAS  Google Scholar 

  • Takakura Y, Maruyama K, Yokoyama M (1999) Passive targeting of drugs. Drug Deliv Syst 14:425–426

    Article  CAS  Google Scholar 

  • Tang Z, Sorensen C, Klabunde K, Hadjipanayiss G (1991) Preparation of manganese ferrite fine particles from aqueous solution. J Coll Interface Sci 146:38–52

    Article  CAS  Google Scholar 

  • Wilson M, Kerlan R, Fidleman N (2004) Hepatocellular carncinoma: regional therapy with a magnetic targeted carrier bound to doxorubicin in a dual MR imaging/conventional angiography suite- initial experience with 4 patients. Radiology 230:287–293

    Article  Google Scholar 

  • Xie J, Peng S, Brower N, Pourmand N, Wang S, Sun S (2006) One-pot synthesis of monodisperse iron oxide nanoparticles for potential biomedical applications. Pure Appl Chem 78:1003–1014

    Article  CAS  Google Scholar 

  • Xu Q, Xubu JinC (2005) Self-aggregates of cholic acid hydrazide-dextran conjugates as drug carriers. J Appl Polymer Sci 95:487–493

    Article  CAS  Google Scholar 

  • Ye X, Daraio C, Wang C, Talbot J, Jin S (2006) Room temperature solvent free synthesis of monodisperse magnetite nanocrystals. J Nanosci Nanotechnol 6:852–856

    Article  CAS  Google Scholar 

  • Yokoyama M, Okano T (1996) Targetable drug carriers: present status and a future perspective. Adv Drug Deliv Rev 21:77–80

    Article  CAS  Google Scholar 

  • Zhang J, Misra R (2007) Magnetic drug-targeting carrier encapsulated with thermosensitive smart polymer: core-shell nanoparticles carriers and drug release response. Acta Biomater 3:838–850

    Article  CAS  Google Scholar 

  • Zhang J, Srivastava R, Misra R (2007) Core-shell magnetite nanoparticles surface encapsulated with smart stimuli-responsive polymer: synthesis, characterization, and LCST of viable drug- targeting delivery systems. Langmuir 23:6342–6351

    Article  CAS  Google Scholar 

  • Zhang J, Rana S, Srivastava R, Misra R (2008) On the chemical synthesis and drug delivery response of folate receptor-activated, polyethylene glycol functionalized magnetic nanoparticles. Acta Biomater 4:40–48

    Article  CAS  Google Scholar 

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Acknowledgments

This work was financially supported by the Department of Science & Technology, New Delhi, under its fast track scheme SR/FTP/PS-109/2010, University Grants Commission, New Delhi under the DS Kothari postdoctoral fellowship awarded to Dr. N. Andhariya (F.4-2/2006(BSR)/13-467/2011(BSR) and Thapar University, Patiala.

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Correspondence to Nidhi Andhariya or Bhupendra Chudasama.

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Andhariya, N., Upadhyay, R., Mehta, R. et al. Folic acid conjugated magnetic drug delivery system for controlled release of doxorubicin. J Nanopart Res 15, 1416 (2013). https://doi.org/10.1007/s11051-013-1416-9

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