Skip to main content

Advertisement

SpringerLink
Log in

PEG-Functionalized Magnetic Nanoparticles for Drug Delivery and Magnetic Resonance Imaging Applications

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

Polyethylene glycol (PEG) functionalized magnetic nanoparticles (MNPs) were tested as a drug carrier system, as a magnetic resonance imaging (MRI) agent, and for their ability to conjugate to an antibody.

Methods

An iron oxide core coated with oleic acid (OA) and then with OA-PEG forms a water-dispersible MNP formulation. Hydrophobic doxorubicin partitions into the OA layer for sustained drug delivery. The T1 and T2 MRI contrast properties were determined in vitro and the circulation of the MNPs was measured in mouse carotid arteries. An N-hydroxysuccinimide group (NHS) on the OA-PEG-80 was used to conjugate the amine functional group on antibodies for active targeting in the human MCF-7 breast cancer cell line.

Results

The optimized formulation had a mean hydrodynamic diameter of 184 nm with an ~8 nm iron-oxide core. The MNPs enhance the T2 MRI contrast and have a long circulation time in vivo with 30% relative concentration 50 min post-injection. Doxorubicin-loaded MNPs showed sustained drug release and dose-dependent antiproliferative effects in vitro; the drug effect was enhanced with transferrin antibody-conjugated MNPs.

Conclusion

PEG-functionalized MNPs could be developed as a targeted drug delivery system and MRI contrast agent.

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
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

REFERENCES

  1. Bulte JW, Kraitchman DL. Monitoring cell therapy using iron oxide MR contrast agents. Curr Pharm Biotechnol. 2004;5:567–84.

    Article  CAS  PubMed  Google Scholar 

  2. Josephson L. Magnetic nanoparticles for MR imaging. US: Springer; 2007.

    Google Scholar 

  3. Bulte JW, Kraitchman DL. Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed. 2004;17:484–99.

    Article  CAS  PubMed  Google Scholar 

  4. Alexiou C, Arnold W, Klein RJ, Parak FG, Hulin P, Bergemann C, et al. Locoregional cancer treatment with magnetic drug targeting. Cancer Res. 2000;60:6641–8.

    CAS  PubMed  Google Scholar 

  5. Beaven GH, Chen SH, d’Albis A, Gratzer WB. A spectroscopic study of the haemin–human-serum-albumin system. Eur J Biochem. 1974;41:539–46.

    Article  CAS  PubMed  Google Scholar 

  6. Lehrer SS, Fasman GD. The fluorescence of lysozyme and lysozyme substrate complexes. Biochem Biophys Res Commun. 1966;23:133–8.

    Article  CAS  PubMed  Google Scholar 

  7. Chipman DM, Grisaro V, Sharon N. The binding of oligosaccharides containing N-acetylglucosamine and N-acetylmuramic acid to lysozyme. The specificity of binding subsites. J Biol Chem. 1967;242:4388–94.

    CAS  PubMed  Google Scholar 

  8. Jeffery GH, Bassett J, Mendham J, Denny RC. Vogel’s text book of quantitative chemical analysis. New York: Wiley; 1989.

    Google Scholar 

  9. Moffat BA, Reddy GR, McConville P, Hall DE, Chenevert TL, Kopelman RR, et al. A novel polyacrylamide magnetic nanoparticle contrast agent for molecular imaging using MRI. Mol Imaging. 2003;2:324–32.

    Article  CAS  PubMed  Google Scholar 

  10. Yolles S, Aslund B, Morton JF, Olson OT, Rosenberg B. Timed-released depot for anticancer agents. II. Acta Pharm Suec. 1978;15:382–8.

    CAS  PubMed  Google Scholar 

  11. Olivier JC, Huertas R, Lee HJ, Calon F, Pardridge WM. Synthesis of pegylated immunonanoparticles. Pharm Res. 2002;19:1137–43.

    Article  CAS  PubMed  Google Scholar 

  12. Gou ML, Qian ZY, Wang H, Tang YB, Huang MJ, Kan B, et al. Preparation and characterization of magnetic poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) microspheres. J Mater Sci Mater Med. 2007;19:1033–41.

    Article  PubMed  Google Scholar 

  13. Liu X, Kaminski MD, Chen H, Torno M, Taylor L, Rosengart AJ. Synthesis and characterization of highly-magnetic biodegradable poly(d, l-lactide-co-glycolide) nanospheres. J Control Release. 2007;119:52–8.

    Article  CAS  PubMed  Google Scholar 

  14. Okassa LN, Marchais H, Douziech-Eyrolles L, Herve K, Cohen-Jonathan S, Munnier E, et al. Optimization of iron oxide nanoparticles encapsulation within poly(d, l-lactide-co-glycolide) sub-micron particles. Eur J Pharm Biopharm. 2007;67:31–8.

    Article  CAS  PubMed  Google Scholar 

  15. Hamoudeh M, Al Faraj A, Canet-Soulas E, Bessueille F, Leonard D, Fessi H. Elaboration of PLLA-based superparamagnetic nanoparticles: characterization, magnetic behaviour study and in vitro relaxivity evaluation. Int J Pharm. 2007;338:248–57.

    Article  CAS  PubMed  Google Scholar 

  16. Bhattacharya S, Eckert F, Boyko V, Pich A. Temperature-, pH-, and magnetic-field-sensitive hybrid microgels. Small. 2007;3:650–7.

    Article  CAS  PubMed  Google Scholar 

  17. Shen F, Poncet-Legrand C, Somers S, Slade A, Yip C, Duft AM, et al. Properties of a novel magnetized alginate for magnetic resonance imaging. Biotechnol Bioeng. 2003;83:282–92.

    Article  CAS  PubMed  Google Scholar 

  18. Bonacchi D, Caneschi A, Dorignac D, Falqui A, Gatteschi D, Rovai D, et al. Nanosized iron oxide particles entrapped in pseudo-single crystals gamma-cyclodextrin. Chem Mater. 2004;16:2016–20.

    Article  CAS  Google Scholar 

  19. Bonacchi D, Caneschi A, Gatteschi D, Sangregorio C, Sessoli R, Falqui A. Synthesis and characterisation of metal oxides nanoparticles entrapped in cyclodextrin. J Phys Chem Solids. 2004;65:719–22.

    Article  CAS  Google Scholar 

  20. Mikhaylova M, Kim DK, Bobrysheva N, Osmolowsky M, Semenov V, Tsakalakos T, et al. Superparamagnetism of magnetite nanoparticles: dependence on surface modification. Langmuir. 2004;20:2472–7.

    Article  CAS  PubMed  Google Scholar 

  21. Kim DK, Mikhaylova M, Wang FH, Kehr J, Bjelke B, Zhang Y, et al. Starch-coated superparamagnetic nanoparticles as MR contrast agents. Chem Mater. 2003;15:4343–51.

    Article  CAS  Google Scholar 

  22. Pardoe H, Chua-anusorn W, St. Pierre TG, Dobson J. Structural and magnetic properties of nanoscale iron oxide particles synthesized in the presence of dextran or polyvinyl alcohol. J Magn Magn Mater. 2001;225:41–6.

    Article  CAS  Google Scholar 

  23. Lee H, Yu MK, Park S, Moon S, Min JJ, Jeong YY, et al. Thermally cross-linked superparamagnetic iron oxide nanoparticles: synthesis and application as a dual imaging probe for cancer in vivo. J Am Chem Soc. 2007;129:12739–45.

    Article  CAS  PubMed  Google Scholar 

  24. Wan S, Huang J, Guo M, Zhang H, Cao Y, Yan H, et al. Biocompatible superparamagnetic iron oxide nanoparticle dispersions stabilized with poly(ethylene glycol)-oligo(aspartic acid) hybrids. J Biomed Mater Res A. 2007;80:946–54.

    PubMed  Google Scholar 

  25. Lutz JF, Stiller S, Hoth A, Kaufner L, Pison U, Cartier R. One-pot synthesis of pegylated ultrasmall iron-oxide nanoparticles and their in vivo evaluation as magnetic resonance imaging contrast agents. Biomacromolecules. 2006;7:3132–8.

    Article  CAS  PubMed  Google Scholar 

  26. Xie J, Xu C, Kohler N, Hou Y, Sun S. Controlled PEGylation of monodisperse Fe3O4 nanoparticles for reduced non-specific uptake by macrophage cells. Adv Mater. 2007;19:3163–6.

    Article  CAS  Google Scholar 

  27. Ditsch A, Laibinis PE, Wang DI, Hatton TA. Controlled clustering and enhanced stability of polymer-coated magnetic nanoparticles. Langmuir. 2005;21:6006–18.

    Article  CAS  PubMed  Google Scholar 

  28. Weissleder R, Elizondo G, Wittenberg J, Lee AS, Josephson L, Brady TJ. Ultrasmall superparamagnetic iron oxide: an intravenous contrast agent for assessing lymph nodes with MR imaging. Radiology. 1990;175:494–8.

    CAS  PubMed  Google Scholar 

  29. McCarthy JR, Weissleder R. Multifunctional magnetic nanoparticles for targeted imaging and therapy. Adv Drug Deliv Rev. 2008;60:1241–51.

    Article  CAS  PubMed  Google Scholar 

  30. Okuhata Y. Delivery of diagnostic agents for magnetic resonance imaging. Adv Drug Deliv Rev. 1999;37:121–37.

    Article  CAS  PubMed  Google Scholar 

  31. Yigit MV, Mazumdar D, Lu Y. MRI detection of thrombin with aptamer functionalized superparamagnetic iron oxide nanoparticles. Bioconjug Chem. 2008;19:412–7.

    Article  CAS  PubMed  Google Scholar 

  32. Jun YW, Huh YM, Choi JS, Lee JH, Song HT, Kim S, et al. Nanoscale size effect of magnetic nanocrystals and their utilization for cancer diagnosis via magnetic resonance imaging. J Am Chem Soc. 2005;127:5732–3.

    Article  CAS  PubMed  Google Scholar 

  33. Jain TK, Richey J, Strand M, Leslie-Pelecky DL, Flask CA, Labhasetwar V. Magnetic nanoparticles with dual functional properties: drug delivery and magnetic resonance imaging. Biomaterials. 2008;29:4012–21.

    Article  CAS  PubMed  Google Scholar 

  34. Bulte JWM, Cuyper MD, Despres D, Frank JA. Preparation, relaxometry, and biokinetics of PEGylated magnetoliposomes as MR contrast agent. J Magn Magn Mater. 1999;194:204–9.

    Article  CAS  Google Scholar 

  35. Zhang Y, Kohler N, Zhang MQ. Surface modification of superparamagnetic magnetite nanoparticles and their intracellular uptake. Biomaterials. 2002;23:1553–61.

    Article  CAS  PubMed  Google Scholar 

  36. Arruebo M, Fernandez-Pacheco R, Ibarra MR, Santamaria J. Magnetic nanoparticles for drug delivery. Nano Today. 2007;2:22–32.

    Article  Google Scholar 

  37. Lewin M, Carlesso N, Tung CH, Tang XW, Cory D, Scadden DT, et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat Biotechnol. 2000;18:410–4.

    Article  CAS  PubMed  Google Scholar 

  38. Seo SB, Yang J, Hyung W, Cho EJ, Lee TI, Song YJ, et al. Novel multifunctional PHDCA/PEI nano-drug carriers for simultaneous magnetically targeted cancer therapy and diagnosis via magnetic resonance imaging. Nanotechnology. 2007;18:1–8.

    Article  Google Scholar 

  39. Jain TK, Reddy MK, Morales MA, Leslie-Pelecky DL, Labhasetwar V. Biodistribution, clearance, and biocompatibility of iron oxide magnetic nanoparticles in rats. Mol Pharmaceutics. 2008;5:316–27.

    Article  CAS  Google Scholar 

  40. Jain TK, Foy SP, Erokwu B, Dimitrijevic S, Flask CA, Labhasetwar V. Magnetic resonance imaging of multifunctional pluronic stabilized iron-oxide nanoparticles in tumor-bearing mice. Biomaterials. 2009;30:6748–56.

    Article  CAS  PubMed  Google Scholar 

  41. Neuberger T, Schopf B, Hofmann H, Hofmann M, von Rechenberg B. Superparamagnetic nanoparticles for biomedical applications: possibilities and limitations of a new drug delivery system. J Magn Magn Mater. 2005;293:483–96.

    Article  CAS  Google Scholar 

  42. Jun YW, Lee JH, Cheon J. Chemical design of nanoparticle probes for high-performance magnetic resonance imaging. Angew Chem Int Ed Engl. 2008;47:5122–35.

    Article  CAS  PubMed  Google Scholar 

  43. Jain TK, Morales MA, Sahoo SK, Leslie-Pelecky DL, Labhasetwar V. Iron oxide nanoparticles for sustained delivery of anticancer agents. Mol Pharmaceutics. 2005;2:194–205.

    Article  CAS  Google Scholar 

  44. Kosaka N, Ogawa M, Longmire MR, Choyke PL, Kobayashi H. Multi-targeted multi-color in vivo optical imaging in a model of disseminated peritoneal ovarian cancer. J Biomed Opt. 2009;14:014023.

    Article  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS

The study reported here is funded by grant R01 EB005822 (to VL) from the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health. SPF is a predoctoral student in Cleveland Clinic’s Molecular Medicine Ph.D. Program, which is funded by the “Med into Grad” initiative of the Howard Hughes Medical Institute (http://www.lerner.ccf.org/molecmed/phd/).

Author information

Author notes

  1. Murali Mohan Yallapu

    Present address: Cancer Biology Research Center, Sanford Research/University of South Dakota, Sioux Falls, SD, 57105, USA

  2. Tapan K. Jain

    Present address: University School of Basic & Applied Sciences, Guru Gobind Singh Indraprastha University, Dwarka, Sector 16C, New Delhi, 110078, India

Authors and Affiliations

  1. Department of Biomedical Engineering/ND-20 Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Murali Mohan Yallapu, Susan P. Foy, Tapan K. Jain & Vinod Labhasetwar

  2. Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, 44195, USA

    Vinod Labhasetwar

Authors
  1. Murali Mohan Yallapu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susan P. Foy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tapan K. Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vinod Labhasetwar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vinod Labhasetwar.

Electronic Supplementary Materials

Below is the link to the electronic supplementary material.

Supplementary materials

(DOC 96 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yallapu, M.M., Foy, S.P., Jain, T.K. et al. PEG-Functionalized Magnetic Nanoparticles for Drug Delivery and Magnetic Resonance Imaging Applications. Pharm Res 27, 2283–2295 (2010). https://doi.org/10.1007/s11095-010-0260-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-010-0260-1

KEY WORDS

Search

Navigation