Skip to main content

Advertisement

SpringerLink
Log in

Alternating Magnetic Field-Induced Hyperthermia Increases Iron Oxide Nanoparticle Cell Association/Uptake and Flux in Blood–Brain Barrier Models

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

ABSTRACT

Purpose

Superparamagnetic iron oxide nanoparticles (IONPs) are being investigated for brain cancer therapy because alternating magnetic field (AMF) activates them to produce hyperthermia. For central nervous system applications, brain entry of diagnostic and therapeutic agents is usually essential. We hypothesized that AMF-induced hyperthermia significantly increases IONP blood–brain barrier (BBB) association/uptake and flux.

Methods

Cross-linked nanoassemblies loaded with IONPs (CNA-IONPs) and conventional citrate-coated IONPs (citrate-IONPs) were synthesized and characterized in house. CNA-IONP and citrate-IONP BBB cell association/uptake and flux were studied using two BBB Transwell® models (bEnd.3 and MDCKII cells) after conventional and AMF-induced hyperthermia exposure.

Results

AMF-induced hyperthermia for 0.5 h did not alter CNA-IONP size but accelerated citrate-IONP agglomeration. AMF-induced hyperthermia for 0.5 h enhanced CNA-IONP and citrate-IONP BBB cell association/uptake. It also enhanced the flux of CNA-IONPs across the two in vitro BBB models compared to conventional hyperthermia and normothermia, in the absence of cell death. Citrate-IONP flux was not observed under these conditions. AMF-induced hyperthermia also significantly enhanced paracellular pathway flux. The mechanism appears to involve more than the increased temperature surrounding the CNA-IONPs.

Conclusions

Hyperthermia induced by AMF activation of CNA-IONPs has potential to increase the BBB permeability of therapeutics for the diagnosis and therapy of various brain diseases.

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

Abbreviations

AMF:

Alternating magnetic field

BBB:

Blood–brain barrier

bEnd.3:

A transformed murine brain/cerebral cortex endothelial cell line

Citrate IONPs:

Citrate iron oxide nanoparticles

CNA-IONPs:

Cross-linked nanoassembly iron oxide nanoparticles

CNS:

Central nervous system

DLS:

Dynamic light scattering

IONPs:

Iron oxide nanoparticles

LY:

Lucifer yellow

MDCKII:

Madin-Darby canine kidney II cells

Papp :

Apparent permeability coefficient

REFERENCES

  1. Bernacki J, Dobrowolska A, Nierwinska K, Malecki A. Physiology and pharmacological role of the blood–brain barrier. Pharmacol Rep. 2008;60(5):600–22.

    CAS  PubMed  Google Scholar 

  2. Agarwal A, Lariya N, Saraogi G, Dubey N, Agrawal H, Agrawal GP. Nanoparticles as novel carrier for brain delivery: a review. Curr Pharm Des. 2009;15(8):917–25.

    Article  CAS  PubMed  Google Scholar 

  3. Peetla C, Labhasetwar V. Biophysical characterization of nanoparticle-endothelial model cell membrane interactions. Mol Pharm. 2008;5(3):418–29.

    Article  CAS  PubMed  Google Scholar 

  4. Dhanikula RS, Hammady T, Hildgen P. On the mechanism and dynamics of uptake and permeation of polyether-copolyester dendrimers across an in vitro blood–brain barrier model. J Pharm Sci. 2009;98(10):3748–60.

    Article  CAS  PubMed  Google Scholar 

  5. Boström M, Hellstroem Erkenstam N, Kaluza D, Jakobsson L, Kalm M, Blomgren K. The hippocampal neurovascular niche during normal development and after irradiation to the juvenile mouse brain. Int J Radiat Biol. 2014;90(9):778–89.

    Article  PubMed  Google Scholar 

  6. Triguero D, Buciak J, Pardridge WM. Capillary depletion method for quantification of blood–brain barrier transport of circulating peptides and plasma proteins. J Neurochem. 1990;54(6):1882–8.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang L, Bai R, Li B, Ge C, Du J, Liu Y, et al. Rutile TiO2 particles exert size and surface coating dependent retention and lesions on the murine brain. Toxicol Lett. 2011;207(1):73–81.

    Article  CAS  PubMed  Google Scholar 

  8. Wang J, Chen C, Liu Y, Jiao F, Li W, Lao F, et al. Potential neurological lesion after nasal instillation of TiO2 nanoparticles in the anatase and rutile crystal phases. Toxicol Lett. 2008;183(1–3):72–80.

    Article  CAS  PubMed  Google Scholar 

  9. Ambruosi A, Gelperina S, Khalansky A, Tanski S, Theisen A, Kreuter J. Influence of surfactants, polymer and doxorubicin loading on the anti-tumour effect of poly(butyl cyanoacrylate) nanoparticles in a rat glioma model. J Microencapsul. 2006;23(5):582–92.

    Article  CAS  PubMed  Google Scholar 

  10. Dan M, Scott DF, Hardy PA, Wydra RJ, Hilt JZ, Yokel RA, et al. Block copolymer cross-linked nanoassemblies improve particle stability and biocompatibility of superparamagnetic iron oxide nanoparticles. Pharm Res. 2013;30(3):552–61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. van der Zee J. Heating the patient: a promising approach? Ann Oncol. 2002;13(8):1173–84.

    Article  PubMed  Google Scholar 

  12. Meenach SA, Anderson KW, Hilt JZ. Synthesis and characterization of thermoresponsive poly(ethylene glycol)-based hydrogels and their magnetic nanocomposites. J Polym Sci Part A: Polym Chem. 2010;48(15):3229–35.

    Article  CAS  Google Scholar 

  13. Silva AC, Oliveira TR, Mamani JB, Malheiros SMF, Malavolta L, Pavon LF, et al. Application of hyperthermia induced by superparamagnetic iron oxide nanoparticles in glioma treatment. Int J Nanomed. 2011;6:591–603.

    CAS  Google Scholar 

  14. Kiyatkin EA, Sharma HS. Permeability of the blood–brain barrier depends on brain temperature. Neuroscience (Amsterdam, Neth). 2009;161(3):926–39.

    CAS  Google Scholar 

  15. Gong W, Wang Z, Liu N, Lin W, Wang X, Xu D, et al. Improving efficiency of adriamycin crossing blood brain barrier by combination of thermosensitive liposomes and hyperthermia. Biol Pharm Bull. 2011;34(7):1058–64.

    Article  CAS  PubMed  Google Scholar 

  16. Sharma HS, Hoopes PJ. Hyperthermia induced pathophysiology of the central nervous system. Int J Hyperthermia. 2003;19(3):325–54.

    Article  CAS  PubMed  Google Scholar 

  17. Kenzaoui BH, Bernasconi CC, Hofmann H, Juillerat-Jeanneret L. Evaluation of uptake and transport of ultrasmall superparamagnetic iron oxide nanoparticles by human brain-derived endothelial cells. Nanomedicine (Lond). 2012;7(1):39–53.

    Article  CAS  Google Scholar 

  18. Watanabe T, Dohgu S, Takata F, Nishioku T, Nakashima A, Futagami K, et al. Paracellular barrier and tight junction protein expression in the immortalized brain endothelial cell lines bEND.3, bEND.5 and mouse brain endothelial cell 4. Biol Pharm Bull. 2013;36(3):492–5.

    Article  CAS  PubMed  Google Scholar 

  19. Abbott NJ, Dolman DEM, Drndarski S, Fredriksson SM. An improved in vitro blood–brain barrier model: rat brain endothelial cells co-cultured with astrocytes. Methods Mol Biol (N Y, NY, U S). 2012;814(Astrocytes: Methods & Protocols):415–30.

  20. Kadam RS, Scheinman RI, Kompella UB. Pigmented-MDCK (P-MDCK) cell line with tunable melanin expression: an in vitro model for the outer blood-retinal barrier. Mol Pharm. 2012;9(11):3228–35.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Fazlollahi F, Angelow S, Yacobi NR, Marchelletta R, Yu ASL, Hamm-Alvarez SF, et al. Polystyrene nanoparticle trafficking across MDCK-II. Nanomedicine (Philadelphia, PA, U S). 2011;7(5):588–94.

    CAS  Google Scholar 

  22. Hellinger E, Veszelka S, Toth AE, Walter F, Kittel A, Bakk ML, et al. Comparison of brain capillary endothelial cell-based and epithelial (MDCK-MDR1, Caco-2, and VB-Caco-2) cell-based surrogate blood–brain barrier penetration models. Eur J Pharm Biopharm. 2012;82(2):340–51.

    Article  CAS  PubMed  Google Scholar 

  23. Lee HJ, Bae Y. Cross-linked nanoassemblies from poly(ethylene glycol)-poly(aspartate) block copolymers as stable supramolecular templates for particulate drug delivery. Biomacromolecules. 2011;12(7):2686–96.

    Article  CAS  PubMed  Google Scholar 

  24. Brown RC, Morris AP, O'Neil RG. Tight junction protein expression and barrier properties of immortalized mouse brain microvessel endothelial cells. Brain Res. 2007;1130(1):17–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Nozinic D, Milic A, Mikac L, Ralic J, Padovan J, Antolovic R. Assessment of macrolide transport using PAMPA, Caco-2 and MDCKII-hMDR1 assays. Croat Chem Acta. 2010;83(3):323–31.

    CAS  Google Scholar 

  26. Basel MT, Balivada S, Wang H, Shrestha TB, Seo GM, Pyle M, et al. Cell-delivered magnetic nanoparticles caused hyperthermia-mediated increased survival in a murine pancreatic cancer model. Int J Nanomed. 2012;7:297–306.

    Article  CAS  Google Scholar 

  27. Riemer J, Hoepken HH, Czerwinska H, Robinson SR, Dringen R. Colorimetric ferrozine-based assay for the quantitation of iron in cultured cells. Anal Biochem. 2004;331(2):370–5.

    Article  CAS  PubMed  Google Scholar 

  28. Zhou Y, Harris WR, Yokel RA. The influence of citrate, maltolate and fluoride on the gastrointestinal absorption of aluminum at a drinking water-relevant concentration: A 26Al and 14C study. J Inorg Biochem. 2008;102:798–808.

    Article  CAS  PubMed  Google Scholar 

  29. Zhou Y, Yokel RA. The chemical species of aluminum influences its paracellular flux across and uptake into Caco-2 cells, a model of gastrointestinal absorption. Toxicol Sci. 2005;87(1):15–26.

    Article  CAS  PubMed  Google Scholar 

  30. Strober W. Trypan blue exclusion test of cell viability. In: Coligan JE, editor. Curr Protoc Immunol. 2001; Appendix 3B.

  31. Bhaskar S, Tian F, Stoeger T, Kreyling W, de la Fuente JM, Grazu V, Borm P, Estrada G, Ntziachristos V, Razansky D. Multifunctional nanocarriers for diagnostics, drug delivery and targeted treatment across blood–brain barrier: perspectives on tracking and neuroimaging. Part Fibre Toxicol. 2010;7.

  32. Neuberger T, Schoepf 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(1):483–96.

    Article  CAS  Google Scholar 

  33. Scott D, Rohr J, Bae Y. Nanoparticulate formulations of mithramycin analogs for enhanced cytotoxicity. Int J Nanomed. 2011;6:2757–67.

    Article  CAS  Google Scholar 

  34. Hoff D, Sheikh L, Bhattacharya S, Nayar S, Webster TJ. Comparison study of ferrofluid and powder iron oxide nanoparticle permeability across the blood–brain barrier. Int J Nanomed. 2012;8:703–10.

    CAS  Google Scholar 

  35. Sun Z, Worden M, Wroczynskyj Y, Yathindranath V, van Lierop J, Hegmann T, et al. Magnetic field enhanced convective diffusion of iron oxide nanoparticles in an osmotically disrupted cell culture model of the blood–brain barrier. Int J Nanomed. 2014;9:3013–26.

    Article  CAS  Google Scholar 

  36. Moriyama E, Salcman M, Broadwell RD. Blood–brain barrier alteration after microwave-induced hyperthermia is purely a thermal effect: I. Temperature and power measurements. Surg Neurol. 1991;35(3):177–82.

    Article  CAS  PubMed  Google Scholar 

  37. Nakagawa M, Matsumoto K, Higashi H, Furuta T, Ohmoto T. Acute effects of interstitial hyperthermia on normal monkey brain–magnetic resonance imaging appearance and effects on blood–brain barrier. Neurol Med Chir (Tokyo). 1994;34(10):668–75.

    Article  CAS  Google Scholar 

  38. Uzuka T, Takahashi H, Tanaka R. Interstitial hyperthermia with intra-arterial injection of adriamycin for malignant glioma. Neurol Med Chir (Tokyo). 2006;46(1):19–23. discussion 23.

    Article  Google Scholar 

  39. Wang Q, Rager JD, Weinstein K, Kardos PS, Dobson GL, Li J, et al. Evaluation of the MDR-MDCK cell line as a permeability screen for the blood–brain barrier. Int J Pharm. 2005;288(2):349–59.

    Article  CAS  PubMed  Google Scholar 

  40. Wilhelm I, Fazakas C, Krizbai IA. In vitro models of the blood–brain barrier. Acta Neurobiol Exp (Wars). 2011;71(1):113–28.

    Google Scholar 

  41. Mannix RJ, Kumar S, Cassiola F, Montoya-Zavala M, Feinstein E, Prentiss M, et al. Nanomagnetic actuation of receptor-mediated signal transduction. Nat Nanotechnol. 2008;3(1):36–40.

    Article  CAS  PubMed  Google Scholar 

  42. Huang H, Delikanli S, Zeng H, Ferkey DM, Pralle A. Remote control of ion channels and neurons through magnetic-field heating of nanoparticles. Nat Nanotechnol. 2010;5(8):602–6.

    Article  CAS  PubMed  Google Scholar 

  43. Sharma HS, Sharma A, Moessler H, Muresanu DF. Neuroprotective effects of cerebrolysin, a combination of different active fragments of neurotrophic factors and peptides on the whole body hyperthermia-induced neurotoxicity: modulatory roles of co-morbidity factors and nanoparticle intoxication. Int Rev Neurobiol. 2012;102(New Perspectives of Central Nervous System Injury and Neuroprotection):249–76.

    Article  CAS  PubMed  Google Scholar 

  44. Sharma HS, Sharma A. Nanowired drug delivery for neuroprotection in central nervous system injuries: modulation by environmental temperature, intoxication of nanoparticles, and comorbidity factors. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2012;4(2):184–203.

    Article  CAS  PubMed  Google Scholar 

  45. Tabatabaei SN, Duchemin S, Girouard H, Martel S. Towards MR-navigable nanorobotic carriers for drug delivery into the brain. IEEE Int Conf Robot Autom. 2012;14:727–32.

    Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

The authors gratefully acknowledge J. Zack Hilt for sharing his AMF equipment and the citrate-IONP synthesis method, Daniel F. Scott for assisting in CNA synthesis, and Markos Leggas and Kuei-Ling Kuo for providing the MDCKII cell line and assisting in the Transwell® model establishment. Mo Dan and the project described were supported by Grant Number R25CA153954 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Author information

Authors and Affiliations

  1. Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky, 40536, USA

    Mo Dan & Robert A. Yokel

  2. Department of Neurosurgery, University of Kentucky, Lexington, Kentucky, 40536, USA

    Thomas A. Pittman

  3. National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing, 100176, China

    Mo Dan

  4. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky Academic Medical Center, 335 Biopharmaceutical Complex (College of Pharmacy) Building, Lexington, Kentucky, 40536-0596, USA

    Mo Dan, Younsoo Bae & Robert A. Yokel

Authors
  1. Mo Dan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Younsoo Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas A. Pittman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert A. Yokel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert A. Yokel.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dan, M., Bae, Y., Pittman, T.A. et al. Alternating Magnetic Field-Induced Hyperthermia Increases Iron Oxide Nanoparticle Cell Association/Uptake and Flux in Blood–Brain Barrier Models. Pharm Res 32, 1615–1625 (2015). https://doi.org/10.1007/s11095-014-1561-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-014-1561-6

KEY WORDS

Search

Navigation