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

Mo Dan, Younsoo Bae, Thomas A. Pittman, Robert A. Yokel

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


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.

Original languageEnglish
Pages (from-to)1615-1625
Number of pages11
JournalPharmaceutical Research
Issue number5
StatePublished - May 1 2015

Bibliographical note

Funding Information:
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. ®

Publisher Copyright:
© 2014 Springer Science+Business Media.


  • alternating magnetic field
  • blood-brain barrier permeability
  • cross-linked nanoassemblies
  • flux
  • superparamagnetic iron oxide nanoparticles

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)


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