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.

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Published in Pharmaceutical Research, v. 32, no. 5, p. 1615-1625.

© Springer Science+Business Media New York 2014

The copyright holder has granted the permission for posting the article here.

The document available for download is the authors' post-peer-review final draft of the article. The final publication is available at Springer via http://dx.doi.org/10.1007/s11095-014-1561-6

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Funding Information

Mo Dan and the project described were supported by Grant Number R25CA153954 from the National Cancer Institute.