Alternating magnetic field-induced hyperthermia increases iron oxide nanoparticle cell association/uptake and flux in blood-brain barrier models.
OBJECTIVE
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.
Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky, 40536, USA.
Mo
M
Dan
Younsoo
Y
Bae
Thomas A
TA
Pittman
Robert A
RA
Yokel
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002199:Capillary Permeability; D002460:Cell Line; D019343:Citric Acid / Q000032:analysis / Q000493:pharmacokinetics; D004285:Dogs; D004867:Equipment Design; D005290:Ferric Compounds / Q000032:analysis / Q000493:pharmacokinetics*; D006801:Humans; D006979:Hyperthermia, Induced / Q000295:instrumentation*; D060526:Magnetic Fields; D058185:Magnetite Nanoparticles / Q000032:analysis* / Q000648:ultrastructure; D051379:Mice
D005290:Ferric Compounds; D058185:Magnetite Nanoparticles; C000499:ferric oxide; D019343:Citric Acid