Kinetics and pathogenesis of intracellular magnetic nanoparticle cytotoxicity

Abstract

Magnetic nanoparticles excited by alternating magnetic fields (AMF) have demonstrated effective tumor-specific hyperthermia. This treatment is effective as a monotherapy as well as a therapeutic adjuvant to chemotherapy and radiation. Iron oxide nanoparticles have been shown, so far, to be non-toxic, as are the exciting AMF fields when used at moderate levels. Although higher levels of AMF can be more effective, depending on the type of iron oxide nanoparticles use, these higher field strengths and/or frequencies can induce normal tissue heating and toxicity. Thus, the use of nanoparticles exhibiting significant heating at low AMF strengths and frequencies is desirable. Our preliminary experiments have shown that the aggregation of magnetic nanoparticles within tumor cells improves their heating effect and cytotoxicity per nanoparticle. We have used transmission electron microscopy to track the endocytosis of nanoparticles into tumor cells (both breast adenocarcinoma (MTG-B) and acute monocytic leukemia (THP-1) cells). Our preliminary results suggest that nanoparticles internalized into tumor cells demonstrate greater cytotoxicity when excited with AMF than an equivalent heat dose from excited external nanoparticles or cells exposed to a hot water bath. We have also demonstrated that this increase in SAR caused by aggregation improves the cytotoxicity of nanoparticle hyperthermia therapy in vitro.

Evaluating Broader Impacts of Nanoscale Thermal Transport Research

“…Further, these iron oxide nanoparticles can be targeted to cancer or even bacterial cells to induce destruction [261][262][263]. Questions as to the extent to which these nanoparticles produce heating localized on the nanoscale versus bulk and whether this Downloaded by [New York University] at 07: 56 12 June 2015 produces enhanced therapeutic effects persist in the field [263,264]. Answering these questions will provide new information that guides improved design and use of nanoparticles in a growing number of heating-based biomedical applications.…”

In vivo imaging and quantification of iron oxide nanoparticle uptake and biodistribution

“…Ongoing studies at Dartmouth have shown that SAR drastically increases when IONPs are aggregated together in a conformation of 200 nm or greater. 8 This finding is important especially if the MRI signal changes due to aggregation, which will lead to a more quantifiable assessment of nanoparticle behavior and prediction of thermal dose in the clinical settings.…”

“…The average size of the aggregates found is significantly larger than 200nm, the size at which SAR values dramatically increase. 8 Such aggregation may also be detectable with SWIFT MRI.…”

Magnetic nanoparticle hyperthermia cancer treatment efficacy dependence on cellular and tissue level particle concentration and particle heating properties

“…2 However, this appears to not be true for all types of IONPs or in some biologic environments. 3 Theoretical models and experiments suggest that there is a threshold for achieving cytotoxic heating and cell death which is dependent on IONP type, field strength, IONP concentration and aggregation, and cell number.…”

“…7 Studies within our lab suggest that cellular uptake occurs much faster in vivo than in vitro. 2 In addition, IONPs encounter a wide array of proteins and biologic environments, beyond those found in vitro. 8 Concerns about the degradation of IONPs in biological settings are also important to address.…”