Detection of breast cancer cells using targeted magnetic nanoparticles and ultra-sensitive magnetic field sensors

Abstract

IntroductionBreast cancer detection using mammography has improved clinical outcomes for many women, because mammography can detect very small (5 mm) tumors early in the course of the disease. However, mammography fails to detect 10 - 25% of tumors, and the results do not distinguish benign and malignant tumors. Reducing the false positive rate, even by a modest 10%, while improving the sensitivity, will lead to improved screening, and is a desirable and attainable goal. The emerging application of magnetic relaxometry, in particular using superconducting quantum interference device (SQUID) sensors, is fast and potentially more specific than mammography because it is designed to detect tumor-targeted iron oxide magnetic nanoparticles. Furthermore, magnetic relaxometry is theoretically more specific than MRI detection, because only target-bound nanoparticles are detected. Our group is developing antibody-conjugated magnetic nanoparticles targeted to breast cancer cells that can be detected using magnetic relaxometry.MethodsTo accomplish this, we identified a series of breast cancer cell lines expressing varying levels of the plasma membrane-expressed human epidermal growth factor-like receptor 2 (Her2) by flow cytometry. Anti-Her2 antibody was then conjugated to superparamagnetic iron oxide nanoparticles using the carbodiimide method. Labeled nanoparticles were incubated with breast cancer cell lines and visualized by confocal microscopy, Prussian blue histochemistry, and magnetic relaxometry.ResultsWe demonstrated a time- and antigen concentration-dependent increase in the number of antibody-conjugated nanoparticles bound to cells. Next, anti Her2-conjugated nanoparticles injected into highly Her2-expressing tumor xenograft explants yielded a significantly higher SQUID relaxometry signal relative to unconjugated nanoparticles. Finally, labeled cells introduced into breast phantoms were measured by magnetic relaxometry, and as few as 1 million labeled cells were detected at a distance of 4.5 cm using our early prototype system.ConclusionsThese results suggest that the antibody-conjugated magnetic nanoparticles are promising reagents to apply to in vivo breast tumor cell detection, and that SQUID-detected magnetic relaxometry is a viable, rapid, and highly sensitive method for in vitro nanoparticle development and eventual in vivo tumor detection.

Magnetic relaxometry as applied to sensitive cancer detection and localization

“…Previously, we showed that anti-Her2-conjugated NPs specifically bind cells expressing Her2 on the surface [11]. Furthermore, we demonstrated that the magnetic moment signal correlates to the levels of Her2 expressed at the cell surface [1].…”

“…The unique behavior of superparamagnetic NPs provides high contrast between bound and unbound NPs. This method has been shown to be extremely sensitive for detection of cancer cells; e.g., SPMR is several orders of magnitude more sensitive than a mammogram [11].…”

Cytotoxicity of nickel zinc ferrite nanoparticles on cancer cells of epithelial origin

“…This is an important consideration when evaluating a newly formulated drug. 25 Hathaway et al 26 Time-response studies are also useful in cytotoxicity determinations because they are indicators of association between functional change and irreversible cell damage. 27,28 The 72 hours of incubation with NiZn ferrite nanoparticles had the most inhibitory effects in BrdU incorporation assays, with loss of cell viability being both dose-and time-dependent.…”

A quantitative study of particle size effects in the magnetorelaxometry of magnetic nanoparticles using atomic magnetometry

“…Many of the earlier studies used multi-core particles, while more recently larger single-core magnetic particles have shown large magnetic signals in observation windows ranging from 50 ms to 2 s [15]. Those and others studies [16][17][18] have demonstrated that (SQUID-based) MRX has a high potential for biomedical imaging applications.…”