Targeted Magnetic Nanoparticles for Mechanical Lysis of Tumor Cells by Low-Amplitude Alternating Magnetic Field

Abstract

Currently available cancer therapies can cause damage to healthy tissue. We developed a unique method for specific mechanical lysis of cancer cells using superparamagnetic iron oxide nanoparticle rotation under a weak alternating magnetic field. Iron oxide core nanoparticles were coated with cetuximab, an anti-epidermal growth factor receptor antibody, for specific tumor targeting. Nude mice bearing a head and neck tumor were treated with cetuximab-coated magnetic nanoparticles (MNPs) and then received a 30 min treatment with a weak external alternating magnetic field (4 Hz) applied on alternating days (total of seven treatments, over 14 days). This treatment, compared to a pure antibody, exhibited a superior cell death effect over time. Furthermore, necrosis in the tumor site was detected by magnetic resonance (MR) images. Thermal camera images of head and neck squamous cell carcinoma cultures demonstrated that cell death occurred purely by a mechanical mechanism.

Keywords: MRI; biomedical; cetuximab; head and neck cancer; magnetic field.

Figure 1

Schematic design of the experimental setup.

Figure 2

Cell viability of 10⁶ A431 cell cultures after various treatments. (a) Untreated cells; (b) cells without magnetic nanoparticles (MNPs) treated with 15 min of alternating magnetic fields (AMFs); (c) cells incubated with MNPs without AMFs; (d) cells incubated with MNPs and treated with 15 min of AMFs; (e) cells with MNPs heated for 5 min on a hot plate. Imaged by Leica microscope X20.

Figure 3

Thermal profile for (a) 10⁶ A431 cells only; (b) solution of coated MNPs immediately after 15 min of AMF treatment; (c) 10⁶ A431 cells after 15 min of AMF treatment; (d) 10⁶ A431 cells incubated with coated MNPs after 15 min of AMF treatment; (e) 10⁶ A431 cells with coated MNPs after 40 min of AMF treatment and (f) 10⁶ A431 cells after 5 min on a hot plate set to 45 °C. Images taken by thermal imaging camera.

Figure 4

Number of cells in a 1 mL solution after AMF treatment for 5 min (a) with different particle concentrations (2 mg/mL–10 mg/mL); (b) The number of live cells in a sample with 10 mg/mL particles over a 5 min treatment.

Figure 5

Axial contrast-enhanced axial T2-weighted MRI slices of a head and neck tumor in a representative mouse from each MNP size group, after three cycles of 30 min AMF treatments given on alternating days: (a) a mouse with 50 nm coated MNPs; (b) a mouse with 100 nm coated MNPs; and (c) a mouse with 200 nm coated MNPs. The yellow arrows indicate the tumor sites. Measurements were performed in 3 slices for each mouse (with 8.5 signal averages per position to improve signal-to-noise ratio) resulting in a total data acquisition time of 10 minutes. All MRI slices were 1.0 mm thick with a 0.15 mm in-plane resolution.

Figure 6

Percentage of tumor volume growth for each AMF treatment in mice injected with 50, 100, and 200 nm coated MNPs, as well as cetuximab alone. N = 5 for the MNP groups and n = 4 for controls at each time point.