Intravenous magnetic nanoparticle cancer hyperthermia

Abstract

Magnetic nanoparticles heated by an alternating magnetic field could be used to treat cancers, either alone or in combination with radiotherapy or chemotherapy. However, direct intratumoral injections suffer from tumor incongruence and invasiveness, typically leaving undertreated regions, which lead to cancer regrowth. Intravenous injection more faithfully loads tumors, but, so far, it has been difficult achieving the necessary concentration in tumors before systemic toxicity occurs. Here, we describe use of a magnetic nanoparticle that, with a well-tolerated intravenous dose, achieved a tumor concentration of 1.9 mg Fe/g tumor in a subcutaneous squamous cell carcinoma mouse model, with a tumor to non-tumor ratio > 16. With an applied field of 38 kA/m at 980 kHz, tumors could be heated to 60°C in 2 minutes, durably ablating them with millimeter (mm) precision, leaving surrounding tissue intact.

Keywords: alternating magnetic field; cancer; hyperthermia; intravenous delivery; magnetic nanoparticles.

Figure 1

Transmission electron microscopy images of the magnetic nanoparticles. (A) Particle cores measured to be 11.3 ± 2.3 nm (scale bar = 100 nm). (B) High-resolution lattice image of a 9.9 nm particle showing its crystalline core (scale bar = 5 nm). (C) Electron diffraction pattern, identifying cores as Fe₃O₄ (scale bar = 10 nm⁻¹).

Figure 2

Biodistribution of iron (after subtraction of normal tissue iron) over time. Notes: The maximum iron concentration in the tumor from the points measured was at 24 hours post-injection, reaching 1.9 mg Fe/mL. Time points were: 5 minutes, 1 hour, and 4, 8, 24, and 96 hours.

Figure 3

Thermal image of subcutaneous tumor being heated by an alternating magnetic field. Notes: The leg was scanned up and down vertically to make the field uniform over the leg. The tumor can be observed to have specifically heated (red region).

Figure 4

Heating of tissues in the magnetic field: 24 hours after an intravenous injection of magnetic nanoparticles (MNPs) (1.7 g Fe/kg) – tumor (filled circles) and leg muscle (no tumor, filled squares) tissues. Notes: Also shown is heating of leg muscle tissue with no injection of MNPs (open circles). The alternating magnetic field applied was 38 kA/m at 980 kHz. Tumors (average size of 206 mm³, three averaged) equilibrated at 66°C after 5 minutes, muscle with MNPs reached 42°C, and muscle without MNPs reached 39°C. Three mice were used per group.

Figure 5

Magnetic nanoparticle (MNP) hyperthermia treatment. Notes: Intravenous injection of 1.7 g Fe/kg and followed 24 hours later by exposure to an alternating magnetic field (38 kA/m, 980 kHz, 2 minutes) resulted in durable ablation of tumors (7/9 = 78%, n = 9, absence of palpable tumor). A repeated experiment showed 90% (n = 10) thermoablation. Controls – no treatment, magnetic field only, and only magnetic nanoparticles – had no measurable effect on survival. Abbreviations: AMF, alternating magnetic field; n, number of animals per group.

Figure 6

There was a rapid decrement in the volume of most tumors and debris was resorbed in 1–2 days, completely deflating fairly large tumors. Note: The average tumor size at time of treatment was 196 mm³.