Proposal of New Safety Limits for In Vivo Experiments of Magnetic Hyperthermia Antitumor Therapy

TLDR

Recent advances in magnetic hyperthermia therapy have improved nanoparticle synthesis and biosafety, yet the magnetic field‑frequency product limit proposed by Atkinson‑Brezovich remains unverified. This study investigates the local and systemic physiological effects of exceeding the Atkinson‑Brezovich field‑frequency product limit in vivo. Using WAG/RijHsd male rats exposed to 591–920 kHz and 10.3–18 kA/m for 21 min, we performed biochemical serum analyses and measured liver temperature, sacrificing half the animals after 12 h and the rest after 10 days. While most groups tolerated the exposure, the highest frequency and intensity (928 kHz, 18 kA/m) caused over 50 % mortality and transient liver and systemic marker elevations that largely recovered by day 10, indicating that exceeding the limit up to 9.59 × 10⁹ A m⁻¹ s⁻¹ may be safe but warrants further investigation.

Abstract

Lately, major advances in crucial aspects of magnetic hyperthermia (MH) therapy have been made (nanoparticle synthesis, biosafety, etc.). However, there is one key point still lacking improvement: the magnetic field-frequency product (H × f = 4.85 × 108 Am-1s-1) proposed by Atkinson-Brezovich as a limit for MH therapies. Herein, we analyze both local and systemic physiological effects of overpassing this limit.Different combinations of field frequency and intensity exceeding the Atkinson-Brezovich limit (591-920 kHz, and 10.3-18 kA/m) have been applied for 21 min to WAG/RijHsd male rats, randomly distributed to groups of 12 animals; half of them were sacrificed after 12 h, and the others 10 days later. Biochemical serum analyses were performed to assess the general, hepatic, renal and/or pancreatic function.MH raised liver temperature to 42.8 ± 0.4 °C. Although in five of the groups the exposure was relatively well tolerated, in the two of highest frequency (928 kHz) and intensity (18 kA/m), more than 50% of the animals died. A striking elevation in liver and systemic markers was observed after 12 h in the surviving animals, independently of the frequency and intensity used. Ten days later, liver markers were almost recovered in all of the animals. However, in those groups exposed to 591 kHz and 16 kA/m, and 700 kHz and 13.7 kA/m systemic markers remained altered.Exceeding the Atkinson-Brezovich limit up to 9.59 × 109 Am-1s-1 seems to be safe, though further research is needed to understand the impact of intensity and/or frequency on physiological conditions following MH.