Magnetic nanoparticle hyperthermia for treating locally advanced unresectable and borderline resectable pancreatic cancers: the role of tumor size and eddy-current heating

Abstract

Purpose: Tumor volume largely determines the success of local control of borderline resectable and locally advanced pancreatic cancer with current therapy. We hypothesized that a tumor-mass normalized dose of magnetic nanoparticle hyperthermia (MNPH) with alternating magnetic fields (AMFs) reduces the effect of tumor volume for treatment.

Methods: 18 female athymic nude mice bearing subcutaneous MiaPaCa02 human xenograft tumors were treated with MNPH following intratumor injections of 5.5 mg Fe/g tumor of an aqueous suspension of magnetic iron-oxide nanoparticles. Mice were randomly divided into control (n = 5) and treated groups having small (0.15 ± 0.03 cm³, n = 4) or large (0.30 ± 0.06 cm³, n = 5) tumors. We assessed the clinical feasibility of this approach and of pulsed AMF to minimize eddy current heating using a finite-element method to solve a bioheat equation for a human-scale multilayer model.

Results: Compared to the control group, both small and large MiaPaCa02 subcutaneous tumors showed statistically significant growth inhibition. Conversely, there was no significant difference in tumor growth between large and small tumors. Both computational and xenograft models demonstrated higher maximum tumor temperatures for large tumors compared to small tumors. Computational modeling demonstrates that pulsed AMF can minimize nonspecific eddy current heating.

Conclusions: MNPH provides an advantage to treat large tumors because the MION dose can be adjusted to increase power. Pulsed AMF, with adjusted treatment time, can enhance MNPH in challenging cases such as low MION dose in the target tissue and/or large patients by minimizing nonspecific eddy current heating without sacrificing thermal dose to the target. Nanoparticle heterogeneity in tumors remains a challenge for continued research.

Keywords: Hyperthermia; bioheat transfer; eddy currents; magnetic nanoparticles; pancreatic cancer; tumor size.

Figure 1.

Schematic of the study design for the magnetic nanoparticle hyperthermia (MNPH) therapy with intratumor injection of magnetic iron-oxide nanoparticles (MIONs) for MiaPACa-02 tumors in mice and photograph of the alternating magnetic field (AMF) system used to perform MNPH treatments in mouse tumors.

Figure 2.

(a) Schematic of the meshed human scale computational model consisting of skin, fat, muscle, pancreas, tumor and magnetic iron-oxide nanoparticles (MIONs) embedded tumor with boundary conditions. (b) Sample pulsed alternating magnetic field (AMF) for a 50% duty-cycle. $\text{\% Duty }=\frac{\text{ Pulse ON time }}{\text{ Pulse ON time }+\text{ Pulse OFF time }}\times 100\text{\%}$.

Figure 3.

(a) An example of temporal temperature rise for small and large tumors during a MNPH treatment in MiaPaCa02 mice model. (b) Relative tumor growth curves for induvial mice. (c) Kaplan–Meier plot showing the outcome of MNPH treatment for untreated control, small and large tumors.

Figure 4.

(a) Representative temperature distribution for tumor sizes with spherical radius of 1 cm and 2 cm, and (b) maximum and minimum tumor temperature as a function of tumor radius in human scale computational model after 20 min of MNPH treatment.

Figure 5.

(a) Temperature distribution for 100%, 50%, 33.3% and 25% duty cycles in human scale computational model after 20 min of MNPH treatment. (b) Temporal temperature rise for 100%, 50%, 33.3% and 25% duty cycles in human scale computational model during the MNPH treatment. Note the change in the time scale on x-axis.