One potential cancer treatment selectively deposits heat to the tumor through activation of magnetic nanoparticles inside the tumor. This can damage or kill the cancer cells without harming the surrounding healthy tissue. The properties assumed to be most important for this heat generation (saturation magnetization, amplitude and frequency of external magnetic field) originate from theoretical models that assume non-interacting nanoparticles. Although these factors certainly contribute, the fundamental assumption of ‘no interaction’ is flawed and consequently fails to anticipate their interactions with biological systems and the resulting heat deposition. Experimental evidence demonstrates that for interacting magnetite nanoparticles, determined by their spacing and anisotropy, the resulting collective behavior in the kilohertz frequency regime generates significant heat, leading to nearly complete regression of aggressive mammary tumors in mice.
Objective: Magnetic nanoparticles conjugated to a monoclonal antibody can be i.v. injected to target cancer tissue and will rapidly heat when activated by an external alternating magnetic field (AMF). The result is necrosis of the microenvironment provided the concentration of particles and AMF amplitude are sufficient. High-amplitude AMF causes nonspecific heating in tissues through induced eddy currents, which must be minimized. In this study, application of highamplitude, confined, pulsed AMF to a mouse model is explored with the goal to provide data for a concomitant efficacy study of heating i.v. injected magnetic nanoparticles. Methods: Thirty-seven female BALB/c athymic nude mice (5-8 weeks) were exposed to an AMF with frequency of 153 kHz, and amplitude (400-1,300 Oe), duration (1-20 minutes), duty (15-100%), and pulse ON time (2-1,200 seconds). Mice were placed in a water-cooled four-turn helical induction coil. Two additional mice, used as controls, were placed in the coil but received no AMF exposure. Tissue and core temperatures as the response were measured in situ and recorded at 1-second intervals. Results: No adverse effects were observed for AMF amplitudes of V700 Oe, even at continuous power application (100% duty) for up to 20 minutes. Mice exposed to AMF amplitudes in excess of 950 Oe experienced morbidity and injury when the duty exceeded 50%. Conclusion: High-amplitude AMF (up to 1,300 Oe) was well tolerated provided the duty was adjusted to dissipate heat. Results presented suggest that further tissue temperature regulation can be achieved with suitable variations of pulse width for a given amplitude and duty combination.These results suggest that it is possible to apply high-amplitude AMF (>500 Oe) with pulsing for a time sufficient to treat cancer tissue in which magnetic nanoparticles have been embedded.
Magnetic nanoparticles with a high specific absorption rate (SAR) have been developed and used in mouse models of cancer. The magnetic nanoparticles are comprised of predominantly iron oxide magnetic cores surrounded by a dextran layer for colloidal stability. The average diameter of a single particle (core plus dextran) is 92±14nm as measured by photon correlation spectroscopy. Small angle neutron scattering measurements under several H2O∕D2O contrast conditions and at varying nanoparticle concentrations have revealed three length scales: >10μm, several hundred nanometers, and tens of nanometers. The latter corresponds to the particle diameter; the several hundred nanometers corresponds to a hard sphere interaction radius of the core/shell nanoparticles; >10μm corresponds to the formation of long-range, many-particle structures held together by magnetic interactions and dextran. The long-range collective magnetic behavior appears to play a major role in enhancing the SAR. For samples having nominally equal concentrations and similar saturation magnetizations, the measured SAR is 1075W/(g of Fe) for tightly associated nanoparticles and 150W/(g of Fe) for very loosely associated nanoparticles at an applied field of 86kA∕m (1080Oe) and 150kHz.
Magnetic nanoparticles are being developed for a wide range of biomedical applications. In particular, hyperthermia involves heating the magnetic nanoparticles through exposure to an alternating magnetic field. These materials offer the potential to selectively treat cancer by heating cancer tissue locally and at the cellular level. This may be a successful method if there are enough particles in a tumor possessing a sufficiently high specific absorption rate (SAR) to deposit heat quickly while minimizing thermal damage to surrounding tissue. High SAR magnetic nanoparticles have been developed and used in mouse models of cancer. The magnetic nanoparticles comprise iron oxide magnetic cores (mean core diameter of 50 nm) surrounded by a dextran layer shell for colloidal stability. In comparing two similar systems, the saturation magnetization is found to play a crucial role in determining the SAR, but is not the only factor of importance. (A difference in saturation magnetization of a factor of 1.5 yields a difference in SAR of a factor of 2.5 at 1080 Oe and 150 kHz.) Variations in the interactions due to differences in the dextran layer, as determined through neutron scattering, also play a role in the SAR. Once these nanoparticles are introduced into the tumor, their efficacy, with respect to tumor growth, is determined by the location of the nanoparticles within or near the tumor cells and the association of the nanoparticles with the delivered alternating magnetic field (AMF). This association (nanoparticle SAR and AMF) determines the amount of heat generated. In our setting, the heat generated and the time of heating (thermal dose) provides a tumor gross treatment response which correlates closely with that of conventional (non-nanoparticle) hyperthermia. This being said, it appears specific aspects of the nanoparticle hyperthermia cytopathology mechanism may be very different from that observed in conventional cancer treatment hyperthermia.
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