Development of a cancer therapy that combines tumor-targeting magnetic nanoparticles with an alternating magnetic field

Dr. Robert Ivkov Triton BioSystems, Inc., Chelmsford, Ma

The advantages of hyperthermia, both classic and ablative, to treat cancer have realized only limited application in clinical practice. This has been due, in part, to the challenge of developing techniques that deliver sufficient heat to cancer without harming nearby healthy tissues. Most techniques have to resort to invasive procedures. One strategy to accomplish a minimally invasive and effective localized heating of cancer involves inductively heating magnetic nanoparticles with an externally applied alternating magnetic field (AMF). Magnetic nanoparticles conjugated to a suitable monoclonal antibody (Mab) can be intravenously injected to target cancer tissue and will rapidly heat when activated by an AMF. The result is necrosis of the tumor microenvironment provided both the specific absorption rate and concentration of particles within the tumor are sufficient to generate lethal heat with AMF amplitudes tolerable to nearby tissues. The development of such a Ònano-targetedÓ therapy requires a comprehensive product development effort that integrates several scientific and engineering disciplines. A magnetic inductor system was designed and manufactured with a suitable power supply to accommodate a mouse and produce an inhomogeneous magnetic field at 150 kHz. Maximum amplitude achieved was 1400 Oe in an approximately 1-cm band appropriate for treating tumor xenografts in a mouse. 111In-ChL6 Mab-linked iron oxide nanoparticles (bioprobes) were developed and their pharmacokinetic, tumor uptake and therapeutic effect when inductively heated by an externally applied AMF were studied in athymic mice bearing human breast cancer (HBT3477) xenografts. High amplitude AMF of between 700 and 1400 Oe was well tolerated provided the duty was adjusted to dissipate heat. When combined with bioprobes, these power levels were sufficient to achieve significant therapeutic responses with minimal toxicity. These studies demonstrate that tumor targeting magnetic nanoparticles with an AMF bind to cancer cell membrane antigen in sufficient amounts to deliver thermoablative cancer therapy. In addition, these studies demonstrate a correlation of therapeutic response in vivo with calculated dose of applied heat. This technology offers the potential to control the time and amount of heat applied to the tumor. This creates the potential to increase therapeutic ratio without resorting to invasive procedures. Also presented are results that describe recent development efforts to produce particles that generate up to ten times more heat per unit mass particle than those used in the studies described above. The results of preliminary in vitro and in vivo studies using these particles will be presented.

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