We propose a new nanomedicine paradigm that non-heating super low frequency alternating magnetic field (AMF) applied to superparamagnetic nanoparticles (MNPs) can lead to mechanical forces and carry out mechanical work at the nanoscale resulting in remotely actuated changes of structure and function of surrounding biological macromolecules and supramolecular structures. In prior work we discovered a new mechanism of toxicity of MNPs in AMF to cancerous cells that involves cytoskeletal disruption and subsequent cell death and can be enacted upon cancerous cells while leaving healthy cells intact. We use this approach to kill cancer cells that are mechanically softer than their benign counterparts and more sensitive to mechano- transduction leading to cytoskeletal damage and cell death. Notably, our MNP system responds to super low frequency and low amplitude magnetic fields with relatively short exposure times, which can greatly diminish possible side effects such as non-specific heating of surrounding tissues. The effect was observed with small magnetite MNPs of 7 to 8 nm in diameter that can be conjugated with targeting antibodies to tumor antigens and delivered systemically to the tumors. This exploratory project aims to obtain the proof of concept for remotely actuated magneto-mechanical cancer nanotherapeutics and use of MNPs for magneto-mechanical destruction of tumors in vivo.
The aims are designed to 1) determine antitumor effects of MNPs induced by super low frequency AMF in an animal model of breast cancer; 2) employ multimodal magnetic field capability accessing alternating current (AC) and direct current (DC) magnetic fields and their combination treatments to increase the treatment outcomes; and 3) develop targeted polymer-coated, biocompatible magnetite MNPs for efficient systemic delivery into HER2 positive tumors and their magneto-mechanical treatment to inhibit tumor growth. The proposal builds upon the existing collaboration between the investigators at M.V. Lomonosov Moscow State University (MSU) and University of North Carolina-Chapel Hill (UNC) where both teams converge their synergistic expertise in chemistry and physics of superpamagnetic nanomaterials, engineering of uniform magnetic field space, polymer therapeutics, drug delivery and cancer nanotechnology to demonstrate feasibility of this new technology for cancer therapy.
We propose exploratory research to obtain a proof of concept to a cancer therapy approach, in which cancer cells are destroyed without use of chemotherapeutic drugs by mechanical motion of magnetic nanoparticles actuated remotely by applied alternating current magnetic fields of super low frequency. Such fields and treatments are safe for surrounding tissues but disrupt cytoskeleton and kill cancer cells while leaving healthy cells intact. The nanoparticles used in this method are very small and will be linked to antibodies (Herceptin) to target the human epidermal growth factor 2 (HER2) at the surface of the breast cancer cells to deliver sufficient amounts of nanoparticles into the tumors. The studies are designed to demonstrate the feasibility of the proposed approach in animal models that would be a decisive step forward in developing novel magneto- mechanical cancer nanotherapeutics.
