Targeted Magneto-Mechanic Nanotherapeutics for Cancer

摘要 我们提出了一种新的纳米医学范式，即非加热超低频交变磁场 (AMF)应用于超顺磁性纳米粒子（MNP）可以导致机械力， 纳米级的机械工作，导致远程驱动的结构和功能的变化， 围绕着生物大分子和超分子结构。在之前的工作中，我们发现了一种新的 AMF中的MNP对癌细胞的毒性机制涉及细胞骨架破坏和随后的 细胞死亡，并且可以在癌细胞上实施，而使健康细胞保持完整。我们使用这种方法来 杀死癌细胞，这些癌细胞在机械上比良性细胞更柔软，对机械更敏感， 转导导致细胞骨架损伤和细胞死亡。值得注意的是，我们的MNP系统响应超低 频率和低幅度磁场，暴露时间相对较短，这可以大大减少 可能的副作用，如周围组织的非特异性发热。观察到的效果与小 直径为7至8 nm的磁铁矿MNP，可与肿瘤抗原的靶向抗体结合 并全身性地输送到肿瘤中。该探索性项目旨在获得以下概念的证明： 远程致动的磁机械癌症纳米疗法和MNP用于磁机械癌症纳米疗法的用途 在体内破坏肿瘤。目的是：1）确定由以下物质诱导的MNP的抗肿瘤作用： 乳腺癌动物模型中的超低频AMF; 2）采用多模式磁场能力 访问交流（AC）和直流（DC）磁场及其组合治疗， 提高治疗效果;和3）开发靶向聚合物涂层、生物相容性磁铁矿MNP， 有效全身递送到HER 2阳性肿瘤中以及它们的磁机械治疗以抑制肿瘤 增长该提案建立在M. V.罗蒙诺索夫研究人员之间现有的合作基础上。 莫斯科州立大学（MSU）和北卡罗来纳大学教堂山分校（UCLA），两支球队 汇聚了他们在超磁性纳米材料的化学和物理，工程 均匀磁场空间，聚合物治疗，药物输送和癌症纳米技术， 证明了这项新技术用于癌症治疗的可行性。

Abstract 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.