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)施加到超顺磁性纳米颗粒(MNPs)会导致机械力并进行 纳米尺度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，我们发现了一个新的 AMF中MNPs对癌细胞毒性作用的细胞骨架破坏及后续机制 细胞死亡，并可在保持健康细胞完好的情况下发生在癌细胞上。我们使用这种方法来 杀死那些机械上比良性癌细胞柔软，对机械更敏感的癌细胞. 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 曝光时间相对较短的频率和低幅度磁场，可大大降低 可能的副作用，如周围组织的非特异性加热。小剂量组观察其疗效。 可与肿瘤抗原靶向抗体偶联的直径为7-8 nm的磁铁矿MNPs 并系统地输送到肿瘤上。该探索性项目旨在为以下项目获得概念验证 遥控磁机械癌症纳米治疗及磁性机械纳米粒子的应用 体内肿瘤的破坏。这些目的是为了1)确定MNPs的抗肿瘤作用 超低频AMF在乳腺癌动物模型中的应用；2)采用多模式磁场能力 交直流电磁场的获取及其组合治疗 提高治疗效果；以及3)开发靶向聚合物涂层、生物相容的磁铁矿MNPs 高效全身给药治疗HER2阳性肿瘤及其磁机械治疗的研究 成长。该提案建立在M.V.Lomonosov调查人员之间现有合作的基础上 莫斯科国立大学(MSU)和北卡罗来纳大学教堂山分校(UNC)，两支球队 汇聚他们在超磁纳米材料、工程的化学和物理方面的协同专业知识 均匀磁场空间、聚合物治疗、药物输送和癌症纳米技术 论证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.