Targeted Magneto-Mechanic Nanotherapeutics for Cancer

癌症靶向磁力纳米疗法

基本信息

批准号：
9382042
负责人：
ALEXANDER V KABANOV
金额：
$ 11.76万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9382042
关键词：
Address Adverse effects Animal Model Animals Antibodies BT 474 Benign Biological Breast Cancer Cell Breast Cancer Model Caliber Cancerous Cell Culture Techniques Cell Death Cells Chemicals Chemistry Collaborations Custom Cytoskeleton Dose Drug Delivery Systems Engineering Epidermal Growth Factor Exposure to Frequencies Glutamic Acid Goals Heating Human Immobilized Enzymes In Vitro Injectable Injection of therapeutic agent Lead Life Ligands Link Magnetic nanoparticles Malignant Neoplasms Mechanics Methods Monoclonal Antibodies Moscow Motion Mus NOD/SCID mouse Nanotechnology North Carolina Nucleosome Core Particle Particle Size Pharmaceutical Preparations Physics Physiologic pulse Physiological Pluronics Polymers Receptor Cell Reporting Research Research Personnel Resources Series Serum Proteins Shapes Structure Surface System Technology Therapeutic Time Tissues Toxic effect Trastuzumab Treatment Protocols Treatment outcome Tumor Antigens Universities Vision Water Work acrylic acid antitumor effect biocompatible polymer biomaterial compatibility cancer cell cancer therapy design enzyme immobilization hydrophilicity improved in vivo killings macromolecule magnetic field magnetite ferrosoferric oxide malignant breast neoplasm mechanical force mechanotransduction multimodality nanomaterials nanomedicine nanoparticle nanoscale nanotherapeutic new technology novel overexpression response targeted delivery treatment effect tumor tumor growth tumor xenograft uptake

项目摘要

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.

抽象的我们提出了一种新的纳米医学范例，即非加热超低频交变磁场（AMF）应用于超顺磁性纳米颗粒（MNP）可以产生机械力并进行纳米级的机械工作导致远程驱动的结构和功能的变化周围的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，并且可以作用于癌细胞，同时保持健康细胞完好无损。我们使用这种方法来杀死机械上比良性细胞更软并且对机械力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 系统可响应超低频率和低振幅磁场的暴露时间相对较短，可以大大减弱可能的副作用，例如周围组织的非特异性加热。用小量观察到效果直径 7 至 8 nm 的磁铁矿 MNP，可与肿瘤抗原的靶向抗体缀合并全身递送至肿瘤。该探索性项目旨在获得概念验证远程驱动磁机械癌症纳米疗法以及 MNP 在磁机械治疗中的应用破坏体内肿瘤。目的旨在 1) 确定 MNP 诱导的抗肿瘤作用乳腺癌动物模型中的超低频 AMF； 2) 采用多模态磁场能力访问交流（AC）和直流（DC）磁场及其组合治疗提高治疗效果； 3) 开发有针对性的聚合物涂层、生物相容性磁铁矿 MNP 高效全身递送至 HER2 阳性肿瘤及其磁机械治疗以抑制肿瘤生长。该提案建立在 M.V. 研究人员之间现有的合作基础上。罗蒙诺索夫莫斯科州立大学 (MSU) 和北卡罗来纳大学教堂山分校 (UNC) 两支球队汇聚超磁性纳米材料化学和物理、工程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证明这项新技术用于癌症治疗的可行性。