Targeted Magneto-Mechanic Nanotherapeutics for Cancer

癌症靶向磁力纳米疗法

• 批准号: 9751229
• 负责人: ALEXANDER V KABANOV
• 金额: $ 11.38万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751229
• 关键词: Address; 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; Injections; 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; anti-cancer; antitumor effect; biocompatible polymer; biomaterial compatibility; cancer cell; cancer therapy; design; human model; hydrophilicity; improved; in vivo; macromolecule; magnetic field; magnetite ferrosoferric oxide; malignant breast neoplasm; mechanical force; mechanotransduction; multimodality; nanomaterials; nanomedicine; nanoparticle; nanoscale; nanotherapeutic; new technology; novel; overexpression; response; side effect; superparamagnetism; targeted delivery; treatment effect; treatment optimization; tumor; tumor growth; tumor xenograft; uptake

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式，即非加热超低频率交替磁场 （AMF）应用于超磁磁性纳米颗粒（MNP）可以导致机械力并执行 纳米级的机械工作导致结构和功能的远程变化 周围的生物大分子和超分子结构。在先前的工作中，我们发现了一个新的 MNP毒性在AMF对癌细胞中的毒性机制，涉及细胞骨架破坏并随后 细胞死亡，可以在使健康细胞完好无损的同时在癌细胞上制定。我们使用这种方法来 杀死比其良性较软的癌细胞，并且对机械的敏感 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系统对超低响应 频率和低振幅磁场，暴露时间相对较短，这可能会大大减少 可能的副作用，例如周围组织的非特异性加热。观察到效果很小 直径为7至8 nm的磁铁矿MNP，可以与靶向肿瘤抗原的抗体结合 并系统地交付给肿瘤。这个探索性项目旨在获得概念证明 远程驱动的磁磁性癌症纳米疗法和MNP用于磁力机械 体内肿瘤的破坏。目的设计为1）确定由MNP诱导的抗肿瘤作用 乳腺癌动物模型中的超低频率AMF； 2）使用多模式磁场能力 访问交替电流（AC）和直流（DC）磁场及其组合处理 增加治疗结果； 3）开发针对靶向聚合物的生物相容性磁铁矿MNP 有效地进入HER2阳性肿瘤及其磁力治疗以抑制肿瘤 生长。该提案建立在M.V.调查员之间的现有合作之上。 Lomonosov 莫斯科州立大学（MSU）和北卡罗来纳大学 - 教堂山（UNC），这两个团队 融合其在超级磁纳米材料的化学和物理学方面的协同专业知识 均匀的磁场空间，聚合物治疗，药物输送和癌症纳米技术 证明了这种新技术用于癌症治疗的可行性。

项目成果

Enzyme Release from Polyion Complex by Extremely Low Frequency Magnetic Field.

通过极低频磁场从聚离子复合物中释放酶。

• DOI: 10.1038/s41598-020-61364-w
• 发表时间: 2020
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Vlasova,KseniyaYu;Vishwasrao,Hemant;Abakumov,MaximA;Golovin,DmitryYu;Gribanovsky,SergeyL;Zhigachev,AlexanderO;Poloznikov,AndreyА;Majouga,AlexanderG;Golovin,YuriI;Sokolsky-Papkov,Marina;Klyachko,NataliaL;Kabanov,AlexanderV
• 通讯作者: Kabanov,AlexanderV