Controlled Functionalization of Composite Magnetic Nanoparticles for Targeted Del

用于靶向删除的复合磁性纳米粒子的受控功能化

• 批准号: 7473306
• 负责人: Shouheng Sun
• 金额: $ 17.17万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7473306
• 关键词: Affect; Antibodies; Antigen Targeting; Antineoplastic Agents; Binding; Biological; Cell Death; Cells; Chemistry; Cisplatin; Cleaved cell; Complex; Condition; DNA; Detection; Dopamine; Drug Delivery Systems; Effectiveness; Electron Microscopy; Electrons; Excision Repair; Future; Glioma; Goals; Heating; Image; Imaging Techniques; Interruption; Iron; Label; Lead; Link; Magnetic Resonance Imaging; Magnetism; Malignant - descriptor; Medicine; Metals; Microscopic; Microscopy; Monoclonal Antibodies; Nanostructures; Nuclear Envelope; Nuclear Localization Signal; Numbers; Object Attachment; Optics; Penetration; Peptides; Pharmaceutical Preparations; Physiological; Polyethylene Glycols; Principal Investigator; Research; Site; Solutions; Structure; Surface; System; Therapeutic; Tissues; Tumor Cell Nuclei; Work; anticancer research; base; cancer therapy; chemical bond; design; iron oxide; magnetic field; nanoparticle; nanoscience; neoplastic cell; particle; programs; targeted delivery; tumor; uptake

DESCRIPTION (provided by applicant): This application aims to develop composite magnetic nanoparticles with controlled surface functionalization and stability in physiological conditions for applications in targeted delivery of platin-like anticancer molecules to tumor cells, and, specifically to study the effectiveness of the platin nanoparticles in elimination of the glioma cells. The work is based on our preliminary research on the synthesis and surface functionalization of monodisperse magnetic iron-based nanoparticles, including Fe3O4, core/shell Fe/Fe3O4, and dumbbell-like Au-Fe3O4 nanoparticles, and may lead to a solution for highly efficient platin-based cancer therapy in the near future. The multifunctional nanostructures proposed here are illustrative of the exciting possibilities that can emerge from the union of nanoscience and medicine. The selective delivery of therapeutic drugs to malignant tissues constitutes one of the greatest challenges in cancer research. We propose that carefully designed bifunctional nanoparticles may provide an exciting practical vehicle to achieve selective and efficacious platin drug delivery. The composite nanoparticles, as shown in Figure 1, have both magnetic iron oxide and optically active noble metal of Au (or Ag) nanoparticle units. The different surface chemistry offered by this composite structure will facilitate the simultaneous attachment of special peptides and cisplatin-like anticancer drugs for the target specific cell recognition and cell entry. The detailed surface functionalization of the composite nanoparticles is also shown in Figure 1, in which the Fe3O4 particles are coated with a monoclonal antibody (Ab) or peptides via polyethylene glycol (PEG) and dopamine and the Au nanoparticles are linked to a TAT-like peptide (Nuclear Localization signal, NLS) through a platin complex and PEG unit. The monoclonal antibody will be used to target an antigen on the surface of tumor cells, while the NLS is to induce nanoparticle penetration through nuclear membrane. When the functionalized nanoparticles are within the tumor cell nucleus, an alternating magnetic field will be applied to remotely heat the magnetic nanoparticles, and the resultant heat will break the Pt-O bond in the structure and induce the formation of an active Pt coordination site that can readily attach to DNA strands, leading to the interruption of the DNA excision repair system and consequent cell death. The composite nanoparticles can also serve as highly sensitive multifunctional labels for the detection of trajectories of the particles within the cells by either magnetic resonance image (MRI) on iron oxide nanoparticles or electron/optical microscopic image on Au (or Ag), facilitating quantification of transporter-conjugate uptake in tumor cells. The ultimate goal of this application is to provide nanoparticle based therapeutics for successful cancer therapy.

描述（由申请人提供）：本申请旨在开发具有受控表面功能化和生理条件下稳定性的复合磁性纳米颗粒，用于将铂类抗癌分子靶向递送至肿瘤细胞，并且特别是研究铂纳米颗粒的有效性消除神经胶质瘤细胞。该工作基于我们对单分散磁性铁基纳米粒子（包括 Fe3O4、核/壳 Fe/Fe3O4 和哑铃状 Au-Fe3O4 纳米粒子）的合成和表面功能化的初步研究，可能会带来高效的解决方案。在不久的将来基于铂的癌症治疗。这里提出的多功能纳米结构说明了纳米科学和医学的结合可以产生令人兴奋的可能性。将治疗药物选择性递送至恶性组织是癌症研究中最大的挑战之一。我们认为，精心设计的双功能纳米颗粒可以提供一种令人兴奋的实用工具，以实现选择性和有效的铂药物输送。如图1所示，复合纳米颗粒同时具有磁性氧化铁和光学活性贵金属Au（或Ag）纳米颗粒单元。这种复合结构提供的不同表面化学性质将有利于特殊肽和顺铂类抗癌药物的同时附着，以实现目标特异性细胞识别和细胞进入。复合纳米颗粒的详细表面功能化也如图 1 所示，其中 Fe3O4 颗粒通过聚乙二醇 (PEG) 和多巴胺涂有单克隆抗体 (Ab) 或肽，而 Au 纳米颗粒则与 TAT 样连接。肽（核定位信号，NLS）通过铂复合物和 PEG 单元。单克隆抗体将用于靶向肿瘤细胞表面的抗原，而 NLS 将诱导纳米颗粒穿透核膜。当功能化纳米粒子位于肿瘤细胞核内时，将施加交变磁场来远程加热磁性纳米粒子，产生的热量将破坏结构中的Pt-O键并诱导形成活性Pt配位位点，很容易附​​着在 DNA 链上，导致 DNA 切除修复系统中断并随后导致细胞死亡。复合纳米颗粒还可以作为高灵敏度的多功能标记，通过氧化铁纳米颗粒上的磁共振图像（MRI）或金（或银）上的电子/光学显微图像来检测细胞内颗粒的轨迹，从而促进对肿瘤细胞中转运蛋白结合物的摄取。该应用的最终目标是为成功的癌症治疗提供基于纳米颗粒的疗法。

项目成果

Conjugating Methotrexate to magnetite (Fe(3)O(4)) nanoparticles via trichloro-s-triazine.

• DOI: 10.1039/b902373a
• 发表时间: 2009-01-01
• 期刊: Journal of materials chemistry
• 作者: Young KL;Xu C;Xie J;Sun S
• 通讯作者: Sun S

Size and Concentration Effect of Gold Nanoparticles on X-ray Attenuation As Measured on Computed Tomography.

• DOI: 10.1021/cm8008418
• 发表时间: 2008-07-08
• 期刊: CHEMISTRY OF MATERIALS
• 影响因子: 8.6
• 作者: Xu, Chenjie;Tung, Glenn A.;Sun, Shouheng
• 通讯作者: Sun, Shouheng

Recent Progress in Syntheses and Applications of Dumbbell-like Nanoparticles.

• DOI: 10.1002/adma.200900320
• 发表时间: 2009
• 期刊: ADVANCED MATERIALS
• 影响因子: 29.4
• 作者: Wang, Chao;Xu, Chenjie;Zeng, Hao;Sun, Shouheng
• 通讯作者: Sun, Shouheng

Porous hollow Fe(3)O(4) nanoparticles for targeted delivery and controlled release of cisplatin.

• DOI: 10.1021/ja903300f
• 发表时间: 2009-08-05
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Cheng, Kai;Peng, Sheng;Xu, Chenjie;Sun, Shouheng
• 通讯作者: Sun, Shouheng

FePt nanoparticles as an Fe reservoir for controlled Fe release and tumor inhibition.

• DOI: 10.1021/ja905938a
• 发表时间: 2009-10-28
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Xu, Chenjie;Yuan, Zhenglong;Kohler, Nathan;Kim, Jaemin;Chung, Maureen A.;Sun, Shouheng
• 通讯作者: Sun, Shouheng