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控制表面功能和稳定性的复合磁性纳米颗粒，用于在生理条件下用于针对靶向铂类似铂样抗癌分子向肿瘤细胞的靶向递送，特别是研究铂纳米颗粒在消除Glioma细胞中的有效性。这项工作基于我们对单分散磁铁基纳米颗粒的合成和表面功能化的初步研究，包括Fe3O4，Core/Shell/Shell/Shell Fe/Fe3O4和类似Dumbbell类的Au-Fe3O4纳米颗粒，并可能导致近乎未来的高效基于Platin的癌症治疗的解决方案。这里提出的多功能纳米结构说明了纳米科学和医学结合所产生的令人兴奋的可能性。将治疗药物的选择性递送到恶性组织中是癌症研究中最大的挑战之一。我们建议精心设计的双功能纳米颗粒可能会提供令人兴奋的实用工具，以实现选择性和有效的Platin药物输送。如图1所示，复合纳米颗粒具有磁氧化铁和光活性贵金属的Au（或Ag）纳米颗粒单元。这种复合结构提供的不同表面化学反应将促进特殊肽和顺铂样抗癌药物的同时附着，以实现特异性细胞识别和细胞进入。 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.单克隆抗体将用于靶向肿瘤细胞表面的抗原，而NLS则是通过核膜诱导纳米颗粒穿透。当功能化的纳米颗粒位于肿瘤细胞核内时，将应用一个交替的磁场来远程加热磁性纳米颗粒，并且所得的热量会破坏结构中的PT-O键，并诱导活跃的PT坐标位点的形成，可以轻松地连接到DNA链中，从而导致DNA启动系统中断，并导致DNA Exciention Secciention Sectimentimissimentimentions extimentions Exentimentions Pections。复合纳米颗粒还可以用作高度敏感的多功能标签，用于通过氧化铁纳米颗粒上的磁共振图像（MRI）检测细胞内颗粒的轨迹，或在AU（或AG）上进行电子/光学显微镜图像，从而促进Tumor intryporter-conjugaugate uptake in Tumor in tumor in tumor in tumor intake in tumor intake in tumor cill in tumor in tumor cill in tumor cill。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治疗剂。

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