Imaging Nanocomposites Targeting Tumor Microvasculature

靶向肿瘤微血管系统的纳米复合材料成像

• 批准号: 7471469
• 负责人: MOHAMED K KHAN
• 金额: $ 26万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-27 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7471469
• 关键词: 3-Dimensional; Animals; Antibodies; Autoradiography; Binding; Biodistribution; Biological Models; Charge; Chemistry; Class; Copper; Daily; Detection; Devices; Dyes; Early Diagnosis; Electron Microscopy; Electrons; Encapsulated; Film; Goals; Gold; Hybrids; Image; Imagery; Imaging Device; Injection of therapeutic agent; Integrins; Isotopes; Life; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Metals; Methods; Microscopic; Modality; Mus; Neutrons; Numbers; Organ; Particle Size; Peptides; Polymers; Positron-Emission Tomography; Process; Property; Prostatic Neoplasms; RGD (sequence); Radioactive; Radioactivity; Radiochemistry; Radioisotopes; Research Personnel; Residual state; Route; Signal Transduction; Specificity; Staining method; Stains; Surface; Surface Properties; Techniques; Technology; Testing; Time; Tissues; Toxic effect; Tumor Burden; Validation; Weight; base; design; image guided therapy; improved; in vivo; intravenous injection; melanoma; micrography; molecular imaging; nanocomposite; nanodevice; nanoparticle; neoplastic cell; novel; particle; programs; single photon emission computed tomography; size; time use; transmission process; tumor

DESCRIPTION (provided by applicant): Objectives: This proposal will develop novel agents for imaging the tumor microvasculature present in all cancers. It proposes to design, synthesize, and characterize novel radioisotope containing nanoparticles (nanocomposite devices or NCDs) made from dendrimer templates and targeted at the angiogenic tumor microvasculature. This technology will encapsulate different radioisotopes within devices of defined size and targeting surface properties. The radioactivity delivered to a tumor is increased by increasing the particle size, or the number or specific activity of the guest atoms, without destroying the targeting ability of the NCD. By varying the particular guest atoms (metals/isotopes), different forms of imaging will be permitted (eg. film, SPECT, PET). These NCDs can deliver at least a log fold more radioactivity to tumors than possible with current antibody technologies, giving the added potential for imaging microscopic tumor burdens, and even molecular imaging. NCDs could permit combined imaging and therapy of all cancers. Specific Aims: (1) To chemically link the angiogenic microvascular targeting peptide, RGD, onto the surface of gold or copper containing NCDs. (2) To carry out biodistribution and biosafety studies with RGD-surfaced 5nm {Au} nanocomposites and RGD-surfaced 5 nm {Cu} nanocomposites to determine whether we can exploit the targeting ability of RGD to deliver nanocomposites to the tumor microvasculature (3) To carry out imaging of the RGD-surfaced NCDs a) lntracellularly, b) intratumorally, and c) in the whole animal. Design and Methods: (1) The NCDs will be made from PAMAM polymer templates, and then linked to RGD or, alternatively they may be made from RGD pre-substituted templates with the later introduction of gold (or copper) based on the principle of reactive encapsulation. Next, {198Au} and {64Cu} NCDs will be developed by direct activation or by using conventional radiochemistry. (2) Specificity of binding studies will be carried out by intravenous injection of the NCDs into B16 melanoma or MatLyLu prostate tumor bearing mice, and isolation of the organs/tissues for analysis of NCD content, and competitive injection of excess RGD. Biosafety studies include daily weights and a detailed toxicity table. (3) intracellular, intratumoral, and whole animal imaging will be accomplished via Transmission Electron Micrography (TEM), an autoradiography and immunohistochemical method, and SPECT imaging respectively.

描述（由申请人提供）：目标：该提案将开发出新颖的药物，以对所有癌症中存在的肿瘤微脉管系统进行成像。 它提出了设计，合成和表征含有纳米颗粒（纳米复合设备或NCD）的新型放射性同位素的，并用树枝状聚合物模板制成，并针对血管生成肿瘤微腔。 该技术将在定义的大小和靶向表面特性的设备内封装不同的放射性同位素。 通过增加粒径或来宾原子的数量或特定活性而不会破坏NCD的靶向能力来增加传递到肿瘤的放射性。 通过改变特定的来宾原子（金属/同位素），将允许不同形式的成像（例如，电影，Spect，Pet）。 这些NCD至少可以通过当前的抗体技术向肿瘤提供至少对肿瘤的放射性，从而为显微镜肿瘤负担甚至分子成像带来了额外的可能性。 NCD可以允许所有癌症的成像和治疗。 具体目的：（1）将血管生成的微血管靶向肽RGD连接到含有NCD的金或铜的表面。 （2）使用RGD曲面5nm {au}纳米复合材料和RGD-SURFACES进行生物分配和生物安全研究，5 nm {cu}纳米复合材料可以确定我们是否可以利用RGD向nanocomposites提供对nanocomposites的靶向能力，以将Nanocomposites运送到tumormov corter nanoccoster（3），以将nanoCompose（3）运送为3）在整个动物中，肿块，b）肿瘤和c）。 设计和方法：（1）NCD将由PAMAM聚合物模板制成，然后链接到RGD，或者，可以根据反应性封装原则，将其由RGD预取代的模板制成。 接下来，{198au}和{64cu} NCD将通过直接激活或使用常规放射化学来开发。 （2）结合研究的特异性将通过将NCD静脉注射到B16黑色素瘤或Matlylu前列腺肿瘤轴承小鼠中，并分离器官/组织以分析NCD含量和竞争性RGD的竞争性注射。 生物安全研究包括每日体重和详细的毒性表。 （3）细胞内，肿瘤内和整个动物成像将分别通过透射电子显微照片（TEM），放射自显影和免疫组织化学方法以及SPECT成像来完成。