Task Specific Project 2: Perfluorocarbon Nanoparticles

8.b任务2：纳米粒子造影剂（Greg Lanza） 8.b.1具体目标 血管生成在淋巴结转移中的作用很少受到关注，但一些研究指出， 肿瘤诱导淋巴管生成与血管内皮生长因子表达的关系 （VEGF）-A、-C和血小板衍生生长因子（PDGF）[126-128]。动物模型中的现有证据， 在乳腺癌患者的人体轴淋巴结中证实， SLN中的转移之前是由原发性肿瘤诱导的血管重组[129]。的 SLN的结构富含来自快速增殖的高分化的功能性血管， 内皮微静脉对原发性肿瘤产生的促血管生成细胞因子的反应。新生血管性 丰富的淋巴结为转移性癌细胞的播种和生长创造了肥沃的“土壤”[129]。各种形式的 整联蛋白如AV| J3，avp5。和A5 PI在血管生成血管中上调，这些蛋白质可被 用RGD（精氨酸-甘氨酸-天冬氨酸）肽或高亲和力肽模拟物有效靶向。在 特别是，该项目开发了生物相容的全氟化碳（PFC）基纳米颗粒 用于成像体内整合素表达的前导物。除了其优异的生物相容性外， 动物和人类，MRI可以成像PFC纳米颗粒和配方，包括荧光染料， 用于光学成像应用。MRI能够显示腋窝淋巴结的新生血管床 以与深度无关的断层摄影方式进行高分辨率成像的节点。因此，我们将开发 多峰全氟化碳基纳米颗粒，可安全用于人体。颗粒可以是 肿瘤周围施用用于直接SLN成像或全身（i. v.）用于淋巴结血管生成成像 船舶. PFC纳米颗粒具有成像淋巴结血管系统的额外优势 通过MRI和PAT方法，并将分子信息添加到PAT数据。本项目的具体目标 是： (1)优化用于PAT的多模态和生物相容性PFC纳米颗粒的配方，以及 SLN和相关的新生血管系统。 (2)通过PAT和MRI对小鼠的淋巴结进行成像。我们将使用高度增殖的肿瘤模型（4 T1 Luc 肿瘤）表达高水平的α v β 3整合素和新生血管系统。支撑 中心将进行MRI研究，并按照第8.c节和第8.d节所述进行PAT成像 (see 8.a以上的补充资料）。

8.b Task 2: Nanoparticle contrast agents (Greg Lanza) 8.b.1 Specific aims The role of angiogenesis in lymph node metastasis has received little attention, but several studies point to the association of tumor induced lymphangiogenesis and the expression of vascular endothelial growth factor (VEGF)-A, -C, and platelet derived growth factor (PDGF) [126-128]. Current evidence in animal models and corroborated in human axial lymph nodes from patients with breast cancer indicates that the establishment of metastases in the SLN is preceded by vascular reorganization induced by the primary tumor [129]. The architecture of the SLN is enriched with functional blood vessels derived from rapidly proliferating high endothelial venules in response to proangiogenic cytokines elaborated by the primary tumor. The neovascular rich lymph node create a fertile "soil" for metastatic cancer cells to seed and grow [129]. Various forms of integrins such as av|J3, avp5. anda5pi are up regulated in angiogenic blood vessels and these proteins can be targeted effectively with RGD (Arginine-Glycine-Aspartic acid) peptides or high affinity peptidomimetic. In particular, biocompatible perfluorocarbon (PFC)-based nanoparticles have been developed by the project leader for imaging the expression of integrins in vivo. In addition to its excellent biocompatibility profile in animals and humans, MRI can image PFC nanoparticles and formulations that include fluorescent dyes have been used for optical imaging applications. MRI is capable of imaging the neovascular bed of axillary lymph nodes with high resolution imaging in a depth-independent, tomographic manner. Therefore, we will develop multimodal perfluorocarbon-based nanoparticles that are safe for use in humans. The particles can be administered peri-tumorally for direct SLN imaging or systemically (i.v.) for imaging lymph node angiogenic vessels. The PFC nanoparticles have the added advantage of imaging the vascular system of the lymph nodes by both MRI and PAT methods and adds molecular information to PAT data. The Specific Aims for this project are to: (1) Optimize formulation of multimodal and biocompatible PFC nanoparticles for PAT, and MRI scanning of SLN and associated neovascular system. (2) Image lymph nodes by both PAT and MRI in mice. We will use a highly proliferating tumor model (4T1Luc tumor) that expresses high levels of av(33 integrins and neovascular systems for this study. The Support Core will perform the MRI studies and the PAT imaging will be carried as described in Sections 8.c and 8.d (see 8.a above for additional information).