Biosignature and Vector Development Core

核心C3：生物特性和媒介开发核心 引言 分子显像剂正在将无创医学诊断的潜力从基础大体扩展到 基于独特细胞表面识别的复杂表型特征的解剖学描述 生化特征。“分子成像”现在是大多数临床相关疾病的显著特征。 成像方式，这为有针对性的诊断研究提供了机会，也为图像监测提供了机会 特定部位的治疗提供，很像保罗·埃利希100年前设想的“神奇子弹”。因为我们 已经证明，整合素靶向的全氟碳纳米颗粒可以将分子成像与局部 药物传递，即合理的靶向治疗，并提供关于预期反应的预后信息 治疗1-4。 所有肿瘤的共同之处是对氧合、营养能量供应的需求，以及 脉管系统。细胞-基质相互作用，肿瘤侵袭和转移的基础，以及血管生成， 与细胞膜黏附分子密切相关，称为整合素。整合素是 异二聚体，跨膜糖蛋白，由19个α和8个β亚基组合而成。在……里面 整合素除了具有黏附功能外，还参与经典信息的传递 被认为影响肿瘤细胞增殖和凋亡的信号通路和激活 内皮细胞。如本SCCNE的几个项目中所述，α-β3整合素和a5b1的拮抗剂 整合素可偶联到纳米颗粒表面，并用于高亲和力、高特异性靶向 新生血管。事实上，α-β3-整合素在黑色素瘤和乳腺癌中的作用已有很好的文献记载。 转移，但在肿瘤类型内和不同类型之间在时间上不同。然而，侵袭性较弱的肿瘤具有低 Anb3-整合素的表达或仅瞬时表达，alambdab1-整合素在Low更频繁地表达 除侵袭性癌外，还有潜在的恶性肿瘤，如卵巢癌6。内皮细胞 胶质母细胞瘤的增殖可能表现为三种亚型：实体肾小球 ICAM-1、α2β1、α3β1、α5β1阴性；2)通道化分支ICAM-1阴性，α2β1、α3β1、α5β1阳性；或3) 通道-毛细血管扩张型ICAM-1、α2β1、α3β1、α5β1阳性。这些分子的可变表达可能 反映了内皮细胞成熟的不同步骤，并进一步说明了开发 靶向药物，以适当分割和治疗肿瘤新生血管的异质性群体。为 配体靶向治疗要有效，患者必须给予适当的个体化药物 (或混合制剂)。 希特曼纳米技术卓越中心将建立这一核心，用于开发和 将与当前和未来的纳米技术平台一起使用的靶向配体的表征 中心，更广泛地说，在其他中心。方法三方结合了最先进的技术 目的：1)肽噬菌体展示，2)重组抗体生产，3)生物信息学，以解决未检测到的 需要独特的肿瘤结合配体。

CORE C3: Biosiqnature and Vector Development Core Introduction Molecular imaging agents are extending the potential of noninvasive medical diagnosis from basic gross anatomical descriptions to complicated phenotypic characterizations based upon the recognition of unique cellsurface biochemical signatures. "Molecular imaging" is now a prominent feature of most clinically relevant imaging modalities, which affords the opportunity for targeted diagnostic studies but also for image-monitored site-specific therapeutic delivery, much like the "magic bullet" envisioned by Paul Erhlich 100 years ago. As we have demonstrated, integrin-targeted perfluorocarbon nanoparticles can combine molecular imaging with local drug delivery, i.e. rational targeted therapy, and provide prognostic information about the expected response to treatment1-4. Common to all tumors are the demands for oxygenation, nutritive energy supplies, and development of a vasculature. Cell-matrix interactions, fundamental to tumor invasion and metastasis, as well as angiogenesis, are closely associated with cell membrane adhesion molecules referred to as integrins. The integrins are heterodimeric, transmembrane glycoproteins resulting from the combination of 19 alpha and 8 beta subunits. In addition to their adhesive functions, integrins are involved in the transduction of information along classical signaling pathways and are presumed to influence cellular proliferation and apoptosis of cancer and activated endothelial cells. As described in several programs of this SCCNE, antagonists of alphavbeta3-integrin and a5b1 integrin maybe coupled to nanoparticle surfaces and utilized for high affinity, high-specificity targeting of the neovasculature. Indeed, the role of alphavbeta3-integrin is well documented in melanoma and breast cancer metastasis, but varies temporally within and across tumor types. Whereas, less aggressive tumors have low expression or only transient expression of anb3-integrin, alambdab1-integrin is more frequently expressed by low malignant potential tumors in addition to aggressive carcinomas, e.g., in ovarian cancers6. Endothelial proliferations of glioblastomas may be phenotypically characterized into three subtypes 6:1) solid-glomeruloid ICAM-1, alpha2beta1,alpha3beta1,alpha5beta1 negative; 2) channeled-branching ICAM-1 negative, and alpha2beta1,alpha3beta1,alpha5beta1 positive; or 3) channeled-telangiectatic ICAM-1 ,alpha2beta1,alpha3beta1,alpha5beta1 positive. The variable expression of these molecules probably reflect different steps in the maturation of endothelium and further illustrates the need to develop arrays of targeted agents to properly segment and treat the heterogeneous population of tumor neovasculature. For ligand-targeted therapies to work efficiently, patients must be administered the appropriate individualized agent (or mixture of agents). The Siteman Center for Nanotechnology Excellence will establish this core for the development and characterization of targeting ligands to be used with current and future nanotechnology platforms within the center and more broadly at other centers. The approach tripartite combines the state-of-the art technologies of: 1) peptide phage display, 2) recombinant antibody production, and 3) bioinformatics to address the unmet need for unique tumor binding ligands.