Targeted Smart Nanoplatforms for Multimode Imaging

纳米技术为人类疾病的新疗法带来了希望。 提供了比当前临床方法显著进步的可能性， 治疗、成像、靶向或其它效应器功能。同时提高 成像剂和药物的药理学性质纳米平台的多功能性质， 因此，非常适合于诊断和治疗涉及多种生理的复杂疾病， 隔室，如癌症。项目3的总体目标是描述血管 靶向肿瘤内新的可编程“智能”纳米平台（SNaPs）的积累。要求1 将研究纳米平台如何靶向癌胚整合素受体的特征-表达在 肿瘤和肿瘤脉管系统-导致这些部位内的积聚。这些研究将侧重于 了解亲和力和亲合力对靶内纳米颗粒最终积聚的影响 绝佳的价钱在AIM 2中。我们将评估靶向的纳米平台进行自发自组装上， “蜂窝”核心，基于主客体化学相互作用。组装取决于以下方面的集成 聚乙二醇聚合物（PEG）共轭分子客体。PEG聚合物的远端 与“可编程”元件如靶向剂或显像剂预缀合。其针对性和 SNaP的稳定性将针对常规纳米颗粒进行测试。AIMS 1和2都将采用 禽类肿瘤模型和具有双报告子的光学成像小鼠的背窗制备（光学& Gd）的纳米颗粒。AIM 3.将多种目标要素纳入战略行动方案的能力， 将使用主体平台和客体锚定部分的简单比例组合来评估 是否组合靶向方法--使用靶细胞上两种不同受体的配体-- 提供了比单一靶向的特异性的任何增加。最后，在AIM 4中。我们将把研究从 简单地对颗粒部位的积聚进行成像，以测试多功能、可成像的纳米颗粒是否可以 在疾病的遗传临床前模型中检测新生肿瘤。这些研究将采用光学和MR 皮下肿瘤生长和转移的小鼠模型和自发鼠模型的成像 肿瘤的发展。我们认为，这些研究应该为新一代的 易于编程的多功能纳米平台，适合于成像和可能的治疗， 人类患者的恶性肿瘤。这种粒子代表了发展的重要的第一步， “现场”可编程和个性化，但可批量生产的诊断/治疗产品。

Nanotechnology holds promise for new treatments for disease in man. Nanoparticle-based approaches offer the possibility of significant advances over current clinical methods accommodating multiple therapeutic, imaging, targeting or other effector functions within each nanoplatform. while improving the pharmacological properties of imaging agents and drugs The multifunctional nature of nanoplatforms is therefore well-suited for the diagnosis and treatment of complex diseases involving multiple physiological compartments, such as cancer. The overall objective of project 3 is to characterize the impact of vascular targeting on the accumulation of new programmable "smart" nanoplatforms (SNaPs) within tumors. AIM 1 will examine the characterize how targeting nanoplatforms to oncofetal integrin receptors - expressed on tumors and tumor vasculature - leads to accumulation within these sites. These studies will focus on understanding the impact of affinity and avidity on the ultimate accumulation of nanoparticle within the target site. In AIM 2. we will assess targeting of nanoplatforms which undergo spontaneous self-assembly on a "honeycomb" core, based on host-guest chemical interactions. Assembly is dependent upon integration of polyethyleneglycol polymer (PEG)-conjugated molecular guests. The distal terminus of the PEG polymers are pre-conjugated to "programmable" elements, such as targeting or imaging agents. The targeting and stability of the SNaPs will be tested against conventional nanoparticles. Both AIMS 1 & 2 will employ MRI of avian tumor models and the dorsal window preparation of optically imaged mice with dual reporter (optical & Gd) bearing nanoparticles. AIM 3. The capacity to incorporate multiple targeting elements into the SNaPs by simple ratiometric combination of the host platform and the guest-anchored moieties will be used to evaluate whether combinatorial approaches at targeting - using ligands for two different receptors on the target cell - offers any increase in specificity over singly targeted. Finally, in AIM 4. we will extend the studies from simply imaging accumulation at particle sites to testing whether multifunctional, imagable nanoparticles can detect nascent tumors in genetic preclinical models of disease. The studies will employ Optical and MR imaging of mouse models of subcutaneous tumor growth and metastasis, and spontaneous murine models of tumor development. We believe that these studies should lay the groundwork for a new generation of easily programmed, multifunctional nanoplatforms, amenable to the imaging and possibly treatment of malignancy in human patients. Such particles represent an important first step towards the development of "on site" programmable and personalized, but mass-producible, diagnostic/therapeutic products.