Nanoparticles in vivo: interactions with Cells and Tissues

所提出的CCNE的主要目标是开发纳米系统，该纳米系统特异性地寻找肿瘤组织以用于治疗。 诊断、监测和治疗肿瘤的目的。这些应用程序中的每一个都需要选择性的 将纳米颗粒递送到肿瘤中和/或在肿瘤中的选择性检测/活性。粒子能够 特异性地进入实质或基质肿瘤细胞提供了进一步的优点。此外，本发明还提供了一种方法， 设计用于某些体内诊断目的的颗粒应该能够从它们具有的肿瘤细胞中退出 输入，允许发送和返回类型的方法。本项目（项目1）的重点是发展 的归巢肽纳米颗粒结构，优化肿瘤归巢，同时避免非特异性 在非靶组织中的累积并使毒性最小化。大量的肽和其他 能够选择性地将纳米颗粒递送到肿瘤脉管系统的化合物是现成的。最大的 在优化这种颗粒的肿瘤归巢中要克服的一个障碍是 网状内皮系统（RES）和巨噬细胞，以消除颗粒从体循环。的 肽影响颗粒进入血管外空间的能力，以及 颗粒及其进入肿瘤细胞和肿瘤内皮细胞的有效载荷也是肿瘤细胞增殖的主要决定因素。 纳米粒子的靶向功效。我们建议开发新技术来处理肝脏摄取， 外渗问题，我们还建议开发促进纳米颗粒从细胞中退出的方法， 这一特性在一些体内诊断应用中可能是有用的，并且还可以减少非特异性 对非预期靶细胞的毒性。一个由肿瘤生物学家、肽化学家、材料科学家和 工程师们奋进通过从组合物中鉴定和表征肽来实现这些目标。 这些文库促进肿瘤中的结合和细胞内进入，并阻止其进入身体的其他部位。 我们期望项目1中的这项工作为合理设计纳米颗粒系统提供基础， 由于肝脏摄取和移动能力降低，改善了有效靶向肿瘤的体内特性 通过细胞层和细胞膜等屏障。该项目的结果将使设计在 用于多功能纳米器件的体内路由系统。建议使用体内发现方法和 路由系统的早期体内测试和优化将加速器件的构建， 很可能在临床上有用。这些肽，以及现有的归巢肽集合， 肿瘤血管和/或肿瘤细胞上的特异性受体，将可用于本CCNE的其他项目。 肽作为纳米颗粒递送载体的有效性和结果对人类细胞的适用性 将结合本CCNE的项目2和项目6进行确认。

A main goal of the proposed CCNE is to develop nanosystems that specifically seek out tumor tissue for the purposes of diagnosing, monitoring and treating tumors. Each of these applications requires selective delivery of nanoparticles into tumors and/or selective detection/activity in tumors. Particles capable of specifically entering into parenchymal or stromal tumor cells provide further advantages. In addition, particles designed for certain in vivo diagnostic purposes should be able to exit from tumor cells they have entered, allowing for send and return type approaches. This project (Project 1) focuses on the development of homing peptide-nanoparticle constructs that optimize tumor homing while avoiding non-specific accumulation in non-target tissues and minimizing toxicity. A large collection of peptides and other compounds capable of selectively delivering nanoparticles to tumor vasculature is on hand. The biggest single obstacle to be overcome in optimizing the tumor homing of such particles is the ability of the reticuloendothelial system (RES) and macrophages to eliminate particles from the systemic circulation. The ability of the peptides to effect passage of the particles into the extravascular space, and internalization of the particles and their payload into tumor cells and tumor endothelial cells are also major determinants in targeting efficacy of nanoparticles. We propose to develop new technology to deal with the liver uptake and extravasation issues, and we also propose to develop ways of promoting the exit of nanoparticles from cells, a trait that could be useful in some in vivo diagnostic applications, and could also reduce non-specific toxicities to non-intended target cells. A team of tumor biologists, peptide chemists, materials scientists, and engineers endeavor to achieve these goals by identifying and characterizing peptides from combinatorial libraries that promote the binding and intracellular entry in tumors and discourage it elsewhere in the body. We expect this work in Project 1 to provide the basis for rational design of nanoparticle systems with greatly improved in vivo properties for effective tumor targeting due to diminished liver uptake and ability to travel through barriers such as cell layers and membranes. The results from this Project will enable the design of in vivo routing systems for multifunctional nanodevices. The proposed use of in vivo discovery methods and early in vivo testing and optimization of the routing systems will accelerate the construction of devices that are likely to be clinically useful. These peptides, and the existing collection of homing peptides that recognize specific receptors in tumor vessels and/or on tumor cells, will be available to the other Projects in this CCNE. The validity of the peptides as nanoparticle delivery vehicles and applicability of the results to human cells and tissues will be validated in conjunction with Projects 2 and 6 of this CCNE.