Nanoparticles in vivo: interactions with Cells and Tissues

提议的CCNE的一个主要目标是开发专门为肿瘤组织寻找肿瘤组织的纳米系统 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地 将纳米颗粒输送到肿瘤中和/或在肿瘤中选择性检测/活性。粒子能够 特别是进入实质或间质肿瘤细胞提供了进一步的优势。此外, 为某些体内诊断目的而设计的颗粒应该能够从它们拥有的肿瘤细胞中退出 已输入，允许发送和返回类型方法。本项目(项目1)重点发展 优化肿瘤归巢同时避免非特异性的归巢多肽-纳米颗粒构建 在非靶组织中蓄积，并将毒性降至最低。一大批多肽和其他 能够选择性地将纳米颗粒输送到肿瘤血管系统的化合物已经问世。最大的 在优化这种颗粒的肿瘤归巢过程中需要克服的单一障碍是 网状内皮系统(RES)和巨噬细胞从体循环中清除颗粒。这个 多肽影响颗粒进入血管外空间的能力，以及内化 粒子及其进入肿瘤细胞和肿瘤内皮细胞的有效载荷也是 纳米粒的靶向功效。我们建议开发新的技术来处理肝脏摄取和 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， 这一特征在一些活体诊断应用中可能很有用，也可以减少非特异性 对非预期目标细胞的毒性。一个由肿瘤生物学家、多肽化学家、材料科学家和 工程师们努力通过从组合多肽中识别和表征多肽来实现这些目标 促进肿瘤中的结合和细胞内进入，并阻止其在体内其他部位的库。 我们期待项目1中的这项工作为纳米粒子系统的合理设计提供很大的基础 由于肝脏摄取和行走能力减弱，有效靶向肿瘤的体内特性得到改善 通过细胞层和细胞膜等屏障。该项目的成果将使In的设计 用于多功能纳米器件的VIVO布线系统。建议使用体内发现方法和 早期的体内测试和路由系统的优化将加快设备的建造， 很可能在临床上有用。这些多肽，以及识别的现有归巢多肽集合 肿瘤血管和/或肿瘤细胞上的特定受体，将可用于本次CCNE的其他项目。 多肽作为纳米粒载体的有效性及其对人类细胞的适用性 和组织将结合本CCNE的项目2和6进行验证。

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.