Directed Transport Physics and Muli-Scale Therapy of Colon Cancer Liver Metatasis

项目总结(见说明)： 肝转移是胃肠道疾病过程中常见的一种疾病。它已被发现于 30%-70%的患者死于各种恶性肿瘤，包括结直肠、乳腺、肺和胰腺 癌症。手术是肝转移的常见治疗方法；然而，5年存活率从25%到25%不等。 40%，这表明需要开发新的治疗方法。开发新疗法的一部分是有必要 了解肝转移的发展。枯否细胞(KC)，肝脏的吞噬细胞， 约占所有肝细胞的10%。KC在肝转移中的作用尚不清楚； 更具体地说，目前还不清楚KC是对肝转移起防御作用还是 增强其血管生成。更好地了解肝转移的发展和KC的作用是 有必要开发新的肝转移治疗方法。癌症治疗中的另一个挑战， 包括肝转移在内，是将成像和治疗剂分布到预定靶点。 全身给药的药物分子或造影剂只达到预期目标的一部分 一万到十万。该项目的总体目标是对物理障碍有更广泛的了解。 结直肠癌原位模型肝转移的生物学因素 以及设计能够克服或利用这些障碍的新型生物兼容递送载体 具有良好的药代动力学和组织分布，可高效地输送新的治疗药物 代理和显像剂。本项目旨在对KC的肝转移发展和定位进行成像。 为了设计用于给药的计算机模型并使用物理建模过程 优化纳米载体的性能。此外，该项目旨在改进、设计和评估 肝病治疗剂和造影剂纳米载体的生物相容性 转移，并确定金纳米粒和金纳米粒联合传递的治疗和成像效果 合理设计的靶向多阶段纳米载体在肝脏活体模型中的细胞毒作用 转移瘤。

PROJECT SUMMARY (See instructions): Liver metastasis is a common occurrence during the course of gastrointestinal disease. It has been found in 30-70% of patients who are dying of various malignancies including colorectal, breast, lung, and pancreas cancer. Surgery is a common therapy for liver metastasis; however, 5-year survival rates range from 25- 40%, indicating the need to develop novel therapies. A part of developing novel therapies is the necessity to understand the development of liver metastasis. Kupffer cells (KC), the phagocytic cells of the liver, comprise approximately 10% of all hepatic cells. The role of KC in liver metastasis is not cleariy understood; more specifically, it is not understood whether KC plays a defensive role against liver metastasis or enhances its angiogenesis. A better understanding of liver metastasis development and the role of KC is necessary to develop novel treatments for liver metastases. Another challenge in the treatment of cancers, including liver metastases, is the distribution of imaging and therapeutic agents to intended targets. Systemically administered drug molecules or contrast agents only reach their desired targets one part per 10,000-100,000. The overall goal of this project is to develop a broader understanding of physical barriers and biological factors involved in the progression of liver metastasis in orthotopic models of colorectal cancer and to design novel biocompatible delivery carriers able to overcome or take an advantage of these barriers with favorable pharmacokinetics and tissue distribution for highly efficient delivery of novel therapeutic agents and imaging agents. This project aims to image liver metastasis development and localization of KC in order to design an in silico model for administration of therapies and use a physical modeling process to optimize the properties of nanocarriers. Additionally, this project aims to refine, design, and evaluate biocompatibility of nanovectors for delivery of therapeutic and contrast agents for treatment of liver metastases, and to detennine therapeutic and imaging efficacy of co-delivery of gold nanoparticles and cytotoxic agents from rationally designed targeted multi-stage nanovectors in in-vivo models of liver metastases.