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

肝转移是胃肠道疾病病程中的常见现象。在30-70%死于各种恶性肿瘤的患者中，包括结肠直肠癌、乳腺癌、肺癌和胰腺癌。手术是肝转移的常用治疗方法；然而，5年生存率在25-40%之间，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。库普弗细胞（KC）是肝脏的吞噬细胞，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，尚不清楚KC是否对肝转移起防御作用或增强其血管生成。更好地了解肝转移的发展和KC的作用对于开发新的肝转移治疗方法是必要的。治疗癌症（包括肝转移）的另一个挑战是将显像和治疗剂分配到预定的靶点。系统给药的药物分子或造影剂只有万分之一到十万分之一达到预期目标。该项目的总体目标是更广泛地了解在结肠直肠癌原位模型中涉及肝转移进展的物理障碍和生物因素，并设计新的生物相容性递送载体，能够克服或利用这些障碍，具有良好的药代动力学和组织分布，以高效地递送新型治疗剂和显像剂。本项目旨在对肝转移的发展和KC的定位进行成像，以便设计一个计算机模型来给药，并使用物理建模过程来优化纳米载体的性能。此外，本项目旨在完善、设计和评估用于肝转移治疗和造影剂的纳米载体的生物相容性，并确定合理设计的靶向多阶段纳米载体共同递送金纳米颗粒和细胞毒性药物在肝转移体内模型中的治疗和成像效果。

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 clearly 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 determine 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.