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

肝转移是胃肠道疾病的常见并发症。在30-70%的死于各种恶性肿瘤的患者中发现了它，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疗法;然而，5年生存率范围为25- 40%，表明需要开发新的治疗方法。开发新疗法的一部分是必须了解肝转移的发展。枯否细胞（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，KC是否对肝转移起防御作用或增强其血管生成尚不清楚。更好地了解肝转移的发展和KC的作用是必要的，以开发新的治疗肝转移。治疗癌症（包括肝转移）的另一个挑战是将成像剂和治疗剂分布到预期靶点。全身给药的药物分子或造影剂仅达到其期望的靶点，每10，000 - 100，000份中有一份。该项目的总体目标是更广泛地了解结直肠癌原位模型中肝转移进展中涉及的物理屏障和生物因素，并设计新型生物相容性递送载体，该载体能够克服或利用这些屏障，具有良好的药代动力学和组织分布，用于高效递送新型治疗剂和显像剂。该项目旨在对KC的肝转移发展和定位进行成像，以便设计用于治疗的计算机模型，并使用物理建模过程来优化纳米载体的特性。此外，该项目旨在改进，设计和评估用于治疗肝转移的治疗和造影剂的纳米载体的生物相容性，并确定从合理设计的靶向多阶段纳米载体中共同递送金纳米颗粒和细胞毒性剂在肝转移体内模型中的治疗和成像功效。

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.