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

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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.