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

结肠癌肝转移的定向传输物理和多尺度治疗

基本信息

批准号：
8564196
负责人：
MAURO FERRARI
金额：
$ 66.71万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-28 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8564196
关键词：
Animal Model Biocompatible Biodegradation Biological Biological Factors Biology Cells Coculture Techniques Collaborations Colon Carcinoma Colorectal Cancer Computer Simulation Contrast Media Cytotoxic agent Development Disease Disorder by Site Drug Delivery Systems Drug Kinetics Drug or chemical Tissue Distribution E-Selectin Endothelial Cells Engineering Epidermal Growth Factor Receptor Evaluation Experimental Models Gastrointestinal Diseases Goals Gold Heating Hepatocyte Home environment Human Image In Vitro Instruction Integrated Delivery Systems Kinetics Kupffer Cells Lesion Ligands Liver Location Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Metastatic Neoplasm to the Liver Methods Modality Modeling Mus Nanotechnology Neoplasm Metastasis Normal tissue morphology Operative Surgical Procedures Patients Phagocytes Pharmaceutical Preparations Physics Play Primary Neoplasm Process Production Property Public Health Role Scheme Shapes Silicon Staging Staging System Surface Properties Survival Rate System Testing Therapeutic Therapeutic Agents Thermal Ablation Therapy Tissues Toxic effect Toxicity Tests Treatment Efficacy Tumor Tissue Tumor-Associated Vasculature Tyrosine Kinase Inhibitor Vascular Endothelial Growth Factor Receptor angiogenesis base biomaterial compatibility cancer cell cancer therapy chemical property chemotherapeutic agent cytokine design effective therapy improved in vivo Model macrophage malignant breast neoplasm mathematical model model development nanocarrier nanoliposome nanoparticle nanovector neovasculature novel novel therapeutics overexpression particle physical model physical property radiofrequency treatment effect tumor tumor growth vector

项目摘要

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.

肝转移是胃肠道疾病过程中的常见发生。在30-70％的患者中发现了各种恶性肿瘤，包括结直肠癌，乳腺癌，肺和胰腺癌。手术是肝转移的常见疗法。但是，5年的生存率范围为25-40％，表明需要开发新的疗法。开发新疗法的一部分是必须了解肝转移的发展。 Kupffer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，尚不理解KC是针对肝转移的防御作用还是增强其血管生成。更好地了解肝转移发展和KC的作用对于开发肝转移的新疗法是必要的。包括肝转移在内的癌症治疗的另一个挑战是成像和治疗剂的分布到预期的靶标。系统施用的药物分子或对比剂仅达到所需的目标，每10,000-100,000个零件。该项目的总体目的是对肝脏转移癌症中肝转移涉及的物理障碍和生物学因素有更广泛的了解药代动力学和组织分布，可高效地递送新的治疗剂和成像剂。该项目旨在对KC的肝转移发展和定位进行图像，以设计用于治疗的硅模型，并使用物理建模过程来优化纳米载体的性质。此外，该项目旨在完善，设计和评估纳米型的生物相容性，用于递送治疗和对比剂以治疗肝转移，并确定金纳米颗粒和细胞毒性剂的治疗和成像功效 - 肝转移体内模型中的阶段纳米分离器。