An Artificial Microvessel Platform for Studying Metastatic Cancer and Drug Delivery

blood vessel;invasion;intravasation;metastasis;tumor microenvironment;drug delivery;in vitro pharmacokinetics;Materials Science & Engineering

Wong, Andrew DouglasKonstantopoulos, Kostas ;

Johns Hopkins University

关键词: blood vessel;    invasion;    intravasation;    metastasis;    tumor microenvironment;    drug delivery;    in vitro pharmacokinetics;    Materials Science & Engineering;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/60580/Wong%2c%20Andrew_Dissertation_v8_ToLibrary.docx?sequence=10&isAllowed=n

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Cancer is currently the second leading cause of death in the U.S.Approximately 90% of cancer-related deaths are due to metastasis, which is the spread of cancer in the body.While there have been significant advances in visualizing metastasis, the details of the biological and physical processes that govern steps in the metastatic cascade, such as invasion and intravasation, remain poorly understood.The difficulty in studying metastasis stems from the complexity of the interface between the tumor microenvironment and the vascular system.To elucidate the mechanistic events taking place during invasion and intravasation, we created a platform that positions tumor cells adjacent to an artificial vessel embedded in an extracellular matrix (ECM).Using live-cell fluorescence microscopy, we studied the complex interplay between highly metastatic cancer cells and a functional artificial microvessel lined with endothelial cells during tumor invasion and intravasation. The engineered platform recapitulates many of the interactions between tumors and vessels thought to occur in the body and allows the systematic study of the physical and biological properties that regulate invasion and intravasation.Further insight into these poorly understood processes may provide new strategies to prevent the spread of cancer and reduce the high mortality rates associated with metastasis.This novel platform is also being used to study vascular drug delivery and treatment of cancer at the single-cell level.Cancer relapse after chemotherapy is understood to be caused by the inability to deliver cytotoxic levels of drugs to all tumor cells within the limited doses administered to patients.It is the survival of single or small clusters of tumor cells within the tumor microenvironment that eventually leads to the resurgence of cancer; however, current techniques for monitoring the efficacy and delivery of drugs largely ignore the response of tumors at the single-cell level.As a proof-of-principle, we use the aforementioned artificial microvessel platform to understand chemotherapeutic drug delivery within the tumor microenvironment.Using live-cell fluorescence microscopy, we observe the introduction of doxorubicin, a widely used anticancer drug, through the artificial microvessel and quantify the delivery and efficacy of chemotherapeutics within the platform. The ability to model drug delivery and quantify drug accumulation and efficacy at the single-cell level within a physiologically relevant tumor microenvironment provides a new capability for in vitro pharmacokinetics and a novel tool for drug discovery.