Reengineering the Tumor Vasculature: Improving Drug Delivery and Efficacy

Abstract

A solid tumor is like an aberrant organ - comprised of cancer cells and a variety of host cells embedded in an extracellular matrix - nourished by blood vessels and drained by lymphatic vessels. In its journey from the blood stream to cancer cells, a therapeutic agent must cross the vessel wall and the extracellular matrix that cancer cells are ensconced in. Growth of tumors in a confined space along with deposition of matrix components, including collagen (yellow) and hyaluronan (pink), increases 'solid stress', which compresses blood and lymphatic vessels and impairs their function. The leakiness of tumor vessels also impairs tumor blood flow and increases 'intratumor fluid pressure'. The abnormal blood flow not only impedes drug delivery, but the resulting hypoxia also aids tumor invasion, metastasis, immunosuppression, inflammation, fibrosis, and treatment resistance. Engineers and physical scientists have dissected the molecular, cellular, and physical mechanisms underlying these abnormalities and developed a number of strategies to reengineer the tumor microenvironment to overcome these barriers and thus improve delivery and efficacy of treatments. Finally, these strategies have been translated from bench to bedside for treatment of cancer and have the potential to improve the treatment outcome for many diseases characterized by an abnormal microenvironment.