Targeting Inflammation to Improve Tumor Drug Delivery

Drug delivery to the tumor is often compromised due to vascular hyperpermeability (leakiness) of tumor blood vessels or vessel compression, both of which can lead to inefficient delivery of the cytotoxic drug and therapeutic failure. Methods of vascular normalization aim to fortify the tumor vessel wall and reduce vessel leakiness, and thus they may improve drug delivery to the tumor, thereby enhancing the efficacy of therapeutic agents. Vascular normalization is usually achieved with the use of anti-angiogenic agents. Vessel leakiness can be potentially reversed by NSAIDs and/or inflammation resolution mediators, inducing vessel normalization and improving tumor drug delivery. Inefficient delivery of drugs is a main cause of chemotherapy failure in hypoperfused tumors. To enhance perfusion and drug delivery in these tumors, two strategies have been developed: vascular normalization, aiming at normalizing tumor vasculature and blood vessel leakiness, and stress alleviation, aiming at decompressing tumor vessels. Vascular normalization is based on anti-angiogenic drugs, whereas stress alleviation is based on stroma-depleting agents. We present here an alternative approach to normalize tumor vasculature, taking into account that malignant tumors tend to develop at sites of chronic inflammation. Similarly to tumor vessel leakiness, inflammation is also characterized by vascular hyperpermeability. Therefore, testing the ability of anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs) or inflammation resolution mediators, as an alternative means to increase tumor drug delivery might prove promising. Inefficient delivery of drugs is a main cause of chemotherapy failure in hypoperfused tumors. To enhance perfusion and drug delivery in these tumors, two strategies have been developed: vascular normalization, aiming at normalizing tumor vasculature and blood vessel leakiness, and stress alleviation, aiming at decompressing tumor vessels. Vascular normalization is based on anti-angiogenic drugs, whereas stress alleviation is based on stroma-depleting agents. We present here an alternative approach to normalize tumor vasculature, taking into account that malignant tumors tend to develop at sites of chronic inflammation. Similarly to tumor vessel leakiness, inflammation is also characterized by vascular hyperpermeability. Therefore, testing the ability of anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs) or inflammation resolution mediators, as an alternative means to increase tumor drug delivery might prove promising. a stromal cell population highly enriched in the tumor microenvironment that is implicated in cancer cell invasion and fibrosis. an enzyme responsible for the formation of prostanoids such as prostaglandin, inhibition of which can provide relief from pain and inflammation. There are two types of COX enzymes, COX-1 and COX-2, both of which produce prostaglandins. However, COX-1 enzymes produce baseline levels of prostaglandins that activate platelets and protect the lining of the gastrointestinal tract, while COX-2 enzymes produce prostaglandins in response to infection or injury. also known as the desmoplastic reaction, desmoplasia is the abnormal growth of fibrous tissue. It is often present in tumors and it is characterized by ECM accumulation. medical term for swelling caused by excess fluid within a tissue. the non-cellular solid component that surrounds cells within tissues and organs and provides support as well as the basic biochemical and molecular signals necessary for fundamental cellular processes such as development, differentiation, growth, homeostasis, and survival. the increase in vascular permeability that is observed in acute and chronic inflammation, wound healing, and cancer. the hydrostatic pressure of the fluid phase of a tissue. more frequent and lower-dose administration of chemotherapy. a class of drugs that include drugs with analgesic and anti-pyretic effects. Although different NSAIDs have different structures, they all act by inhibiting COX enzymes. vascular permeability refers to the capacity of the blood vessel wall to allow the flow of molecules such as drugs or nutrients in and out of the vessel. fatty acids that contain more than one double bond in their backbone. reactive molecules and free radicals derived from molecular oxygen, such as hydrogen peroxide, superoxide, hydroxyl ion, and nitric oxide. They are mainly produced as byproducts of aerobic respiration and mitochondrial electron transport, in particular. They are implicated in cell signaling related to apoptosis and are associated with several deleterious processes, and elevated ROS levels are detected in almost all cancers. a multifunctional secreted cytokine involved in processes such as cell proliferation, differentiation, and apoptosis. a growth factor that promotes angiogenesis.