Overview of Methods for Overcoming Hindrance to Drug Delivery to Tumors, with Special Attention to Tumor Interstitial Fluid.

Every drug used to treat cancer (chemotherapeutics, immunological, monoclonal antibodies, nanoparticles, radionuclides) must reach the targeted cells through the tumor environment at adequate concentrations, in order to exert their cell-killing effects. For any of these agents to reach the goal cells, they must overcome a number of impediments created by the tumor microenvironment (TME), beginning with tumor interstitial fluid pressure (TIFP), and a multifactorial increase in composition of the extracellular matrix (ECM). A primary modifier of TME is hypoxia, which increases the production of growth factors, such as vascular endothelial growth factor and platelet-derived growth factor. These growth factors released by both tumor cells and bone marrow recruited myeloid cells form abnormal vasculature characterized by vessels that are tortuous and more permeable. Increased leakiness combined with increased inflammatory byproducts accumulates fluid within the tumor mass (tumor interstitial fluid), ultimately creating an increased pressure (TIFP). Fibroblasts are also up-regulated by the TME, and deposit fibers that further augment the density of the ECM, thus, further worsening the TIFP. Increased TIFP with the ECM are the major obstacles to adequate drug delivery. By decreasing TIFP and ECM density, we can expect an associated rise in drug concentration within the tumor itself. In this overview, we will describe all the methods (drugs, nutraceuticals, and physical methods of treatment) able to lower TIFP and to modify ECM used for increasing drug concentration within the tumor tissue.

Tumor interstitial fluid: proteomic determination as a possible source of biomarkers.

Tumor interstitial fluid (TIF) is formed largely by an imbalance between the forces that govern the filtration of liquid between the luminal and abluminal parts of tumor neo-vessels. TIF is a dynamic solution that varies according to tumor type, and is generally rich in proteins, lipids, and various enzyme-derived substances. These enzyme-derived substances can have important roles as both regulatory and inflammatory factors. Furthermore, the oncotic pressure caused by the presence of these proteins and peptides in TIF leads to a proinflammatory condition in which macrophages produce cytokines such as Interleukins 1 and 6. With the recent advent of proteomics, TIF has been studied extensively and can be used as a source of potential biomarkers for cancer, including breast, ovarian, and head and neck cancer. In the present review, we discuss the process of TIF formation, its composition, the effects of its accumulation, the methods of sampling, and the proteomic analyses performed on it, which make TIF a valuable tool in monitoring several cancer types.

Tumor interstitial fluid as modulator of cancer inflammation, thrombosis, immunity and angiogenesis.

Tumor interstitial fluid (TIF) is a watery phase that accumulates inside the tumor interstitium. Its genesis and fate depend on various factors, namely tumor type, metabolic state of the tumor, expression of vascular endothelial growth factor, and absence of lymphatic system. For almost 30 years TIF remained a neglected entity until it was demonstrated that TIF, and in particular its high pressure, constitutes an important obstacle to drug delivery and immunotherapy. The present review not only summarizes the abundant literature on the processes of TIF genesis and on its effects on therapy but it also presents data that, in our opinion, point towards what is perhaps the real physiological purpose of TIF: a primitive means of providing nourishment, oxygen, cytokines and matrikines to tumor cells that furthermore promotes the invasion of the normal surrounding tissue and passive metastatization through lymphatics. It is also an inducer of inflammation through increased osmolarity due to albumin loss. Recently, a role for TIF as a possible source of biomarkers has also been suggested.