Abstract
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.
Highlights
To produce its effects, a drug should reach the target tissue in a uniform and selective way
Tumor interstitial fluid pressure (TIFP), interstitial fluid flow (IFF), extracellular matrix cell packing, and vascular permeability, we have mentioned in green frames, the methods used to decrease or modulate them
They noted that the reduction of tumor interstitial fluid pressure (TIFP) was temperature and time dependent, and the biological response was correlated with the TIFP reduction
Summary
A drug should reach the target tissue in a uniform and selective way. They are (a) an unbalanced Starling mechanism acting in tumor microcirculation, (b) increased vascular permeability, due to an abnormal tumor vasculature, (c) a malfunctioned lymphatic system inside the tumor mass Both these factors generate an increased interstitial pressure (TIFP) and interstitial fluid flow (IFF), moving from the tumor into the near microenvironment. Even if the molecular size of the molecules are ≤1 nm, they encounter several difficulties in penetrating into tumor mass These impediments are as follows: (a) the increased distance between the vessel wall and the cancer cells due to the increased volume of tumor interstitium; (b) the diffusion coefficient of tumors; and (c) the presence of a centrifuge flow (IFF) from the tumor center toward the periphery, governed by the IFP. Tumor interstitial fluid pressure (TIFP), IFF, extracellular matrix cell packing, and vascular permeability, we have mentioned in green frames, the methods used to decrease or modulate them. As suggested by Hassid, we must take into account gadolinium’s side effects (fibrosis) to the kidneys [98]
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