Radiation-induced changes in microcirculation and interstitial fluid pressure affecting the delivery of macromolecules and nanotherapeutics to tumors

Abstract

The immature, chaotic microvasculature of most solid tumors can present a significant impediment to blood-borne delivery, uneven distribution, and compromised penetration of macromolecular anticancer drugs and diagnostic agents from tumor microvessels across the interstitial space to cancer cells. To reach viable tumor cells in relevant concentrations, macromolecular agents are confronted with several barriers to vascular, transvascular, and interstitial transport. Amongst those (1) heterogeneous and poor blood supply, (2) distinctly reduced or even abolished hydrostatic and oncotic pressure gradients across the microvessel wall abrogating the convective transport from the vessel lumen into the interstitial space (impairment of transvascular transport), and (3) impediment of convective transport within the interstitial compartment due to elevated interstitial fluid pressure (IFP) (resulting from hyperpermeable blood vessels coupled with non-functional lymphatics) and a dense structure of the interstitial matrix are the major mechanisms hindering drug delivery. Upon irradiation, changes in these barrier functions are inconclusive so far. Alterations in vascular transport properties following fractionated radiation up to 40 Gy are quite inconsistent in terms of direction, extent, and time course. Total doses above 45 Gy can damage tumor microvessels, additionally impeding vascular delivery. Vascular permeability for macromolecules might be enhanced up to a total dose of 45 Gy. However, this effect is counteracted/abolished by the elevated IFP in solid tumors. When assessing IFP during fractionated radiotherapy in patient tumors, inconsistent alterations have been observed, both in direction and extent. From these data it is concluded that modulations in vascular, transvascular, and interstitial transport by irradiation of solid tumors are rather unclear so far. Translation of experimental data into the clinical setting thus needs to be undertaken with especial care.

Elastography Can Map the Local Inverse Relationship between Shear Modulus and Drug Delivery within the Pancreatic Ductal Adenocarcinoma Microenvironment

“…Several groups have proposed the use of radiotherapy (45)(46)(47), the use of antistromal therapy (19)(20)(21), and the targeting of hyaluronic acid (6,13,14) to reduce tissue pressure. Stromal density is responsible for high tissue pressure; therefore, we predict that antistromal therapy will yield the greatest reduction in tissue pressure.…”

Vascularized microfluidic platforms to mimic the tumor microenvironment

“…Hyperpermeability of the vasculature within the tumor environment along with a lack of lymphatic drainage is responsible for elevated interstitial fluid pressure that can dramatically alter flow patterns as the tumor expands (Azzi, Hebda, & Gavard, ; Butler, Grantham, & Gullino, ; Huang et al, ; Jain, ; Jain, Martin, & Stylianopoulos, ; Niederhuber, Armitage, Doroshow, Kastan, & Tepper, ; Vaupel, Kallinowski, & Okunieff, ). These hydrodynamic behaviors may lead to increased expression of angiogenic factors and formation of microvessels inside the tumor allowing for cancer growth while transport and drug uptake can be reduced by the fluid dynamics of the tumor vasculature (Azzi et al, ; Galmarini, Galmarini, Sarchi, Abulafia, & Galmarini, ; Gkretsi, Zacharia, & Stylianopoulos, ; Jain et al, ; Jang, Wientjes, Lu, & Au, ; Multhoff & Vaupel, ; Tredan, Galmarini, Patel, & Tannock, ; Vaupel et al, ). Macromolecules and nanotherapeutics can fail to reach viable tumor cells due to the irregular extravasation and extravascular convection caused by the conditions of the tumor microenvironment.…”

“…These hydrodynamic behaviors may lead to increased expression of angiogenic factors and formation of microvessels inside the tumor allowing for cancer growth while transport and drug uptake can be reduced by the fluid dynamics of the tumor vasculature (Azzi et al, 2013;Galmarini, Galmarini, Sarchi, Abulafia, & Galmarini, 2000;Gkretsi, Zacharia, & Stylianopoulos, 2017;Jain et al, 2014;Jang, Wientjes, Lu, & Au, 2003;Multhoff & Vaupel, 2012;Tredan, Galmarini, Patel, & Tannock, 2007;Vaupel et al, 1989). Macromolecules and nanotherapeutics can fail to reach viable tumor cells due to the irregular extravasation and extravascular convection caused by the conditions of the tumor microenvironment.…”

Spatiotemporally photoradiation-controlled intratumoral depot for combination of brachytherapy and photodynamic therapy for solid tumor

“…For example, the efficacy of high dose radiation for hypoxic tumors has been evaluated [37]. Pre-radiation therapy could attain the same effect by reducing interstitial fluid pressure for the re-oxygenation of the hypoxic area [38]. Furthermore, nanoparticles are an attractive platform to overcome drug resistance.…”