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

Gabriele Multhoff,Peter Vaupel

doi:10.3389/fonc.2012.00165

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.

Highlights

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, and (3) impediment of convective transport within the interstitial compartment due to elevated interstitial fluid pressure (IFP) and a dense structure of the interstitial matrix are the major mechanisms hindering drug delivery
The chaotic microvasculature of solid tumors leads to significant impediment of delivery, uneven distribution, and compromised penetration of macromolecules and nanotherapeutics from tumor microvessels across the interstitial compartment to cancer cells, especially to cells distant from microvessels
CONCLUDING REMARKS Preceding cellular pharmacodynamics, three important pharmacokinetic steps govern the delivery of anti-cancer drugs and diagnostic agents to tumor cells: vascular, transvascular, and interstitial transport

Summary

Introduction

The chaotic microvasculature of solid tumors leads to significant impediment of delivery, uneven distribution, and compromised penetration of macromolecules and nanotherapeutics from tumor microvessels across the interstitial compartment to cancer cells, especially to cells distant from microvessels. 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.

Results

Conclusion