Transport of drugs from blood vessels to tumour tissue

Abstract

The effectiveness of anticancer drugs in treating a solid tumour is dependent on delivery of the drug to virtually all cancer cells in the tumour. The distribution of drug in tumour tissue depends on the plasma pharmacokinetics, the structure and function of the tumour vasculature and the transport properties of the drug as it moves through microvessel walls and in the extravascular tissue. The aim of this Review is to provide a broad, balanced perspective on the current understanding of drug transport to tumour cells and on the progress in developing methods to enhance drug delivery. First, the fundamental processes of solute transport in blood and tissue by convection and diffusion are reviewed, including the dependence of penetration distance from vessels into tissue on solute binding or uptake in tissue. The effects of the abnormal characteristics of tumour vasculature and extravascular tissue on these transport properties are then discussed. Finally, methods for overcoming limitations in drug transport and thereby achieving improved therapeutic results are surveyed.

Figure 1 ∣. The pathway that drugs take from an intravenous infusion site to a solid tumour.

Drug is transported by convection in the bloodstream through the systemic veins, the heart, the lungs and the systemic arteries to peripheral microvessels. Owing to rapid mixing of solutes in the blood, all parts of the circulatory system are exposed to the drug. Exchange between blood and tissue occurs primarily inthe microcirculation. Drug passes through microvessel walls and extravascular tissues to cancer cells by a combination of molecular diffusion and convection in interstitial fluid. Convective fluid motion in tissue is driven by fluid that filters through vessel walls. This fluid loss is balanced by resorption through other vessels and by the lymphatic system. For low-relative-molecular-mass drugs, diffusion is dominant over convection in the extravascular space.

Figure 2 ∣. Limitations of drug transport within the microcirculation.

a ∣ Microvascular networks are often depicted as having ideal symmetric branching structures so that drugs in the blood are uniformly distributed throughout the branches of the network, b ∣ In reality, microvascular networks have highly asymmetric structures with extensive variation among branches in flow path lengths and blood flow rates. Some branches receive very low flow, and the drug may be depleted before the terminal branches are reached, such that some tissue regions are not treated. Conversely, short high-flow pathways may form functional shunts between the arterial and venous systems, greatly restricting exchange of solute between blood and tissue. This effect is accentuated in tumours relative to normal tissues.

Figure 3 ∣. Limitations of drug transport in extravascular tissue.

A drug must pass several potential barriers in order to reach tumour cells. High tissue pressures may cause vessel collapse, restricting blood flow. The endothelial cells lining microvessels restrict extravasation of drug. Dense stroma, consisting of extracellular matrix (ECM) and cells such as fibroblasts, can be a physical barrier, particularly for large molecules and nanoparticles, and is a binding site for some drugs. The pathway for transport within tumours may be tortuous owing to stroma and parenchymal cells. Large transport distances may result in incomplete drug distribution. High interstitial fluid pressure (IFP) acting in all directions (denoted by the crossed arrows) may reduce fluid flow and restrict drug delivery by convection. Pink background shading represents the oxygen level decreasing with distance from the blood vessel.

Figure 4 ∣. Principle of thermally triggered drug release from liposomes.

This illustration is based on experimental imaging of drug distribution. Local application of heat during the delivery of liposomes causes pores to form in the lipid bilayer and thus release of drug, which diffuses into the tissue. With heating, penetration of liposomes through blood vessel walls into tissue is not required for drug delivery to tumour. Here, drug release occurs intravascularly. Green shading indicates the level of drug.