The transport of anticancer drugs throughout all regions of a solid tumour is a crucial factor in the effectiveness of the drug.
Generally, drugs are delivered by convection in the blood and then permeate vessel walls and penetrate the surrounding tissue by diffusion or convection.
The distribution of drug in tumour tissue is strongly influenced by the structure and function of the tumour vasculature, which typically has aberrant properties. The abnormal properties of the extracellular matrix in the tumour tissue can also limit drug distribution.
Physical properties of the drug, including size, charge, lipid solubility and surface properties (for nanoparticles), have major effects on the transport of the drug to tissue. The penetration distance of the drug into tissue also depends on solute binding and uptake rates in the tissue.
A number of methods have been developed for overcoming limitations in drug transport and thereby achieving improved therapeutic results.
In the design and usage of drugs, increased attention to transport properties has the potential to result in better treatments for solid tumours.
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.
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This work was supported by National Institutes of Health (NIH) grants CA040355 and HL034555.
T.W.S. has no conflicts of interest. M.W.D. was involved in the development of the thermally sensitive liposome described in this paper and has stock in Celsion Corporation, the company that licensed the drug. M.W.D. is also a consultant for Siva Therapeutics and Kaio Therapy and a member of the Scientific Advisory Board of Innovate Biopharmaceuticals.
The time-dependent variation of drug concentrations in various compartments of the body following administration of a drug; often understood to refer to concentration in the blood plasma.
The dependence of therapeutic effects on the level and time course of exposure to a drug; for cancer therapies, therapeutic effect is often described in terms of cell survival fraction or tumour growth inhibition.
- Enhanced permeability and retention (EPR) effect
The increased permeability of tumour microvessels relative to normal tissue vasculature, particularly in lipid and macromolecular agents and nanoparticles, leading to increased accumulation of such agents in the extravascular space in tumours. Enlarged gaps between endothelial cells occur where there is active angiogenesis. The gaps permit accumulation of nanoparticles within the tissue.
A physical parameter describing the rate of molecular diffusion of a solute in the presence of a concentration gradient; defined as the ratio of the diffusive flux to the spatial derivative of concentration.
- Hydraulic conductivity
A parameter defined as the ratio of the average fluid flow through the blood vessel wall per unit area divided by the net transmural (occurring across the entire vessel well) pressure driving filtration.
- Tumour cords
Cylindrical masses of tumour cells with a small blood vessel running centrally along their axes, appearing in pathological sections as structures with a central vessel and concentric ring of viable tumour cells. A typical radius of up to 100–150 μm corresponds to the maximal diffusion distance of oxygen in tissue. Beyond the oxygen diffusion distance, necrosis is often observed.
- Hypoxic regions
Tumour subregions where the partial pressure of oxygen (pO2) in tissue is >0 and <10 mmHg.
- First-pass metabolism
The reduction in the concentration of a drug in blood as a result of the initial metabolism of the drug in the liver before reaching the systemic circulatory system.
- Vascular endothelial growth factor
(VEGF). A cytokine (small protein) that potently stimulates blood vessel growth and increases vascular permeability.
Pertaining to a blood vessel; the presence of multiple bends and twists in the path of the vessel between its branch points as quantified by the ratio of the length of the vessel measured along its curved path to the straight-line distance between branch points. In tumours, this ratio tends to be greater than one, whereas in normal tissue, it is close to one.
- Vascular shunts
A relatively short, high-flow pathway from the arterial to the venous circulation. Identifiable shunt vessels are referred to as 'anatomical shunts', whereas shunting occurring because of abnormal network structure is referred to as 'functional shunting'.
- Vessel wall shear stress
The tangential force per unit area exerted on a solid boundary by a moving fluid such as blood.
- Stokes–Einstein radius
With reference to a solute, the radius of a hard sphere that diffuses at the same rate as the solute.
- Multicellular layer system
An experimental system in which tumour cells are allowed to proliferate on a semipermeable membrane until they reach a thickness of several cell layers. The membrane is placed between two reservoirs, and drugs or other solutes that are added to one reservoir pass to the other reservoir by diffusion across the multiple layers. Rates of diffusion and metabolism are estimated from the rates at which the concentrations vary in the reservoirs.
- Interstitial fluid pressure
(IFP). The hydrostatic pressure of the fluid that permeates the spaces between cells in a tissue; generally occurring as a result of fluid filtration from blood through the walls of blood vessels into the extravascular space.
- K trans
The rate constant describing the mass transfer between blood plasma and extravascular extracellular space per unit volume of tissue. This measurement is obtained using dynamic contrast-enhanced MRI.
- Vascular rarefaction
A decrease in the total length of blood vessels per unit volume of tissue.
- Dynamic contrast-enhanced MRI
(DCE-MRI). A method used to quantify the change in signal intensity in tissue over time after intravenous injection of an MRI contrast agent. The rates at which the contrast agent washes in and out of the tumour are used to estimate parameters related to perfusion and permeability of the microcirculation, including Ktrans.
- Texture analysis
A method used in image processing to assess the geometric arrangement of intensities within an image.
- T1 relaxivity
In MRI, T1 relaxation time is the time constant for aligned spins to decay to baseline after an MR pulse. Relaxivity is a measurement of how a contrast agent influences the T1 relaxation time. With calibration, relaxivity can be used to measure concentration of the contrast agent in tissue.
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Dewhirst, M., Secomb, T. Transport of drugs from blood vessels to tumour tissue. Nat Rev Cancer 17, 738–750 (2017). https://doi.org/10.1038/nrc.2017.93
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