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Page 6 of 29 Dastidar et al. Vessel Plus 2020;4:14 I http://dx.doi.org/10.20517/2574-1209.2019.36

the macroscopic and microscopic levels. The resulting spatial and temporal heterogeneities in blood supply
is thus responsible for non-uniform distribution of the therapeutic agent. Generally, the average uptake of a
therapeutic agent decreases with an increase in tumour mass.

Poor extravasation and high interstitial fluid pressure limit transport across the microvascular
wall
Diffusion and convection are the main mechanisms behind the transport of drug molecules across the
vascular wall. The concentration gradient of the therapeutic agent across the plasma (C ) and interstitial
p
fluid (C ) is the driving force for the diffusion process. This mass transfer process is proportional to
i
the surface area; the proportionality constant is known as vascular permeability P (cm/s). Transfer of
therapeutic agents by convection is associated with the leakage of plasma/fluid across the vascular wall
due to differences in hydrostatic pressure of fluid in the blood vessel and interstitial space. The associated
experimental constant is known as hydraulic conductivity, L (cm/mmHg-s). Similarly, the convection
p
process is also proportional to the osmotic pressure difference between the blood vessel and the interstitial
[27]
space . This proportionality constant is known as the osmotic reflection coefficient (σ). These three
experimental constants (P, L , and σ) are used to describe the extent of transport of plasma content across
p
tumour vessels. Tumour vessels have relatively high P and L values [28,29] as they have wide endothelial
p
junctions, a large number of fenestrae and trans-endothelial channels, discontinuous or absent basement
membrane and significant spatial heterogeneities [30,31] . Although these physiological characteristics increase
vascular permeability, tumours also have poor extravasation, which is a significant barrier to the delivery
of therapeutic agents. This can be explained as follows: tumour vessels have sluggish blood flow. The
hydrostatic fluid pressure in the blood vessel (P ) is less than that of fluid in the interstitial space (P). Of
i
v
[32]
note, the Pi in animal/human tumours is even higher than that of normal tissue . Furthermore, it has been
reported that Pi increases with the growth of a tumour. This is mainly due to high vascular permeability
and poor, impaired lymphatic drainage [32-35] . Both tumour hyperplasia around a blood vessel and increased
production of extracellular matrix components contribute to high interstitial fluid pressure (IFP). In normal
[36]
tissue, IFP is 0 mmHg but in tumour blood vessel, the IFP varies from 10-40 mmHg . The IFP is elevated
throughout the mass of a tumour except at the periphery, where it becomes equal to normal physiological
values. Therefore, intratumoral fluid may extravasate from the periphery of a tumour, resulting in non-
delivery of a therapeutic agent. In different animal and human tumour models, it was found that 1%-14%
of plasma entering the tumour leaked into the periphery [28,37,38] . Again, the tumour interstitial space has a
higher concentration of endogenous plasma protein, leading to higher interstitial osmotic pressure. Thus,
the transfer of therapeutic agents by diffusion is further limited.

Resistance to transport through the interstitial space and distribution into the tumour
microenvironment
Diffusion and convection are the main mechanisms behind the movement of therapeutic agents that
[39]
have extravasated into the interstitial space . The concentration gradient is the driving force behind
diffusion whereas fluid velocity determines the convection process. The interstitial diffusion coefficient
[32]
(D) and hydraulic conductivity (K) are the experimental constants used for quantitative measurements
of therapeutic agent distribution in the interstitial space. The interstitial space of a tumour is located at the
TME (tumour microenvironment) and composed largely of a collagen and elastic fibre network, filled with
[40]
a hydrophilic gel made up of interstitial fluid and macromolecular constituents . Its structural integrity
is maintained by collagen and elastin whereas resistance to transport is provided by macromolecular
constituents such as glycosaminoglycans and proteoglycans [40,41] . Compared to normal tissues, tumours have
[32]
a higher collagen content but lower concentrations of hyaluronate and proteoglycans due to increased
activity of lytic enzymes such as hyaluronidase in the tumour interstitial space. Thus, the tumour interstitial
space should provide lower resistance to the distribution of therapeutic agents, suggesting larger values of
D and K. Paradoxically however, therapeutic agents are not distributed homogeneously in tumours. This