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can be explained as follows: the time constant for a molecule with diffusion coefficient, D is proportional
to the diffusion path length, raised to a power of two. Therefore, if the diffusion path length is doubled, the
required time will be increased by four times. In solid tumours, the exchange vessels are at a large distance
apart (~200 µm) [42,43] . Therapeutic agents will need a prolonged transit time for homogenous distribution.
High interstitial pressures also slow down the distribution process. Thus, low molecular weight (M <
r
1000 D ) anticancer drugs do not accumulate in the tumour because of their small size and hence, rapid
a
[44]
clearance . The drug distribution process in a tumour may be further limited by the high affinity of the
drug molecule for proteins present in interstitial fluid.

Growth induced solid stress
A tumour mass consists of proliferating cancer cells and stromal cells (i.e., fibroblasts, immune, and
[45]
perivascular cells) . It is supplied by a dense ECM, and a tortuous and chaotic network of blood
[45]
vessels . During tumour growth, there is rapid proliferation of cancer cells in a limited space resulting
in the generation of mechanical forces from different structural components such as cancer cells, various
host cells, and the ECM. Thus, there is also a growth induced solid stress, which commonly ranges from
10 to 142 mmHg , that can deform the vascular and lymphatic structures and cause limited perfusion
[46]
[47]
and hypoxia throughout tumour tissue. This creates a barrier to the penetration of therapeutic agents
which restricts their flow to cells within the perivascular space, such that resistant cells in hypoxic regions
[45]
are missed . Shear stress can also induce vascular endothelial growth factor receptor type 2 (VEGFR2)
expression and ligand-independent phosphorylation. This causes activation of MAPK, PI3K, and Akt
[46]
signalling pathways that are involved in promoting angiogenesis . Additionally, there is VEGFR2
membrane clustering and downstream signalling. Recently VEGFR3 has also been found to be a part of
this mechanosensory complex. Depletion of VEGFR2 or VEGFR3 thus causes significant reduction in
[46]
endothelial cell response to mechanical stress .

[46]
Specific integrins can also contribute to tumour angiogenesis and tumour progression . In endothelial
cells, VEGF upregulate the expression of α1β1 and α2β1 integrins. The α5β1, αvβ3 and αvβ5 integrins are
also expressed in angiogenic vasculature to facilitate the growth and survival of newly forming vessels .
[46]

Therefore, the general strategy to overcome the barriers to vascular and tumour tissue permeability is
functionalization of the surface of nanoparticles with tissue and cell-penetrating peptides, such as the
[48]
iRGD . It interacts with αν integrins on the endothelium and stimulates proteolytic cleavage. The released
[45]
CendR peptide subsequently binds with neuropilin-1 to ensure the homing of and penetration of tumour
tissue by nanoparticles.

TARGETED DELIVERY OF THERAPEUTIC AGENTS BY EXPLOITING TUMOUR VASCULATURE
A therapeutic agent is delivered to the target tissue via supplying arterioles to that particular tissue. As
discussed in the previous sections, there are a number of barriers that hinder the distribution process of
therapeutic agents in the tumour. First, the tumour vasculature is highly heterogeneous in distribution.
Unlike the tight endothelium of normal blood vessels, the vascular endothelium in tumour microvessels
is discontinuous and leaky. Elevated levels of growth factors such as VEGF and bFGF cause vasodilatation
and enhancement of vascular permeability. Therefore, the gap sizes between endothelial cells can range
from 100 to 780 nm, depending on the anatomic location of the tumour . As such, low molecular weight
[49]
anticancer drugs (M < 1000 D ) can easily enter the tumour microenvironment but at the same time,
r
a
they can also be easily removed because of their small size. Consequently, when delivered as an aqueous
[51]
[50]
[52]
solution, small-molecule chemotherapeutic agents like paclitaxel , gemcitabine , cisplatin , etc. do not
accumulate in the tumour at the desired concentration for an adequate duration. These potent anticancer
drugs undergo unwanted bio-distribution, leading to unfavourable pharmacokinetics characterized by a
large volume of distribution, high renal clearance and short half-life . Furthermore, these cytotoxic agents
[53]