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Page 8 of 29 Dastidar et al. Vessel Plus 2020;4:14 I http://dx.doi.org/10.20517/2574-1209.2019.36

can cause severe dose-dependent side effects such as myelosuppression, neurotoxicity, mucositis, nausea,
[54]
vomiting, and alopecia that may become fatal for patients , or even, the development of drug resistance
[55]
and relapse of cancer .
This problem can potentially be solved by delivering anticancer drugs encapsulated within nanoparticles [56,57]
or as drugs conjugated to the nanoparticle’s surface [58-61] . Due to their size range, nanoparticles are
inherently able to permeate through leaky tumour microvessels but impaired lymphatic drainage of the
solid tumour, together with a higher interstitial fluid pressure, hinders clearance of nanoparticles from the
TME. Thus, retention of anticancer drugs is enhanced when delivered as nanomedicine. This mechanism of
passively targeting a solid tumour is known as the enhanced permeation and retention (EPR) effect, which
[62]
was first described by Matsumura and Maeda in 1986.

The size of the tumour, degree of tumour vascularization, and angiogenesis are the main factors affecting
[66]
EPR [63-65] . Thus, the stage of the disease is critical for drug targeting using the EPR effect . Another
factor is the challenge for the chosen delivery system to penetrate deep into tumour tissue due to the high
interstitial fluid pressure at the centre of a tumour . This results in initial tumour regression, followed
[67]
[68]
eventually by recurrence from residual cells in the non-accessible regions of the tumour . Therefore, the
drug delivery system needs to be optimized for deep tumour penetration [69-71] . This can be achieved by
(1) enhancing blood perfusion to a tumour; (2) modulating the structure of tumour vasculature; and (3)
destroying the mass of cancer cells to increase passage of nanoparticles.

Enhancing blood perfusion to a tumour
As discussed earlier, tumour blood vessels have sluggish blood flow. The hydrostatic fluid pressure in
a blood vessel (P ) is less than that of fluid in the interstitial space (P). This limits the distribution of
i
v
therapeutic agents in the TME. Therefore, an increased rate of blood flow in tumour vessels will enhance
the distribution of nanoparticles in the TME because of higher extravasation. Strategically there are two
ways to increase the rate of blood flow in tumour vessels. First, vasoconstrictors such as angiotensin can
be parenterally administered . This will constrict normal blood vessels but not tumour blood vessels
[72]
which will remain unaffected because of their impaired muscular structure. As a result, more blood will
be delivered to tumour blood vessels. Second, vasodilators like NO and CO should be delivered directly to
[73]
tumour blood vessels without affecting blood vessels of normal tissue .
[74]
In experimental rats with subcutaneously transplanted AH109A solid tumours, Suzuki et al. found a
5.7 fold enhancement of blood flow in the tumour after intravenous administration of angiotensin II.
This enhanced the chemotherapeutic effect of mitomycin C on the main tumour and metastatic foci in
[72]
lymph nodes. Nagamitsu et al. then successfully treated patients with SMANCS (neocarzinostatin, the
anti-tumour antibiotics conjugated with a hydrophobic copolymer of styrene) under angiotensin induced
hypertensive states. The induction of hypertension at ~15-30 mm Hg higher than normal blood pressure
for 15-20 min resulted in remarkably enhanced and passively targeted delivery of neocarzinostatin to the
tumour. This resulted in faster reduction of tumour size with the least toxicity to normal tissue.

Many research groups have developed nano-medicines that induce tumour-specific vasodilatation by
[73]
releasing mediators such as NO [75,76] and CO in situ. This helped in the accumulation of nanoparticles
within the TME. Tahara et al. incorporated NONOate, a typical NO donor, into PEGylated liposomes.
[77]
Its retention in blood was similar to that of empty PEGylated liposomes but its accumulation within the
tumour was doubled. Due to successful augmentation of the EPR effect, this liposome could be a potential
vehicle for the targeted delivery of potent chemotherapeutic agents.

[78]
Wei et al. then developed tumour vascular-targeted multifunctional hybrid polymeric micelles for the
targeted delivery of doxorubicin [Figure 3]. Poly (d,l-lactide) (PLA) and poly (ε-caprolactone) (PCL)