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Page 20 of 29 Dastidar et al. Vessel Plus 2020;4:14 I http://dx.doi.org/10.20517/2574-1209.2019.36

In tumour tissue, perfusion rates are increased by 1.5-2 folds only [178,179] . Due to this insufficient perfusion,
the temperature of tumour tissues raises further. This causes shut down of local blood flow due to (1)
endothelial denaturation; (2) vasoconstriction in large pre-existing arterioles at the tumour periphery; and
(3) increase in flow resistance because of high viscosity due to the formation of thrombus and fibrinogen
gel. Ultimately, tumour cells are killed due to heat only.

Controlled, local heating of tumour tissue with radiofrequency [180] , microwave or ultrasound to
temperatures between 40-45 °C has the following effects: (1) dilatation of tumour vessels leading to
enhanced blood flow; (2) enhancement in microvascular permeability to macromolecules [181] and
nanomedicine [181,182] . This further increases the EPR effect; and (3) triggering the release of cargo molecules
(therapeutic agents) from thermoresponsive nanomedicine [179] .

There are different well-studied thermoresponsive nanomedicines such as liposomes [183-188] , nanogels [189-192] ,
hydrogel coated metal nanoparticles [193] , polymeric nanoparticles [194-197] and elastin-like peptide-drug
conjugates [179] . Thermodox® is a doxorubicin loaded thermoresponsive liposome, approved for the
treatment of liver cancer. It is capable of delivering 25 times more doxorubicin to tumour tissues compared
[23]
to intravenous infusion, and 5 times more doxorubicin than standard/ordinary liposomal formulation .
Again, to control drug release at mild hyperthermia, leucine zipper peptide was incorporated into the
[24]
liposome . At ~42 °C, the leucine zipper gate dissociated to release the drug precisely.
[24]
The thermo-responsive bubble generating liposomes was also developed [Figure 6]. It consists of an
ammonium bicarbonate loaded core, which generates CO upon application of hyperthermia (42 °C) and
2
increases the permeability of the liposome bilayer by triggering the release of the drug.

Gold nanoparticles coated with thermo-responsive hydrogel was developed for cancer therapy [198,199] . Local
hyperthermia enhances the accumulation of nanoparticles within the tumour [200] . The gold nanoparticle has
strong plasmon absorption, resulting in the generation of heat and removal of the polymeric shell. Thus,
the gold nanoparticle acts as an anticancer agent [201,202] .

Sato et al. [203] successfully applied threefold strategies to chemotherapy with Fe (Salen) nanoparticle. After
intravenous injection, this magnetic nanoparticle was guided to the tumour site for delivery in a rabbit
toung tumour model. The nanoparticle, at the target site, was heated with an alternating magnetic field for
the local induction of hyperthermia that helped in further distribution of the nanoparticle into the TME
due to the EPR effect.

Hyperthermia by NIR laser irradiation causes shrinkage of blood vessels and tumour ablation. Combining
hyperthermia and chemotherapy could be an efficient treatment approach. This is known as photothermal
chemotherapy [204] . Docetaxel loaded polypyrrole and hyaluronic acid-modified phospholipid nanoparticle
were used for photothermal chemotherapy [205] . There was complete inhibition of tumours in 4T1 tumour-
bearing mice.

Whole-body hyperthermia at the mild fever range (39.5 °C, for 4-6 h) was found to help in the therapeutic
efficacy of doxorubicin-loaded liposome in syngeneic CT26 colorectal mice carcinoma [206] . There was a
threefold increase in drug uptake in the tumour. It was also reported to be associated with decreased IFP
and an increased fraction of perfused microvessels [207] .

CONCLUDING REMARKS
Hypoxia-induced formation of new blood vessels is the key factor in the progression of tumours. Tumour
vasculature is heterogeneous, tortuous, irregularly branched, and hyperpermeable. Due to poor lymphatic