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Page 10 of 29 Dastidar et al. Vessel Plus 2020;4:14 I http://dx.doi.org/10.20517/2574-1209.2019.36

formed the inner core to encapsulate doxorubicin. The poly (ethylene glycol) (PEG) was linked to PLA
with disulphide linkages to form the outer surface of the particle. Copper ion-chelated porphyrin (PpIX-Cu)
was then added to the end of the PEG segment, providing a catalytic function to decompose endogenous
NO donors like S-nitroso-glutathione (GSNO), S-nitrosocysteine, and S-nitrosoalbumin. Since these
endogenous NO donors are also present in human plasma and all tissue fluid, 2-propionic-3-methyl-maleic
anhydride (CDM)-modified methoxy polyethylene glycol (mPEG) (mPEG-CDM) was linked to the PpIX-
Cu component as a pH-sensitive protective layer, in order to mask the positive charges of the micelles and
avoid copper ion-catalysed NO production in the general circulation. Copper catalysed NO production
occured only in mildly acidic (pH 6.5) tumour tissue. Furthermore, cRGD grafted PCL-PEG-cRGD (PCE-
cRGD) copolymer was added during the synthesis of micelles. The grafted cRGD peptide then effectively
targeted the tumour vasculature and tumour cells, on which αvβ3 integrin is overexpressed. Once taken up
by the cancer cell, doxorubicin was immediately released due to the high cytoplasmic level of GSH. Thus,
this complex hybrid polymeric micelle structure was very effective in treating tumours in an animal model.

[79]
Fang et al. reported augmentation of the EPR effect and efficacy of anticancer nanomedicine by CO
generating agents. Haem oxygenase (HO) catalyses the degradation of haem to produce CO which
causes vasodilatation similar to NO [80-82] . Pegylated hemin is the HO inducer whereas tricarbonyl-di-
[79]
chloro-ruthenium (II) dimer (CORM2) is the CO-releasing molecule . The authors showed that in
tumour-bearing mice, the accumulation of intravenously administered Evans blue-albumin complex
(a macromolecule) in a tumour can be enhanced by the intradermal injection of recombinant haem
oxygenase-1, intra-tumoral injection of tricarbonyl-dichloro-ruthenium (II) dimer (CORM2) and
intravenous administration of PEGylated hemin. Thus CO plays a significant role in tumour uptake of
[83]
macromolecular drugs by EPR . They have also developed polymeric micelles of CORM2 copolymer and
styrene maleic acid. It had a prolonged plasma half-life and was able to maintain a sustained release of CO.
[79]
They used it for photodynamic therapy with pyropheophorbide-a .
Modulating the structure of tumour vasculature
The balance between pro-angiogenic (e.g., VEGF, PDGFB, IGF, PDGFRB, FGF-2, and TIE2) and anti-
angiogenic factors (e.g., thrombospondin-1, angiostatin and endostatin) is responsible for the formation
of normal tissue vasculature. This balance tips in favour of overexpression of pro-angiogenic factors in
[84]
pathological conditions such as the progression of solid tumours . The purpose of such is to meet the
high demand for oxygen and nutrients of tumour cells. Therefore, restoring this balance of factors may
restore tumour vasculature back to normal. This process involves the inhibition of pro-angiogenic factors
at a different level of their cell signalling pathways [Figure 2], which will reduce the diameter of tumour
microvessels, prune immature vasculature, increase vasculature maturity with higher pericyte coverage,
reduce tortuosity of microvessels, and decrease IFP. Although normalization of tumour vasculature is the
[85]
rationale for inhibition of tumour growth , it is not effective enough alone in clinical settings. Instead,
it has been found in clinical trials that combinations of radiotherapy or chemotherapy together with anti-
angiogenic agents are very effective [84,86] . Ionizing radiation generates ROS that leads to DNA damage and
cell death. Since the presence of oxygen helps in the generation of ROS, a well-vascularized and perfused
[86]
tumour tissue would be more susceptible to radiotherapy . It has also been shown that under low-dose
irradiation, cancer cells are induced to express proangiogenic factors (e.g., VEGF, PIGF) at a level sufficient
[87]
to stimulate endothelial cell migration and sprouting. This is known as the vascular rebound effect ,
which can be overcome by combining anti-angiogenic agents with radiotherapy. In one clinical trial on
advanced pancreatic cancer patients, a combination of optimal dosages of bevacizumab, capecitabine
[88]
and radiotherapy was found to be very effective . In another clinical study with rectal cancer patients,
promising results were reported when radiotherapy was combined with bevacizumab, capecitabine, and
oxaliplatin . In cases of chemotherapy used in combination with anti-angiogenic agents, normalization of
[89]
tumour vessels will not only reduce vascular permeability but at the same time, enhance the trans-capillary