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Page 16 of 29 Dastidar et al. Vessel Plus 2020;4:14 I http://dx.doi.org/10.20517/2574-1209.2019.36

preclinical study using the MX-1 human breast cancer xenograft model, different doses of paclitaxel
were administered in combination with 5 mg/kg bevacizumab. 30 mg/kg paclitaxel in combination with
bevacizumab was as effective as 100 mg/kg single dose of paclitaxel in inhibiting the growth of a tumour.
This observation can be attributed to treatment with bevacizumab, which significantly enhances the
effective concentration of paclitaxel within the tumour.

Gold nanoparticles have also been used for the targeted delivery of anti-angiogenic agents, either alone
or in combination with an anticancer drug. Bartczak et al. [107] synthesized gold nanoparticles of ~15 nm
and capped them with mono-carboxy (1-Mercaptoundec-11-yl) hexa (ethylene glycol). These particles
were then further functionalized through surface coating with a peptide (KATWLPPR) that specifically
binds to neuropilin-1 receptor to inhibit angiogenesis. In an in vitro study using human endothelial cells,
it was found that this peptide coated gold nanosphere could block capillary formation by endothelial cells
without causing toxicity. Patra et al. [108] then used gold nanoparticles for targeted co-delivery of cetuximab
and gemcitabine. Cetuximab has been approved for the treatment of EGFR positive colorectal cancer
whereas gemcitabine is used for pancreatic carcinoma. “2 in 1” nanoconjugates containing both cetuximab
and gemcitabine on a single gold nanoparticle core were synthesized. Physically, this was more stable than
a gold nanoparticle-containing either of the agents. This nanoconjugate could target metastatic EGFR
expressing cells and inhibited 80% tumour growth and was significantly better than all other non-targeted
groups.

EGFR tyrosine kinase inhibitors like cetuximab, lapatinib, afatinib, gefitinib, erlotinib, fedratinib are
well studied for anticancer therapy when used in combination with different chemotherapeutic agents
including doxorubicin, gemcitabine, paclitaxel, and carboplatin. They help in the normalization of tumour
vasculature and sensitize tumour cells to cytotoxic drugs. Additionally, monoclonal antibodies such as
cetuximab have been used as a targeting agent. Lin et al. [109] conjugated both paclitaxel and cetuximab on
the surface of carbon nano-diamond particles of 3-5 nm diameter. This was found to enhance the mitotic
catastrophe and tumour inhibition in the drug resistance of colorectal carcinoma in vitro and in vivo.
Among the other inhibitors, lapatinib also inhibits human epidermal growth factor receptor 2 (HER2)
tyrosine kinases and ATP-binding cassette transporters, thereby sensitizing multidrug-resistant (MDR)
cancer cells to chemotherapeutic agents. Lapatinib was clinically approved by the US FDA in 2007 for
anticancer therapy. There have been many studies since where lapatinib has been used in combination
with paclitaxel, and liposomes and polymeric micelles used as drug delivery vehicles. Li et al. [110] developed
stealth polymeric micelles using an amphiphilic diblock copolymer named poly (ethylene glycol) -block-
poly (2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol) which formed a core-shell structure
by self-assembly. Hydrophobic molecules like paclitaxel, lapatinib are loaded into the hydrophobic core
while the hydrophilic shell of PEG prevents their aggregation, restricts plasma protein adsorption, prevents
recognition by the RES, and minimizes rapid elimination from the bloodstream. This ~60 nm particle
successfully overcame multidrug resistance in an athymic nude mouse xenograft model established with
DU145-TXT MDR prostate cancer cells. The strategies of tumour-targeted drug delivery exploiting tumour
vasculature aresummarised in Table 2. The FDA-approved anti-angiogenic agents for the treatment of
cancer is summarized in Table 3.

Enhancement of vasculature permeability by physical treatment
EPR is a highly heterogeneous phenomenon. It is variable, even amongst different regions of the same
tumour. In fact, within a single tumour, not all blood vessels are permeable to the same extent. Moreover,
in many clinical settings, it has been found that tumours do not have a sufficient level of EPR to ensure
the accumulation of nanomedicines. This is mainly because of the insufficient permeability of the vascular
endothelium of tumour blood vessels. This problem can be addressed by local application of physical
treatments such as sonoporation, hyperthermia, and radiotherapy that enhance tumour vasculature
permeability, and aid in extravasation of nanomedicines uniformly throughout the TME.