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Dastidar et al. Vessel Plus 2020;4:14 I http://dx.doi.org/10.20517/2574-1209.2019.36 Page 11 of 29

pressure gradient (due to lowering of IFP), resulting in better distribution of small molecule anticancer
[84]
drugs and nanoparticles (< 60 nm) into the TME .

Strategically, one may either block the pathways for synthesis of pro-angiogenic factors and their target
receptor proteins, or neutralize the effects of these factors by inhibiting the corresponding target receptors
with monoclonal antibodies. Such angiogenesis inhibitors can either target endothelial cells of the growing
vasculature (known as direct inhibitors) or tumour cells and tumour-associated stromal cells (indirect
[93]
[91]
[92]
inhibitors). Direct inhibitors like angiostatin , endostatin , arrestin , canstatin and tumastatin [94,95]
[90]
bind with integrin receptor to prevent the proliferation and migration of endothelial cells in response to
different pro-angiogenic factors. Indirect inhibitors prevent the expression of pro-angiogenic proteins
(e.g., VEGF) expressed by tumour cells or block the expression of corresponding endothelial cell receptors
(VEGFR). Many angiogenesis inhibitors have been approved by the FDA for cancer therapy including
[98]
[97]
[99]
[96]
thalidomide , bevacizumab , pazopanib and everolimus amongst others. There are also many
candidate anti-angiogenic drug molecules such as siRNA, shRNA, VEGF aptamer, KPQPRPLS-peptide
currently under study.
Different types of nanomedicines such as polymeric nanoparticles, lipid nanoparticles, micelles,
mesoporous silica particles, metal nanoparticles, noisomes, and liposomes have been developed for the
delivery of anticancer drugs. Amongst them, liposomal delivery systems are mostly approved by the FDA
for clinical use.

Therapeutic nucleic acids like small interfering RNA (siRNA) and short hairpin RNA (shRNA) are
negatively charged and thus, frequently delivered with liposomes made up of cationic phospholipids.
Cai et al. [100] developed Bio-reducible fluorinated peptide dendrimers for efficient and safe delivery of VEGF
siRNA. It improved physiological stability, serum resistance; promoted intratumoral enrichment, cellular
internalization, as well as facilitated endosomal/lysosomal escape and reduction-triggered cytoplasm
siRNA release. It had found to have excellent VEGF gene silencing efficacy (~65%) and a strong ability
to inhibit HeLa cell proliferation. Upon intratumoral injection in mice with HeLa tumor xenografts, it
significantly retarded tumour growth. Yang et al. [101] developed strategy for co-delivery of VEGF siRNA
and docetaxel. This dual peptide modified liposome binds specifically to glioma cells, undergoes specific
receptor-mediated endocytosis and deep tissue penetration. Once within target cells, the siRNA silences
the VEGF gene to inhibit angiogenesis while docetaxel kills tumour cells.

Chen et al. [102] studied the effect of silencing the VEGF gene using siRNA for the treatment of breast cancer
(MCF7 xenograft model) with doxorubicin. They prepared calcium phosphate/siRNA nanoparticles and
further encapsulated it in a liposome. The liposome was injected intratumorally while doxorubicin was
administered intraperitoneally. This combination therapy resulted in 91% tumour inhibition using only
60% of the standard dose of doxorubicin. In a more recent study, Zheng et al. [103] utilized mesoporous silica
nanocarriers (148.5 nm) for the co-delivery of sorafenib (a multikinase inhibitor) and VEGF targeted
siRNA to treat hepatocellular carcinoma. The particles were further coated with lactobionic acid to target
asialoglycoprotein receptors that are overexpressed on cancer cells. Taking one step further, Shen et al. [104]
co-delivered sorafenib and survivin shRNA with nano-complexes to reverse multidrug resistance in human
hepatocellular carcinoma. Survivin is an angiogenesis promoting agent. Suppression of survivin with
shRNA thus resulted in the reversal of drug resistance and promoted sensitization to sorafenib treatment,
leading to cell cycle arrest and apoptosis.

While positively charged liposomes are best suited for the delivery of negatively charged RNA molecules,
they undergo nonspecific electrostatic adsorption with blood components and are quickly recognized by
the immune system, leading to rapid clearance from the blood by the reticuloendothelial system (RES). This
limitation can be overcome by coating the positively charged liposomes with negatively charged anionic