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Kamal et al. J Cancer Metastasis Treat 2019;5:11 I http://dx.doi.org/10.20517/2394-4722.2018.89 Page 5 of 14

local concentration of nanosized anticancer drugs in tumor tissues enhances the therapeutic effect with
[49]
minimal side effects in both preclinical and clinical settings .

Various important factors such as circulation time, targeting and the capability to overcome BBB are
heavily reliant on the shape, size and the surface area of these particles. In passive diffusion, lipid solubility,
molecular weight, and the presence of tight junctions greatly affect the degree of permeation [50,51] .

Conventionally, a particle must be at least 10 nm in diameter to avoid clearance by first-pass renal filtration
and the optimal size range of 100-180 nm will ensure longer circulation time, increased accumulation
within the tumor mass and lower renal clearance [52,53] . Moreover, surface characteristics also play a very
important role in determining the extent of internalization of these nanoparticles into cells. Relatively, the
surface can be modified by the polymer composition, thus governing an extra amount of hydrophobicity
[51]
or hydrophilicity to these particles . Supplementary Table 1 illustrates some of the papers using passive
targeting technology in targeting BCBM.

Nanotechnology as a tool for targeting EPR
Nanotechnology paved the road towards safer and more likely effective cancer treatment strategies that can
overcome some of the hurdles for drug delivery. Nano-medicines primarily aim to improve the circulation
[54]
time of the conjugated or entrapped (chemo-) therapeutic drugs . Examples of nanoparticles commonly
used include: polymeric particles, polymeric micelles, dendrimers, and liposomes. Nanoparticles represent
versatile tools to encapsulate various types of drugs, either hydrophilic or hydrophobic moieties altering
[55]
their physicochemical parameters and pharmacokinetics profile .
Beside increasing drug-site contact time, some polymers used in nanoparticles formulations such as
polylactic-co-glycolic acid (PLGA) have high cell adhesion property, increasing the drug concentration
[56]
gradient at the adhesion site by longer drug carrier contact time with the targeted cells .
[57]
However, nanoparticles can show some serious adverse effects . Adverse effects of nanoparticles depend
on individual factors such as genetics, existing disease conditions, exposure, nanoparticle chemistry, size,
[57]
shape, agglomeration state, and electromagnetic properties . The key to understanding the toxicity of
nanoparticles is their size; nanoparticles are smaller than cells and cellular organelles, which allow them to
[57]
penetrate these biological structures, disrupting their normal function . Examples of toxic effects include
tissue inflammation, and altered cellular redox balance toward oxidation, causing abnormal function
[57]
or cell death . Furthermore, a major drawback is the difficulty in scaling up the formulation and its
transformation to clinical use, due to high cost and instability during storage. The NP materials must be
[58]
biocompatible and safe when administered .
Lipsomes
Liposomal (Liposome: lipid vesicle in Latin) nanocarrier systems are vesicular lipid bilayer colloidal
[59]
spheres formed by self-assembly . Without the use of surface modification by a hydrophilic polymer such
as polyethylene glycol (PEG), the biological half-lives of liposomes are very short due to several factors
including the tendency of the liposome to exchange lipid materials with cell membranes and their uptake
[60]
by phagocytes. Mohammad et al. noticed increased survival rates in animals treated with liposomal
irinotecan (nal-IRI) that sustained the accumulation of irinotecan and its active metabolite in the brain
metastases lesions, unlike non-liposomal irinotecan whose distribution in the CNS was hampered by BBTB
and various efflux proteins. The size of nal-IRI was between 100-110 nm, which enhanced its preferential
[60]
accumulation within tumor due to EPR through the leaky vasculature of the tumor . Drawbacks of
liposomes involved their rapid uptake by the Reticulo-Endothelial System (RES) and consequent removal
from circulating blood.