Biomedical Engineering Reference
In-Depth Information
deep into the tumor, to the cells away from the blood vessels, but become
effectively sticky upon interacting with tumor cells for fast cell internalization.
To be stealthy for a long circulation time in the blood compartments has
been recognized as essential for a nanocarrier to achieve passive tumor
targeting, 123,124 whereas transport in the tumor tissue after extravasation has
been gradually realized in recent years. 125,126 Tumor resistance to anticancer
drugs not only involves the cellular and genetic drug resistance mechan-
isms, 78,127 but also the physiological barriers of solid tumor tissues. 128,129 It is
found that tumor drug distribution is not uniform. Drugs are rich in the areas
surrounding the blood vessels and the concentration declines sharply away
from the blood vessels, owing to the compact structure of tumor tissues. 130
Thus, the most aggressive tumor cells located in these hostile microenviron-
ments (low pH and low pO 2 ) are actually exposed to few drugs. 7 Moreover, the
exposure of those cancer cells to sublethal concentrations of anticancer drugs
may facilitate the development of resistance. 7 Therefore, it is important for the
nanocarrier to remain stealthy after extravasation for tumor penetration. It
can be imagined that a nanocarrier strongly interacting with surrounding cells
and matrix will be trapped there and cannot travel a long distance.
d n 4 y 3 n g | 2
3.2.2.1
Approaches to Stealth Surfaces
(1) In circulation
The nanocarrier's stealth character hinges on many factors, including
surface properties, 123 size, 131 and even shape. 132,133 In circulation, those with
molecular weights below the renal threshold (e.g. 40 kDa for PEG) or sizes
below 5 nm are rapidly cleared from the blood by glomerular filtration, 86 while
those with diameters above 200 nm will be scavenged by the RES, mainly the
liver and spleen. 131,134
Most stealth carriers capable of avoiding opsonization 135 and interaction
with the mononuclear phagocyte system (MPS) 131 are made from
HPMA, 136,137 PEG, or polysaccharides 138 (e.g. heparin 139 ). Nanoparticles
coated with a layer of these polymers become stealthy by both hydration and
steric hindrance. 140 For example, pegylation of particles or liposomes is well
established, 135,141 and the DOX-loaded stealth liposome named Doxil 1 was
approved by the FDA for cancer therapy. 142 Huang et al. reported that, on
100 nm liposomes pegylated with 1,2-distearoyl-sn-glycero-3-phosphoethanola-
mine-PEG 2000 (DSPE-PEG 2000 ), PEG chains were arranged in a mushroom
configuration at a DSPE-PEG fraction less than 4 mol% but in a brush
configuration at a DSPE-PEG content greater than 8 mol%. 124 The high density
of PEG chains on the liposome surface with the brush configuration was the key
to reduce liposome liver sequestration. 124 Discher et al. incorporated the PEG
brushes onto polymersomes and obtained polymersomes having a blood
circulation time two-fold longer than pegylated liposomes. 143 Dai et al.
pegylated single-wall carbon nanotubes (SWNT) and found that, with the
increase of linear PEG chain length from 2 kDa to 5 kDa, the blood circulation
 
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