Biomedical Engineering Reference
In-Depth Information
time of pegylated SWNTs was significantly extended, but a further increase of
the PEG chain length showed no significant effect.
144
Although pegylation
reduces the recognition of the carriers by the MPS system and thereby extends
their blood circulation time, the ''accelerated blood clearance (ABC)''
phenomenon was observed upon repeated injection of pegylated liposomes
145,146
due to IgM bound to pegylated liposomes secreted into the bloodstream after the
first dose.
147
Such an immune reaction against the pegylated liposomes occurred
in the spleen at least 2-3 days after the first administration.
145,146
The carrier shape is also recognized as an important parameter that can
substantially affect the blood circulation time. In fact, Mitragotri et al. reported
that the particle shape, not size, played a dominant role in phagocytosis of
polystyrene (PS) particles of various sizes and shapes: the rod-like particles
entered the cells much faster.
148
Discher et al. found that flexible worm-like
micelles efficiently evaded the RES and circulated in the blood for a week,
149,150
much longer than spherical micelles. Dai et al. found that carbon nanotubes
pegylated with long PEG chains exhibited a long blood circulation time (t
1/2
5
22.1 h) upon intravenous injection into mice.
151
All these studies suggest that
particle phagocytosis can be inhibited by minimizing its size-normalized
curvature.
148,152
Thus, particle shape is an important variable to make it remain
stealthy in circulation long enough for enhanced tumor accumulation.
149,150,153
d
n
4
y
3
n
g
|
2
(2) In tumor tissue
Solid tumors are characteristic of poorly structured blood vessels,
154
a stiff
extracellular matrix (ECM),
155-157
tightly packed cells,
158
high interstitial fluid
pressure (IFP),
159,160
and drug metabolism and binding.
126
Together they
impose strong diffusion barriers to nanocarriers, and even small molecules
(Figure 3.8).
125,161
For instance, it seems intuitive that as long as a nanocarrier extravasates
from tumor blood capillaries and releases the carried small molecular drugs,
the drug molecules will diffuse deep into the tumor tissue. Actually, free drugs,
either hydrophobic or carrying positive charges, cannot migrate far from the
nanocarrier due to their avid binding.
162
Diffusion of larger macromolecules,
such as bovine serum albumin (BSA, 68 kDa, 9 nm in diameter) and
immunoglobulin G (IgG, 150 kDa, 11 nm in diameter), in the tumor ECM
is also hindered compared to that in buffered saline.
163
After extravasation,
dextrans with a molecular weight between 40 and 70 kDa (and a diameter of
11.2-14.6 nm) were observed to be concentrated near the vascular surface.
130
Apparently, nanocarriers, which are larger in size than BSA and dextrans, are
likely to face greater difficulties in tumor penetration.
161
Chan et al.
systematically examined the effect of nanoparticle size on tumor penetration
using sub-100 nm pegylated gold nanoparticles.
164
As expected, larger
nanoparticles appeared to stay near the vasculature while smaller nanopar-
ticles (20 nm in diameter) rapidly diffused into the tumor matrix (Figure 3.9).
Similarly, Lee et al. demonstrated that PEG-PCL micelles with a mean
diameter of 25 nm diffused further away from the blood vessels compared to
those with diameters of 60 nm, which mainly remained in the perivascular
