Biomedical Engineering Reference
In-Depth Information
extravasation but should further diffuse deep into the tumor. This requires the
nanocarrier to remain slippery and have as small a size as possible. Thus, it is
better for the nanocarrier to be neutral and not to present any binding groups
(including targeting groups) until reaching the center of the tumor.
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3.2.2.2 Approaches to Becoming Sticky to Tumor Cells for
Cellular Uptake
After reaching the targeted region the nanocarrier should efficiently enter the
cells for drug release. Now the same properties that impart stealth to the
nanocarrier prevent it from cellular uptake by tumor cells. Nanocarriers that are
negatively charged will be repelled from the cell membrane due to the electrostatic
repulsion. The PEG corona of pegylated polymeric micelles or liposomes retards
their interaction with cell membranes due to steric hindrance. Thus, once in the
tumor, the carrier must become cell-binding or sticky to targeting tumor cells for
fast cellular uptake.
178
The challenge is how to reconcile these two opposite
requirements, stealth for circulation and diffusion versus sticky for targeting. For
instance, it is well known that positively charged carriers reliably stick to cell
membranes due to electrostatic adsorption triggering fast cellular uptake, but
positively charged carriers are not suitable for in vivo applications because they
are systemically toxic
179
and have short circulation times.
180
One strategy to convert a carrier from stealth circulation to sticky targeting
is to equip it with PEG groups that are cleavable upon encountering a tumor-
specific stimulus. Once the PEG chains are removed, the bare particle can be
adsorbed onto the cell membrane. Toward this end, Thompson et al. prepared
acid-labile PEG-conjugated vinyl ether lipids to stabilize fusogenic DOPE
liposomes.
181
At lower pH, the PEG layer was removed by the acid-catalyzed
hydrolysis of the vinyl ether bond, triggering membrane fusion. Similarly,
Harashima et al. connected PEG to the lipid through a matrix of
metalloproteinase (MMP)-cleavable peptide.
182,183
MMP is overexpressed in
tumor-tissue angiogenesis, invasion, and metastasis
184
and thus the peptide can
be degraded quickly in tumors. They prepared a multifunctional envelope-type
nano device (MEND) using the PEG-peptide lipid and found that pDNA
expression was dependent on the MMP expression level in the host cell.
Positive charges can promote carrier adsorption on the negatively charged
membrane and hence trigger adsorption-mediated endocytosis. Thus, an
alternative is to use tumor extracellular acidity to impart positive charges to the
carrier by a ''charge-reversal'' technique (illustrated in Figure 3.11). Amine-
containing carriers, such as PCL-b-PEI,
108
poly(
L
-lysine) (PLL),
185
and PAMAM
dendrimers,
110
were amidized to acid-labile b-carboxylic acid amides to make
them negatively charged at physiological pH. Once in weakly acidic tumor
extracellular fluid, the amides hydrolyzed and regenerated the amines with
cationic charges, which led to fast cellular uptake (Figure 3.11A). In yet another
example, a pH-responsive layer becomes positively charged at tumor extracellular
acidity but collapses, forming a middle layer, at neutral pH (Figure 3.11B).
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