Biomedical Engineering Reference
In-Depth Information
d
n
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y
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Figure 11.3
Chemical structures of EZN-2208 and CT-2103 polymer prodrugs.
(Reproduced from Pasut and Veronese
39
and Singer
50b
with permission
from Elsevier.)
prerequisite for in vivo applications is that the prodrug and the modifier must
be smaller than the renal threshold if their excretion pathway is through the
kidneys. The current strategy to reconcile these conflicting requirements is to
choose a polymer molecular weight close to the threshold, for example 30 kDa
for PHPMA, but this way inevitably shortens the blood circulation time of the
prodrug. Therefore, new strategies resolving these dilemmas are required to
design novel polymer prodrugs with higher drug content and better therapeutic
indices.
11.3
New Strategies for Polymer Prodrugs
11.3.1 Self-Assembling Prodrugs
Given that prodrugs with a high hydrophobic drug content are not water
soluble, we may take advantage of the hydrophobicity and directly use the
drugs as the hydrophobic part and the modifier as the hydrophilic segment to
make amphiphilic prodrugs that can self-assemble into vesicles or micelles as
nanocarriers. An important advantage of this way is that even though a single
prodrug molecule is small (several kDa) and far below the renal threshold, the
formed vesicles or micelles are generally larger (tens of nanometers in
diameter) than the kidney threshold (y5.5 nm) and thus can be retained for
long blood circulation.
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The second advantage of this strategy is that because
the drug molecules are used as a part of the nanocarrier and replace some of
the inert carrier materials, the nanocarrier's drug content is high. For instance,
the anticancer drug CPT is very hydrophobic, with a water solubility of
