Biomedical Engineering Reference
In-Depth Information
conjugated to PHPMA and biodegradable star polymers via such linkers
demonstrated a fast DOX release at pH 4.
20
An interesting example is the
dual pH-responsive prodrug PPC-Hyd-DOX-DA developed by Du and co-
workers.
21
At tumor extracellular pH (y6.8), the prodrug reversed its surface
charge from negative to positive via acid-labile amide bonds for fast
internalization; at endosomal or lysosomal pH (y5.0), the drug was fast
released due to the breakable hydrazone bonds. Esterases are ubiquitously
distributed in the body and can readily hydrolyze ester bonds in prodrugs;
thereby esterase-labile linkers, such as carboxyl, carbonate, and carbamate
esters, are also employed.
22
For instance, in IT-101, CPT was conjugated to the
linear b-cyclodextrin (b-CD) and PEG copolymer via the ester bond.
23
The
conformation of released CPT was not changed compared to the parent CPT
and the release rate of the conjugated CPT can be tuned.
24
Lysosomal
degradable peptides [e.g., glycylphenylalanylleucylglycine (GFLG)], which are
cleavable by lysosomal enzymes, are also useful linkers in prodrugs.
25
Recently, the disulfide bond,
26
which can be cleaved by intracellular
glutathione (GSH), has attracted increasing attention as linkers for intracellu-
larly triggered drug release. The underlying rationale is the elevated
intracellular GSH concentration, particularly in cancer cells, but low in the
blood.
27
d
n
4
y
3
n
g
|
5
11.2.2 Modifiers
The modifier may consist of a polymer chain and targeting moieties and others
such as a tracer moiety. The main roles of the polymer chain are to endow the
prodrug with water solubility and a long blood-circulation time for altered
ADME and tumor targeting capability. The targeting moiety facilitates the
prodrug's active targeting, as discussed in Chapter 2.
Most anticancer drugs are water insoluble, giving them poor bioavail-
ability.
28
Anchoring drugs to water-soluble polymer chains makes them water
soluble. For instance, PTX is an extremely water-insoluble anticancer drug
(,0.01 mg mL
21
).
29
Conjugating PTX to a PEG
30
or poly(
L
-glutamic acid)
(PGA)
31
resulted in highly water-soluble prodrugs with antitumor effects
superior to PTX itself.
31,32
It is generally assumed that by prolonging the blood circulation time, a
polymer prodrug has more opportunity to pass through the hyperpermeable
tumor blood vessels and extravasate into tumor tissue via the EPR effect.
1b
Prodrugs with a stealth property may evade the reticuloendothelial system
(RES) screening
33
and thus circulate for a long time in the blood
compartments, resulting in greatly increased tumor drug concentrations (10-
fold or higher) and MTD relative to administration of the free drug.
34
The
stealth character of a polymer prodrug is mainly determined by the polymer's
properties. The polymer must be water soluble and, very importantly, not
immunogenic. A very interesting example is the natural biopolymer dextran. It
is usually assumed to be non-immunogenic, but drugs conjugated to dextran
