Biomedical Engineering Reference
In-Depth Information
carrier (Figure 11.5A). As an anticancer prodrug, the formed nanoparticles
had a high and fixed curcumin-loading content of 25.3 wt%, and released
active curcumin in the intracellular environment. Curc-OEG had high
inhibition ability for several cancer cell lines due to apoptosis. Intravenously
injected Curc-OEG had a bioavailability (the area under curve value) 250 times
of that of the parent curcumin, and thus a high overall tumor concentration.
As a result, it significantly reduced tumor weights and tumor numbers in the
athymic mice xenografted with intraperitoneal SKOV-3 tumors and subcuta-
neous (mammary fat pad) MDA-MB-468 tumors (Figure 11.5B). Preliminary
systemic toxicity studies found that Curc-OEG did not cause acute or
subchronic toxicities in mouse visceral organs at high doses. As a drug carrier,
Curc-OEG nanoparticles could carry other anticancer drugs, such as DOX,
and ship them into drug-resistant cells, greatly enhancing the cytotoxicity of
the loaded drug. Thus, Curc-OEG is a promising prototype that merits further
study for cancer therapy.
d
n
4
y
3
n
g
|
5
11.3.2 Prodrug Micelles
Besides the phospholipid-mimicking amphiphilic prodrugs, another type of
prodrug capable of self-assembly is the diblock copolymer in which one block
is a water-soluble chain such as PEG and the other is conjugated with
hydrophobic drug molecules as the water-insoluble block. Such block
copolymers form micelles in aqueous solution with drug molecules anchored
in the micelle core. For instance, the Matsumura group conjugated SN38 to
the PGA block of a PEG-PGA copolymer.
60
The resulting conjugate PEG-
PGA(SN38) containing approximately 20 wt% drug, named NK012, self-
assembled into micelles with a diameter of 20 nm (Figure 11.6). NK012 was
reported to eradicate liver metastases and achieve a significantly longer
survival rate than CPT-11 (P 5 0.0006). More recently, our group conjugated
SN38 as the hydrophobic group to short poly(methacrylic acid) and obtained
amphiphilic PEG-polySN38.
61
This prodrug formed nanoparticles with a high
drug-loading content (y20 wt%) and tailorable sizes. Sub-100 nm nanopar-
ticles were also self-assembled from a PEG-poly(
L
-lactide) (PEG-PLA)-based
polymer-cisplatin
prodrug
in
which
cisplatin
was
anchored
to
the
PLA
terminal via a hydrazone bond.
62
Another interesting self-assembly prodrug for continuous slow release of
PTX was developed by Kwon and co-workers.
63
PTX was conjugated to PEG-
p(Asp) through hydrazone linkers made from levulinic acid (LEV) or 4-
acetylbenzoic acid (4AB) to give amphiphilic PEG-p(Asp-Hyd-LEV-PTX) and
PEG-p(Asp-Hyd-4AB-PTX), which assembled into polymeric micelles with
diameters of 42 and 137 nm, respectively. Mixing the two prodrugs produced
micelles with diameters of 85 and 113 nm, respectively, having pH-dependent
release. Detailed reviews can be found elsewhere.
64
