Biomedical Engineering Reference
In-Depth Information
and carboxymethyldextran can be captured by the RES, causing dose-limiting
toxicity.
35
PHPMA
36
and PEG
37
are the most studied bio-inert polymers able
to render prodrugs stealthy. For example, NKTR-102, a PEG prodrug of
irinotecan (a chemotherapy drug that is metabolized to its active metabolite
SN38 in the body), increased the half-life of SN38 90-fold (from 4 h to 15 days)
and 10-fold in colorectal and lung cancer treatment, respectively.
38
Other
PEG-based prodrugs of docetaxel (NKTR-105), SN38 (EZN-2208), and CPT
(Pegamotecan) also showed longer half-life times and increased accumulation
at tumor sites and thereby tumor growth suppression.
39
Incorporating targeting ligands in the polymer modifier, such as antibodies,
peptides, aptamers, and folic acid, may promote tumor targeting (building on
the EPR effect) by receptor-mediated delivery,
40
as discussed in Chapter 2. For
example, PK1 conjugated with galactosamine, named PK2,
41
delivered 3.3 ¡
5.6% of the dose to the tumor and 16.9 ¡ 3.9% to the liver, whereas
PK1 showed no obvious targeting.
42
Zhu et al.
43
and Borgman et al.
44
also proved that incorporating targeting ligands in polymer modifiers in-
creased the prodrug's tumor accumulation. More examples have been reviewed
elsewhere.
45
d
n
4
y
3
n
g
|
5
11.2.3 Drawbacks of Current Polymer-Based Prodrugs
An inherent dilemma in polymer prodrugs is their drug-loading content versus
the water solubility and thereby the stealth capability. A high drug-loading
content in a nanocarrier reduces use of excipients and minimizes the related
side effects, and should be considered as a demanding criterion to judge a
prodrug's quality.
46
As most parent drugs are highly hydrophobic, the
modifier or the water-soluble polymer chain must be sufficiently long to make
the prodrug water soluble. Therefore, in most polymer prodrugs the drug
content is less than 10 wt%.
47
Typical examples are PEG-DOX prodrugs using
PEG with different molecular weights from 5,000 to 20,000 g mol
21
, which
contain 2.7-8.0 wt% DOX.
48
A four-armed PEG-SN38 prodrug named EZN-
2208, prepared by coupling SN38 to multiarm PEGs (Figure 11.3A), had an
increased drug content, but only of 3.7 wt%, compared to the CPT-PEG-diol
prodrug Pegamotecan.
39
As for PHPMA-drug conjugates, for instance PK1,
the drug contents are also as low as 8 wt%.
49
Some prodrugs have high drug-
loading contents. For instance, the prodrug CT-2103, PTX conjugated to PGA
through its 29-hydroxyl group (Figure 11.3B),
50
has a drug content of
approximately 37 wt% and a PGA-20(S)-CPT prodrug has a 30-35 wt% drug
content.
51
However, increasing the drug content not only lowers the prodrug
water solubility but may also cause opsonization,
37
resulting in rapid blood
clearance.
Another complication is also related to the polymer chain's molecular
weight. To have a long blood-circulation time for passive tumor targeting, the
molecular weight of a prodrug must be higher than the polymer's renal
threshold, e.g. 40 kDa for PEG
52
and 45 kDa for PHPMA,
53
but the safety
