Chemistry Reference
In-Depth Information
Fig. 8.5
Levels of OAS 1
detected by densitometric
analysis in mouse liver tissues
treated with interferon-
α
(IFN-
α
), two kinds of HA-g-
INF
α
derivatives prepared
with 10 mol% and 45 mol%
aldehyde modified HA, and
PEG-Intron (Reproduced
with permission, copyright
2011 Elsevier [
89
])
serum and an in vitro efficacy lower than free INF-
α
but comparable to that of
commercial available PEG-Intron.
rapidly
distributed to all body compartments and was completely eliminated after 24 h,
while dye-labeled HA-g-INF-
In animals, dye-labeled INF-
α
accumulated just after 60 min mostly into the liver
and prolonged its circulation time for more than 96 h. The detection of protein
OAS1 (enzyme involved in the activation of a RNAse that inhibits viral replication)
was considered as a marker of the INF-
α
α
activity in the animals treated with INF-
α
,
PEG-Intron, and two batches of HA-g-INF-
bearing the same amount of interferon
(6 mol%) but obtained starting from a HA bearing 10 and 45 mol% of aldehyde,
respectively.
As shown in Fig.
8.5
, 10 mol% functionalized HA-g-INF-
α
α
resulted much more
efficient if compared to PEG-Intron and the more functionalized HA-g-INF-
α
derivative, confirming that a HA glucuronic functionalization lower than
30 mol% does not reduce hepatic accumulation while more functionalized
derivatives escape hepatic targeting.
Similar HA-g-INF-
copolymers were proposed also by Fidia Advanced
Biopolymers that employed for the grafting procedure hemiacetalic HA derivatives
generating HA-aldehyde with a chemical structure similar to that showed in
Scheme
8.6
c[
92
]. In this procedure, aldehyde is deprotected just before the protein
conjugation with an acidic treatment. Moreover, the functionalization of HA with
the masked aldehyde can be performed with EDC/NHS or CDI chemistry
employing HA-TBA and hemiacetal amines.
An example of HA-g-peptide copolymer applied for a non-hepatic targeting has
been presented recently by Hahn research group that tested the antidiabetic effect of
the short peptide exendin 4. The exendin 4 is an incretin mimetic with gluco-
regulatory activity commercialized as Byetta
®
for the treatment of type 2 diabetes
that however has found a limited clinical application because of a very short
α
