Chemistry Reference
In-Depth Information
Fig. 8.4
Antiangiogenic
activity of anti-Flt1 peptide,
HA-g-Anti-Flt1, and Avastin
measured by inhibition of
neovascularization in silver
nitrate cauterized corneas of
rats in 2 weeks (Reproduced
with permission, copyright
2009 Elsevier [
33
])
recognition by hepatic receptors including LYVE-1 and HARE [
86
,
87
]. As
described in Sect.
8.3.1
, Hahn's research group demonstrated that biodistribution
and pharmacokinetic of HA can be affected by the degree of substitution of the
glucuronic COOH groups [
88
].
In particular using HA-ADH tethered to Qdots having a COOH functionalization
with ADH lower than 30 mol%, the interaction with HARE hepatic receptors was
not masked, and HA-ADH-g-Qdots accumulated mainly into liver. Starting from
these findings, Yang and colleagues [
89
] described the production and the in vivo
efficacy of a HA-g-interferon-
α
α
α
) is extensively
employed for the treatment of hepatitis C, even if the employ of free peptide is
limited by its side effects related to the not optimal pharmacokinetic. PEGylation
has been employed to obtain long-acting derivatives through the production and
commercialization of PEGASYS or PEG-Intron [
90
,
91
]. However, even if these
pegylated derivatives improved interferon-
derivative. Interferon-
(IFN-
activity, only the 39 % of patients
affected by hepatitis C respond completely to the treatment. To test the potentiality
of HA as PEG substitute, a HA-aldehyde derivative, obtained by periodate oxida-
tion, was employed to conjugate the INF-
α
via the formation of imidic linkage with
the primary amine of a lysine portion. This reaction was very efficient in aqueous
environment at pH 5.5. However, the aldehyde functionalization performed by
periodate oxidation offers several concerns, related to the HA stability during the
oxidative reaction and to the stability of the HA-aldehyde derivative during the
storage. Starting from HA-aldehyde derivatives with a molar functionalization in
aldehyde groups ranging from 10 to 45 % and using a molar ratio INF-
α
α
/aldehyde
from 2 to 9, HA-g-INF-
derivatives, with a bioconjugation efficiency near to the
95 %, were obtained. The unreacted free aldehyde can be blocked by treatment with
an excess of ethylcarbazate. HA-g-INF
α
α
shows a stability three times longer in
