Chemistry Reference
In-Depth Information
with potential application for drug delivery or as scaffolds for tissue engineering.
Synthetic polymeric chains, having peculiar properties such as thermorespon-
siveness, can be linked to obtain HA graft derivatives with in vivo gel-forming
ability. Polymers such as polyesters [polylactic acid, poly(lactic-co-glycolic) acid,
polycaprolactone] have been exhaustively employed, and related derivatives have
been described for the production of drug-loaded nanoparticles for drug targeting or
scaffolds for tissue engineering. In this section, representative examples of these
HA-graft derivatives will be reported describing synthetic procedures, characteri-
zation, and applications.
8.3.1 HA-Graft Synthetic Polymers to Produce Nanostructures
and Hydrogels for Drug Delivery
The potential utility of nanometric aggregates such as nanoparticles, nanogels, or
micelles constituted by HA is mainly related to the targeting ability toward specific
receptors expressed in tumors or tissues. High molecular weight HA binds multiple
receptors, and if a drug is linked to the HA backbone, a specific endocytosis can
occur; for certain drugs, this can offer the opportunity to escape multidrug resis-
tance efflux pumps [
41
]. However, applicability of HA as targeting moiety may be
hindered by the difficulty to escape hepatic accumulation [
42
,
43
]. As example
ONCOFID, a prodrug of taxol proposed by Fidia Advanced Biopolymers is finding
application more for the treatment of locoregional therapies than for the treatment
of tumors by systemic delivery because of a preferential hepatic accumulation [
44
].
Therefore, to improve potential application of HA as suitable targeting carrier,
strategies must be developed to reduce hepatic clearance. HA binds CD44, HARE,
or LYVE-1 receptors with a minimum length of 6-8 HA disaccharides [
45
]. As
recently studied, analyzing the binding of both free HA and HA linked to
liposomes, high molecular weight HA-binding affinity seems to increase increasing
HA molecular weight, being HA with low molecular weight faster dissociated from
the CD44 interaction. Longer HA chains better interact with CD44 receptors
because of the instauration of a multivalent interaction with the binding receptors.
Considering such properties and selecting HA with dimension suitable to interact
with CD44 but not with receptor HARE into the liver, it could be theoretically
possible to tailor the biodistribution of HA or HA-coated nanocarriers avoiding
hepatic accumulation [
46
,
47
]. However, the employ of short oligosaccharides of
HA limits the possibility to produce nanocarriers or polymeric prodrugs. Recently,
Hanh and colleagues described the influence of glucuronic COOH degree of
functionalization on tissue biodistribution of HA derivatives. In particular by
linking HA hydrazide derivatives to QDots photoluminescent nanocrystals, these
authors investigated relationships between HA dimension, chemical functiona-
lization, and biodistribution [
48
].
Obtained results demonstrated that increasing glucuronic functionalization, HA
derivatives accumulated in less extent into HA receptor-rich tissues such as liver
