Polysaccharides as Nanomaterials for Therapeutics - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 139

resulted in 20 times improved in vitro serum stability without loss
of bioactivity. The size of these HA-exendin 4 conjugates was not
reported. HA-exendin 4 conjugates lowered glucose levels in type
2 db/db mice and the hypoglycemic eff ect lasted up to 3 days after
injection. In addition, insulin immunohistochemical analysis of islets
in db/db mice confirmed the improved insulinotropic activity of the
HA-exendin 4 conjugates. HA conjugates have also been suggested
for the treatment of acute promyelocytic leukemia (APL) [107]. APL
patients often relapse due to resistance to the therapy, all-trans
retinoic acid. Because of the molecular basis of APL alteration and
previous success with treating tumors with HA conjugated to the
histone deacetylase inhibitor butyric acid [108, 109], conjugation of
HA to both all-trans retinoic acid and butyric acid has been tested.
The size of these HA conjugates was not reported. In vitro , the HA
conjugates induced growth arrest and terminal diff erentiation in
retinoic acid sensitive cells and apoptosis in retinoic acid resistant
cells. In vivo , HA conjugates led to a significant increase in survival
time of a retinoic acid sensitive APL murine model in comparison
with that induced by a maximum tolerated dose of retinoic acid
alone. In addition, in a retinoic acid resistant murine model, the
HA conjugates were active in contrast to retinoic acid that was
completely ineff ective [107].
As described above, PEC have been used to prepare HA-based
nanoparticles. HA-chitosan nanoparticles have demonstrated the
ability to transport genes across the ocular mucosa and transfect
ocular tissue [110]. The nanoparticles were prepared by ionically
cross-linking of chitosan with TPP, which was followed by PEC with
HA. The HA-low-Mw chitosan nanoparticles led to high expression
levels of the transfected alkaline phosphatase in a human corneal
epithelium model. Upon topical administration to rabbits, the
nanoparticles managed to overcome cellular barriers and were
located inside the corneal and conjunctival cells, suggesting that
they penetrate the epithelia by a transcellular pathway. In addition,
the in vivo transfection levels reached were significant.
As with other polysaccharides, self-assembly of hydrophobically
modified HA has been used for nanoparticle preparation. Poly(lactic-
co-(glycolic acid)) (PLGA)-modified HA copolymers were shown to
self-assemble in aqueous solution into micelle nanoparticles [111].
The sizes of doxorubicin loaded HA micelle nanoparticles were ranging
from 120-285 nm in diameter depending on the Mw of HA and the