Chemical Modifications of Hyaluronan for Therapeutic Applications - Hyaluronic Acid for Biomedical and Pharmaceutical Applications - page 161

released the cytotoxic drug upon endocytosis. HA is a biodegradable
polymer and high molecular weight HA upon endocytosis degrades
to tetrasaccharides by enzyme hyaluronidase-1 which is abundantly
present in endosomes [22]. This implies that if a drug is conjugated
to HA without any cleavable linker, it should retain its cytotoxicity.
Oommen and co-workers directly conjugated DOX without any
cleavable linker and have verified that such covalent conjugation
indeed rendered an active prodrug, though drug loading was limited
due to steric crowding [22]. Several interesting reviews on various
NP and prodrug HA formulations are also available, offering new
insight into the role of HA in drug delivery applications [23, 46]. The
other way to tailor the HA micelle involves designing amphiphilic
block copolymers by conjugating hydrophobic polymers to HA [58].
Liu and co-workers have conjugated polylactic acid to the reducing
end of HA which was pre-aminated with 1,2-ethylenediamine and
subsequently reduced using sodium cyanoborohydride [59]. Dox
was also encapsulated in the HA-poly(lactic- co -glycolic acid) (PLGA)
micelle, which was synthesised by conjugating PLGA to HA via a
PEG spacer. This NP displayed enhanced tumour accumulation when
functionalised with HA [60].
8.4.1.2 Hyaluronic Acid-Liposome Formulations
Liposomes are stable nanocarriers which are used clinically to deliver
therapeutic agents for various anticancer treatments. HA coated
liposomes have also been developed which significantly improved
the pharmacokinetics, biodistribution and circulation half-life in the
blood. These liposomes are developed following either of the two
different strategies.
One of the oldest methods involves conjugation of HA oligosaccharide
to phosphatidylethanolamine by reductive amination via the reducing
end of HA. This amphiphilic HA is incorporated into the bilayer of the
liposome by mixing with suitable lipid components like cholesterol,
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and so on, in
different ratios. This HA-dioleoylphosphatidylethanolamine was