Chemical Modifications of Hyaluronan for Therapeutic Applications - Hyaluronic Acid for Biomedical and Pharmaceutical Applications - page 150

tissues, has a role in maintaining cell integrity and water content
in the ECM while degraded HA fragments are known to induce
receptor-mediated intracellular signalling [2]. These fragmented
oligosaccharides produced during matrix turnover are known
to display proinflammatory properties, whereas high MW HA
present in the intact matrix induces immunosuppression, reflecting
differences in the capacity of each size fraction either to activate toll-
like receptors or to bind cell surface CD44 receptor and stimulate
FoxP3+ CD25+ regulatory T cells, respectively [3]. The levels of HA
present in a tissue depend upon several factors which is governed by
HA synthesis by HA synthases [4], HA internalisation by cell surface
receptors [5] and extracellular degradation by hyaluronidases [6].
CD44 [7], the receptor for hyaluronate-mediated motility [8], the
endocytosis receptor present on the cell surface of lymphatics [9]
(lymphatic vessel endothelial hyaluronan receptor-1) and hyaluronan
receptor for endocytosis receptor on liver sinusoidal endothelial
cells [10] have been identified as HA receptors involved in various
biochemical processes. Many of the downstream pathways following
CD44 activation become deregulated in cancer, leading to tumour
growth, progression and metastasis [11]. HA has a half-life of over
a day in skin, while in plasma it is only 2.5-5.5 min [12]. However,
the chemically modified HA or nanoparticles (NP) derived from HA
show good stability and a long circulation time in blood, which is
slightly lower than that of polyethylene glycol (PEG) coated NP. It
is important to note that with higher synthetic modifications of HA
(over 30% of disaccharide units), one can achieve higher enzymatic
stability, albeit poor receptor recognition or biological function.
Interaction of HA to CD44 is weak and therefore multiple binding
sites (between six and eight unmodified saccharide repeating units) are
required for efficient CD44 binding. Thus HA with higher chemical
modification has a lower capability of CD44 binding and affects
other biological processes (see Section 8.4.1 ). Interestingly, in cancer
patients, elevated levels of hyaluronidase inhibitors are found in the
serum, which slows down HA degradation [13, 14].