Abstract
Hyaluronan (HA) is among the most important bioactive polymers in mammals, playing a key role in a number of biological functions. In the last decades, it has been increasingly studied as a biomaterial for drug delivery systems, thanks to its physico-chemical features and ability to target and enter certain cells. The most important receptor of HA is ‘Cluster of Differentiation 44’ (CD44), a cell surface glycoprotein over-expressed by a number of cancers and heavily involved in HA endocytosis. Moreover, CD44 is highly expressed by keratinocytes, activated macrophages and fibroblasts, all of which can act as ‘reservoirs’ for intracellular pathogens. Interestingly, both CD44 and HA appear to play a key role for the invasion and persistence of such microorganisms within the cells. As such, HA is increasingly recognised as a potential target for nano-carriers development, to pursuit and target intracellular pathogens, acting as a ‘Trojan Horse’. This review describes the biological relationship between HA, CD44 and the entry and survival of a number of pathogens within the cells and the subsequent development of HA-based nano-carriers for enhancing the intracellular activity of antimicrobials.
Highlights
Intracellular pathogens are considered to be among the major bacterial public health threats [1].The outcome of intracellular infections is largely due to the ability of pathogens to utilise specific cell receptors [2] and host components [3] for invading and subverting cellular activities
This review describes the biological relationship between HA, Cluster of Differentiation 44’ (CD44) and the entry and survival of a number of pathogens within the cells and the subsequent development of HA-based nano-carriers for enhancing the intracellular activity of antimicrobials
There is a degree of uncertainty in HA biology; areas which require further exploration, include (I) the mechanism by which enzymes of synthesis and degradation of HA are able to cooperate for providing a proper HA size, (II) the binding of HA to CD44 and the subsequent internalisation within the cells; (III) the explicit role HA plays during the inflammation: evidences suggest in the alveolar tracts, released fragments of HA play a pivotal role in the host defenses, stimulating the innate immune responses, by activating TLR2 and TLR4 receptors promoting lung inflammation [50] and HA role in the resolution of inflammation, [51] and (IV) the role HA plays during the infection processes
Summary
Intracellular pathogens are considered to be among the major bacterial public health threats [1]. The outcome of intracellular infections is largely due to the ability of pathogens to utilise specific cell receptors [2] and host components [3] for invading and subverting cellular activities. Further work by Karl Meyer and his associates led to the resolution of the chemical an uronic acid, the name “hyaluronic acid” (HA) was coined by joining three words: hyaloid (vitreous) structure of HA by the 1950s [11]. In early 1980s, Endre Balazs poly-anionic polysaccharide composed of alternating D-glucuronic acid and N-acetyl-D-glucosamine was successful in isolating a purified high molecular weight HA, which was used to produce plastic monomeric units linked together through β-1,4 and β-1,3 glycosidic bonds.
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