Biomedical Engineering Reference
In-Depth Information
One of the prerequisites for designing HA based delivery systems is
to identify the biological criteria required for cell surface receptor
targeting and endocytosis. Although high MW HA-drug conjugates
will bind to the CD44 receptor endocytosis of HA-drug conjugates
occurs only upon degradation of HA to suitable sizes [48]. The critical
factors governing the cellular uptake and receptor interaction are:
(i) binding affinity of HA to its CD44 receptor is very weak, and for
successful translocation into cells HA needs to be bound to multiple
receptors [49]; (ii) between six and eight unmodified saccharide
repeating units are needed for effective binding to one CD44 receptor
[46], however, oligosaccharides larger than 20 residues are required
for effective binding with more than one CD44 receptor [50]; and
(iii) HA with MW below 31 kDa binds only to one CD44 receptor,
while above 132 kDa it binds between five and eight CD44 receptors
[51]. Taking these factors into account, several drug conjugates and
NP formulations have been developed which demonstrated CD44
mediated cellular uptake and targeted delivery.
8.4.1.1 Hyaluronic Acid Micelles
The simplest strategy to design a HA micelle is by inducing
amphiphilicity by conjugating small hydrophobic molecules to the
HA polymer. This is achieved in numerous ways by conjugating
molecules such as fatty acids or ceramides [52], cholesterol [53],
nicotinamide-based hydrotropic agents [54], 5β-cholanic acid [55]
and deoxycholic acid [56]. This results in the self-assembly of these
conjugates to form a micelle, where the hydrophobic drug molecule
forms the core, while the hydrophilic HA polymer forms the shell.
However, by conjugating the anticancer drug molecules directly to
the glucuronic carboxylate residue of HA (without any cleavable
linker), small molecule drugs like Dox or paclitaxel could attain a
micellar assembly. Luo and co-workers have discovered that this
strategy failed to induce toxicity for cancer cells possibly due to poor
drug release from this construct [57]. Thus, several degradable linkers
like disulfides, hydrazone, esters and self-immolative peptide linkers
have been successfully employed to design these prodrugs, which
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