Biomedical Engineering Reference
In-Depth Information
3.3.2 Overcoming the Challenges in Encapsulating Small
Interfering Ribonucleic Acid and Small Molecule Drugs
As stated in the previous section, Jiang and co-workers, developed
a PEI conjugated HA derivative with 24 mol% PEI content for
target-specific intracellular siRNA delivery. They reported that HA
modified with less than 25 mol% of PEI was considered not to affect
its receptor-mediated endocytosis [21].
Since our goal was also to use the HA systems to deliver siRNA to
tumours, we assessed siRNA payload encapsulation using different
HA-derivatives. As others had noted with their derivatives, we also
realised that the HA-derivatives with varying degrees of modification
and nitrogen content required individual optimisation (
Table 3.1
).
Interestingly, an optimal encapsulation efficiency of approximately
90-100% with an optimal particle size in the range of 150-300 nm
was obtained only at certain polymer:siRNA mass ratios [19]. Also,
the parameters changed from one class of lipid to another, probably
because the net charge contribution and the nitrogen content in
the polymer played a significant role in the siRNA encapsulation/
complexation and self-assembly. Zeta potential values indeed
varied from one set of formulations to the other (from -20 to +16
mV), confirming the proposed role of charge on complexation
and formation of self-assembled nanosystems. For instance,
the experimentally observed results for siRNA encapsulation in
monofunctional fatty amine-modified HA were not encouraging,
although not surprising. This observation can in part be explained
by the absence of positively-charged domains to promote siRNA
complexation. However, the addition of extra nitrogen atoms to
the fatty acid chains (such as diamine-containing HA) favourably
enhanced the encapsulation of siRNA. In this class of HA polymers,
under mild acidic conditions (pH = 5.0-5.5), the free primary amine
residues were protonated to generate a net positive charge on the
polymer to facilitate siRNA encapsulation. For this class of HA
polymers, namely HA-1,6 diaminohexane, HA-1,8-diaminooctane
and HA-choline (with approximately 8-10% lipid modification), the
best observed polymer:siRNA mass ratio was found to be 450:1 (at
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