Biomedical Engineering Reference
In-Depth Information
92, 93
weight polyanion with siRNA.
Despite its great advantage in
improving the delivery efficiency of NPs, there are several concerns
with calf thymus DNA, such as the immunogenic response.
140
The
FDA is unlikely to approve the use of DNA from an animal source for
clinical trials.
In order to minimize the immunotoxicity of the particles, an
alternative biocompatible anionic biopolymer, hyaluronic acid
(HA), may be used to replace the high molecular weight carrier
DNA. HA is a polyanionic polysaccharide, which is one of the major
extracellular components of connective tissues.
141, 142
Recently, HA
has been found to bind to tumor cells that overexpress CD44 when
being administered as an anticancer therapy.
143-146
Aside from
the beneficial targeting properties, the most pronounced effect
of replacing carrier DNA with HA is the relatively low toxicity and
immunogenicity, owing to the absence of immune stimulatory CpG
motifs. HA has already been approved by the FDA for injection, which
is a great benefit in drug development.
The size and zeta potential of the LPH NPs were found to be
comparable to those of previous formulation, LPD, regardless of the
targeting moiety. This indicates that the replacement of calf-thymus
DNA with HA did not affect the physicochemical properties of both
formulations. The targeting ligand, anisamide, was found to enhance
the siRNA delivery efficiency as well as the gene silencing effect of
the LPH NPs in B16F10 cells and in the B16F10 lung metastasis
mouse model. Also, LPH NPs did not produce any significant amounts
of IL6 and IL12 proinflammatory cytokines over a wide dose range
of 0.15-1.2 mg/kg. In contrast, the LPD formulation containing calf
thymus DNA significantly increases both cytokines at doses higher
than 0.45 mg/kg, limiting the therapeutic dose range. Thus, the LPH
formulations can greatly improve the therapeutic window without
immunotoxicity while having the same gene silencing effect, when
compared to the targeted LPD NPs. The results suggest that LPH
might have a greater potential than LPD for clinical use.
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3.4.2 LCP
As described above, the LPD formulation has shown efficient
delivery of siRNA and a potential therapeutic effect for metastatic
lung tumor treatment. However, several possible improvements
have been suggested, since the efficiency of release of siRNA from
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