Biomedical Engineering Reference
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CaP core and not the outer leaflet lipid. Based on this observation,
it could be concluded that using cationic lipid for binding with the
negatively charged endosomal membrane lipid may not be required
to release the cargo from LCP NPs. Unlike in the
study, only
the LCP NPs containing DOTAP showed significant down-regulation
of the target gene (approximately 50%) when 0.6 mg/kg of siRNA
was injected to the H460 xenograft mouse model. LCP with DOPC,
a neutral lipid, as the outer leaflet lipid showed no silencing effect
even with the siRNA dose of 0.12 mg/kg. Such inconsistent results
may be better understood when the amount of internalized LCP
particles in the endosome is considered.
There are two demonstrated mechanisms for endosome
destabilization and cargo escape. The first is that the cationic
polymers containing secondary or tertiary amines may increase
the osmotic pressure inside the endosome by the buffering effect
of the crowded amines, also known as the proton sponge effect.48
in vitro
48
The other mechanism is related to the destabilization of both the
endosomal membrane and the cationic vector by the formation of
ion pairs between the positively charged groups of either cationic
polymer or lipid and the negatively charged groups of the endosomal
membrane.
153, 154
Ion-pair formation significantly reduces the surface
hydration of a membrane promoting non-bilayer structures. If there
is sufficient amount of internalized LCP in a certain endosome at
one time, similar to the
condition, the release of nucleic acid
will be mostly mediated by the elevated osmotic pressure caused by
CaP dissolution in the acidic endosome.
in vitro
147
However, when there is
insufficient amount of NP in the endosome to increase the osmotic
pressure, just as the
situation, cationic lipid may play an
important role in releasing the nucleic acid cargo.
Since LCP has several advantages over LPD, including
improved cargo release activity, it has been used as a delivery
carrier for combination siRNA therapy for potential treatment of
melanoma metastasis in the lung. LCP is a perfect vector to deliver
multiple siRNAs for simultaneous obstruction of several signaling
pathways. The combination of three siRNAs targeting MDM2, c-Myc,
and VEGF has been successfully delivered to the tumor by the
targeted LCP, which resulted in a significant reduction of B16F10
metastatic burden in the lung. Targeted LCP with control siRNA
failed to show any therapeutic effect. The mean survival period of
the animals in the group treated with therapeutic siRNA formulated
in vivo
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