Biomedical Engineering Reference
In-Depth Information
with. the. structural. evolution. of. lipoplexes/anionic. lipids. from. a. stable. bilayer. phase. to.
an. unstable. phase.. Although. the. precise. mechanisms. of. endosomal. escape. may. vary,.
three.models.have.been.proposed:.the.charge-charge.destabilization.model,.the.ion-pair.
formation.model,.and.the.proton.sponge.model.
24.8.1 Charge-Charge Destabilization Model
During. endocytosis,. the. cationic. LNPs. adhere. to. and. undergo. fusion. with. the. anionic.
membrane.of.the.early.endosome,.enabling.their.internalization.into.the.cell..In.this.model,.
the.negatively.charged.endosomal.membrane.lipids.destabilize.the.interaction.between.the.
cationic.lipids.and.the.negatively.charged.siRNAs..This.facilitates.the.release.of.siRNA.out.
of.the.endosome.(Tseng.et.al..2009)..Sainya.et.al..deined.the.membrane.charge.density.in.
terms.of.σM.(charge.per.unit.area).(Leal.et.al..2010)..They.found.that.siRNA-LNPs.with.low.
σM.are.unable.to.escape.the.endosome,.resulting.in.low.transfection.eficiency..According.
to.this.theory,.the.higher.the.σM,.the.greater.the.siRNA.transfection.eficiency.
24.8.2 ion-Pair Formation Model
In.this.model,.after.endocytosis,.cationic.lipids.interact.with.anionic.phospholipids.within.
the.endosome.membrane,.forming.ion.pairs.that.adopt.non-bilayer.structures..These.interac-
tions.result.in.destabilization.of.both.the.LNP.and.endosome.membranes..Electrostatic.inter-
action.between.cationic.lipid.and.anionic.lipid.further.promotes.the.formation.of.an.inverted.
hexagonal.H
II
.phase,.which.is.a.destabilizing.structure..Molecular.shape.is.used.to.describe.
the.lipid.polymorphism.(Hafez.and.Cullis.2001)..Lipids.with.a.large.head.group.and.a.small.
hydrocarbon.tail.can.self-assemble.into.micelles.(Figure.24.4a)..Lipids.with.nearly.equal.head.
Hydration
Micelle
Hydration
Bilayer
Hydration
Inverted hexagonal
Figure 24.4
(See companion CD for color igure.)
.Molecular.shape.of.lipids.and.the.predicted.self-assembled.structures:.(a).
micelle,.(b).bilayer.(L
α
),.and.(c).inverted.hexagonal.(H
II
).
