Biomedical Engineering Reference
In-Depth Information
These. two. types. of. liposomes. have. been. used. to. increase. the. intracellular. delivery. of.
1-β-arabinofuranosylcytosine.(ara-C).on.KB.human.oral.cancer.cells.in.vitro..Ara-C.acts.
speciically.on.the.process.of.DNA.synthesis,.and.most.of.it.is.deaminated.to.an.inactive.
form.in.the.irst.20.min.after.i.v..administration.to.animals.or.humans.
80
.Also,
N-glycosidic.
linkage.of.ara-C.is.degraded.by.lysosomal.hydrolases.being.inactivated.within.the.lyso-
somes..The.folate.(f).receptor.(FR),.on.the.other.hand,.which.is.ampliied.in.many.types.
of. human. tumors,. has. been. shown. to. mediate. the. internalization. of. f-derivatized. lipo-
somes.into.an.acidic.intracellular.compartment..The.incorporation.of.f-Peg.derivatives.into.
eggPC/DDAB/CHEMS/Tween. 80/PE-Peg
350
-f. (25:25:49:1:0.1). and. eggPC/CHEMS/Tween.
80/OAlc/Chol-Peg-f. (50:50:2:80:0.5). liposomes. enhances. the. cytotoxicity. of. entrapped.
ara-C,.as.shown.by.an.11-fold.reduction.in.the.50%.inhibitory.concentration.(IC
50
).(for.cat-
ionic.formulation),
78
.and.17.times.greater.cytotoxicity.(for.OAlc.formulation)
79
.on.KB.cells.
than.on.FR-targeted.pH-insensitive.liposomes.
In.a.recent.application,.pH-sensitive.liposomes.made.of.DMPC/DDAB/sodium.oleate/
Tween.80.(180:10:14:2).were.used.to.release.the.water-soluble.cationic.Fe-porphyrin.on.the.
gastric.cancer.cell.line.MKN28..Fe-porphyrin.acts.as.a.superoxide.dismutase.(SOD).mimic,.
converting.O
2
*
-
.in.H
2
O
2
,.to.further.generate.OH*.radical,.and.inducing.stronger.cytotox-
icity. for. cancer. cell. lines. than. for. normal. cells. without. any. phototoxic. effect.. A. sixfold.
decrease.of.50%.lethal.dose.(LD
50
).with.liposomal.Fe-porphyrin.was.achieved,.in.compari-
son.to.the.free.porphyrin..The.cytotxicity.was.reduced.when.the.cells.were.pretreated.with.
chloroquine,.indicating.the.action.of.a.pH-dependent.mechanism.
81
20.4 DOPEpH-SensitiveLiposomes
+
CleavablePeg
These.strategies.are.based.on.DOPE.transition.to.a.nonlamellar.phase.that.is.triggered.by.
acid.hydrolisis.of.labile.linkages,.leading.to.the.detachment.of.the.Peg.layer.that.impairs.
interbilayer.interaction.
The. irst. labile. linkages. were. designed. to. proit. from. the. reductive. environments. on.
the.cell.surface,.endosomes,.and.tumor.cells.
82
.For.instance,.pH-sensitive.DOPE/CHEMS.
liposomes. bearing. Peg. 3-6. mol%. possessing. the. disulide. linkage. dithiobis(propanoic.
dihydrazide)
69
. or. the. benzyl. carbamate. linkage. substituted. with. a. disulide. in. the.
para
.
or.
ortho
. position
83
. showed. promising. in. vitro
results
.
However,. in. humans,. despite. the.
oxidizing.environment.in.circulation,.reduction.of.disulide.bonds.does.occur.due.to.the.
presence.of.low.concentrations.of.cysteine.(∼8.µM).and.glutathione.(∼2.µM)..In.vivo,.pegy-
lated. pH-sensitive. liposomes. with. redox-sensitive. linkage. are. leaky. and. are. cleaved. in.
circulation.
72,84
The. pH-sensitive. linkages. were. shown. to. be. more. stable. in. circulation.. In. theory,. the.
pH-sensitive.linkage.would.allow.the.detachment.of.Peg.both.in.the.periphery.of.acid.sites.
(therefore.increasing.the.site-selective.uptake).and.intracellularly.(increasing.the.pH.sensi-
tivity.of.the.phase.transition)..However,.up.to.now.the.design.of.extracellular.pH-sensitive.
linkages. responding. to. a. slight. pH. decrease. in. the. periphery. of. tumors. has. failed,. and.
only.polymeric.micelles.have.successfully.made.pH.sensitive.to.extracellular.tumors.
85,86
.
Indeed,.the.hydrolysis.at.pH.5-6.of.the.hydrazone.(Hz).linkage.in.eggPC/Chol.(6:3).lipo-
somes. containing. up. to. 18. mol%. PE-Peg
5000
-Hz. and. 0.5-1. mol%. PE-Peg-TAT. (TAT. is. a.
cell-penetrating.peptide.that.enters.cell.cytoplasm.directly)
87
.detaches.the.shielding.Peg,.
revealing.TAT.peptide,.and.liposomes.enter.the.cells.more.eficiently.than.pH-insensitive.
