Biomedical Engineering Reference
In-Depth Information
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FIGURE 20.3 (Continued)
Chemistry.structures.of.(A).dioleoylphosphatidylethanolamine.(DOPE),.(B).DSPE-Peg
2000
,.(C).1,3-didodecyloxy-
2-glycidyl. glycerol. with. 114. ethylene. oxide. monomer. units. of. the. Peg. chain. (DDGG)
4
EO
114
. (Mw. =. 6,800),.
(D).oleyl.alcohol.(OAlc).forming.a.hydrogen.bond.through.its.hydroxyl.to.an.oxygen.atom.on.the.phosphate.group.
on.the.phosphatidylcholine.molecule,.(E).proposed.hydrolysis.pathways.for.1,2-di-
O
-(1'
Z
,9'
Z
-octadecadienyl)-
glyceryl-3-(ω-methoxy-poly(ethylene.glycolate)).(BVEP;.Mw.=.5,000),.indicating.the.sequential.cleavage.of.the.
two. alkenyl. chains,. (F). 1'-(4'-cholesteryloxy-3'-butenyl)-ω
-
methoxy-poly(ethylene. glycolate). (CVEP),. (G). Peg-
diorthoester-distearoyl.glycerol.conjugate.(POD),.and.(H).mechanism.of.POD.hydrolysis..The.quick.degrada-
tion.of.POD.at.a.pH.of.5-6.is.claimed.to.occur.with.a.higher.sensitivity.than.that.of.acetals,.vinyl.ethers,.and.
polyorthoesters..Such.higher.sensitivity.of.POD.is.attributed.to.the.following.two.factors..First,.the.dialkoxy.
carbocation.intermediate.of.orthoester.hydrolysis.has.four.lone.pairs.of.electrons.over.which.to.distribute.the.
positive.charge.from.the.carbon,.and.hence.is.much.more.stable.than.the.monoalkoxy.carbocation.intermediate,.
stabilized.by.two.lone.pairs.of.electrons,.in.the.case.of.acetals.and.vinyl.ethers..Second,.the.Peg.headgroup.of.
POD.is.more.hydrophilic.than.the.functional.groups.of.the.reported.polyorthoesters,.allowing.better.hydration.
and. faster. proton. transfer. to. the. diorthoester. linkage.. (I). Schematic. illustration. of. the. randomly. (1). and. ter-
minally.alkylated.(2).poly(NIPA-co-MAA-co-DODA).copolymers.anchored.to.liposomes..(J).Poliphosphazene.
grafted.with.up.to.three.different.substituents:.ethoxyethoxyethoxy.(EEE).groups,.stearyl.chains,.and.amino.
butyric.acid.(ABA)..(K).SucPG..(L).GluPG..(M).MGluPG.
The.addition.of.cholesterol.(Chol).does.not.diminish.the.leakage.and.also.decreases.the.
pH. sensitivity. of. DOPE. liposomes.. In. vitro,. DOPE/OA/Chol. liposomes. show. a. biphasic.
release. of. calcein. (aqueous. content. marker):. 95%. of. calcein. is. released. within. 1. h,. with.
more. than. 60%. OA. being. transferred. to. albumin;. the. remaining. 5%. is. released. in. the.
following.8.h.
66
.Seventy-ive.percent.of.the.i.v..injected.dose.of.DOPE/OA/Chol.liposomes.
in. mice. is. degraded. in. the. irst. 5. min,. wheres. the. remaining. 25%. is. mainly. distributed.
between.the.liver.and.spleen.
67
The.addition.of.40.mol%.cholesterol.to.DOPE/PHC.liposomes.also.diminishes.the.pH.
sensitivity.and.fusogenic.activity.
38
On. the. other. hand,. the. addition. of. poly(ethylene. glycol). (Peg). to. DOPE/CHEMS. lipo-
somes.reduces.the.leakage,.but.the.pH.sensitivity.is.diminished.
65,68,69
.DOPE/CHEMS.lipo-
somes.lose.36%.of.calcein.after.1.h.in.pH.7.4.buffer,.whereas.in.95%.rat.plasma.47%.of.the.
aqueous.content.marker.
111
In.is.released.after.1.h,.increasing.to.69%.after.19.h..In.buffer.at.
pH.5.5,.the.calcein.release.is.84%,.but.in.culture.media.supplemented.with.10%.fetal.bovine.
serum.(FBS).it.diminishes.to.29%..DOPE/CHEMS/PE-Peg.(5.mol%).liposomes.release.5%.
of.calcein.in.pH.7.4.buffer,.and.20%.of.
111
In.after.1.h,.increasing.to.32%.after.19.h,.in.rat.
plasma..However,.liposomes.having.very.small.amounts.of.PE-Peg.(e.g.,.1.mol%).hamper.
