Biomedical Engineering Reference
In-Depth Information
20.7 PreclinalApplicationsofPegylatedpH-SensitiveLiposomes
20.7.1 Tumor Therapy/Cisplatin
Cis
-diamminedichloroplatinum(II).(cisplatin).is.a.platinum.complex.employed.in.the.treat-
ment.of.ovary,.lung,.testicle,.head,.and.neck.carcinoma.that.is.mainly.limited.by.its.severe.
nephrotoxicity.. Additionally,. it. generates. intrinsic. and. acquired. resistance.. A. sterically.
stabilized. liposomal. formulation. of. cisplatin. was. developed. by. ALZA. Pharmaceuticals.
(Mountain.View,.California),.but.phase.I-II.clinical.studies.between.2002.and.2006.were.
unsuccessful..The.lack.of.eficacy.was.attributed.to.the.low.bioavailability.and.slow.release.
kinetics. of. cisplatin,. in. such. a. way. that. the. cisplatin. concentration. fails. to. exceed. the.
threshold.for.therapeutic.effect.
146-148
Aiming. to. increase. the. cisplatin. bioavailability. in. tumors,. cisplatin-pegylated. pH-
sensitive. liposomes. (DOPE:CHEMS:PE-Peg,. 5.7:3.8:0.5,. 110. nm). were. administered. as. a.
single. i.v.. bolus. in. solid. Ehrlich. tumor-bearing. mice.
149
. Cisplatin-pegylated. pH-sensitive.
liposomal.treatments.resulted.in.a.2.1-fold.higher.blood.AUC.and.2.6-fold.higher.tumor.
AUC.than.free.cisplatin..The.tumor.AUC/blood.AUC.ratio.is.higher.for.cisplatin-pegylated.
pH-sensitive. liposomes. than. for. free. cisplatin. (1.51. vs.. 1.23).. However,. the. kidney. (the.
major. site. of. toxicity. for. cisplatin). AUC. produced. by. pH-sensitive. liposomes. is. 1.5-fold.
higher.than.that.corresponding.to.free.cisplatin.
Recently. the. same. researchers. evaluated. the. acute. toxicity. in. mice. upon. a. single. i.p..
administration. of. cisplatin. pegylated. pH-sensitive. liposomes. (7,. 12,. 30,. 45,. and. 80. mg/
kg). and. free.cisplatin. (5,. 10,.and. 20.mg/kg).
150
. Mice. treated. with. the.higher. dose. of. free.
cisplatin.(20.mg/kg).showed.strong.weight.loss.and.a.longer.time.of.recovery.than.those.
receiving.the.liposomal.drug..The.LD
50
.values.in.male.and.female.mice.for.liposomal.cis-
platin.were.2.7-.and.3.2-fold.higher,.respectively,.than.those.for.free.cisplatin..No.hema-
tological.toxicity.is.registered.for.liposomal.cisplatin,.and.neither.were.histopathological.
alterations.observed.after.either.treatment..Free.cisplatin,.however,.leads.to.an.appearance.
of. mild. anemia. and. a. reduction. in. total. white. blood. cell. counts,. as. well. as. pronounced.
alterations.in.the.blood.urea.and.creatinine.levels.of.mice..In.contrast,.these.parameters.are.
slightly.altered.only.after.liposomal.cisplatin.treatment.at.a.dose.of.30.mg/kg..Microscopic.
analysis.of.kidneys.from.mice.treated.with.the.liposomal.drug.showed.no.morphological.
alteration.
20.7.2 Tumor Therapy/Gemcitabine
Recently,. pegylated. antibody-conjugated. pH-sensitive. liposomes. (DOPE/CHEMS/PE-.
Peg-PDP,. 6:4:0.1,. 150. nm). were. developed. to. overcome. the. short. in. vivo
half-life,. lack. of.
targetability,.and.cytoplasmic.delivery.of.gemcitabine.(GEM).
151
.GEM.(2',2'-diluoro-2'-de-
oxycytidine).is.a.deoxycytidine.nucleoside.analogue,.with.cytotoxic.activity.in.non-small-
cell.lung.cancer.cells..It.induces.an.S-phase.arrest.and.inhibits.DNA.synthesis,.but.has.shown.
hematotoxicity. with. other. toxic. effects.. pH-sensitive. liposomes. containing. PDP-Peg-PE.
(a. derivative. where. α-amino-ω-hydroxy. Peg. is. coupled. with. SPDP. (N-succinimidyl-3-(2-
pyridyldithio).propionate),.and.then.with.DOPE).were.conjugated.to.a.maleimidophenyl-
butyrate-derivatized.monoclonal.antibody.against.epidermal.growth.factor.receptor.(EGFR).
that.is.overexpressed.in.solid.tumors..The.antiproliferative.effect.of.conjugated.and.noncon-
jugated.pH-sensitive.liposomes.in.A549.cells.is.twofold.higher.than.for.pH-insensitive.lipo-
somes.(DPPC/Chol).or.the.free.drug,.and.~10%.apoptosis.for.pH-sensitive.liposomes.with.
