Nanomedicine (Lond.) (Epub ahead of print) ISSN 1743-5889
part of
Research Article
10.2217/nnm-2016-0430 © 2017 Future Medicine Ltd
Aim: Our goal was to improve vincristine (VCR) based rhabdomyosarcoma (RMS)
therapy by encapsulating the drug into liposomes. A targeting strategy was
attempted to enhance tumor accumulation. Materials & methods: VCR was loaded
in control and peptide-decorated liposomes via an active method. The interaction of
an RMS-specific peptide with the presumed target furin and the cellular uptake of
both liposomal groups were studied in vitro. Pharmacokinetics and biodistribution of
VCR-containing liposomes were assessed in an RMS xenograft mouse model. Results:
Liposomes ensured high VCR concentration in plasma and in the tumor. Peptide-
decorated liposomes showed modest uptake in RMS cells. Conclusion: The investigated
peptide-modified liposomal formulation may not be optimal for furin-mediated RMS
targeting. Nevertheless, VCR-loaded liposomes could serve as a delivery platform for
experimental RMS.
First draft submitted: 23 December 2016; Accepted for publication: 14 March 2017;
Published online: 27 April 2017
Keywords: biodistribution•furin•liposomes•peptide•pharmacokinetic
•rhabdomyosarcoma•targeting•vincristine
Rhabdomyosarcoma (RMS) is the most com-
mon pediatric soft tissue sarcoma, account-
ing for approximately 10% of all solid can-
cers in children [1] and is subdivided into two
main histological groups, embryonal RMS
and alveolar RMS (aRMS) [2] . Embryonal
RMS arises in around 60–70% of all patients
and has a rather good prognosis. In contrast,
aRMS represents the more aggressive subtype
and is associated with the poorer prognosis,
with a 5-year survival below 30% [3,4] .
The first-line therapy for RMS is based on
a combination of chemotherapeutics, includ-
ing vincristine (VCR), followed by radiation
therapy or surgery [4] . However, suboptimal
pharmacokinetic properties of VCR, such as
short half-life and large volume of distribu-
tion, preclude an optimal application of this
agent [5] .
It has been shown that encapsulation of
VCR in liposomes prolongs its circulation
time and improves its therapeutic efficacy in
leukemia tumor models [6,7] . In fact, Mar-
qibo
®
, a sphingomyelin/cholesterol-based
liposomal VCR formulation, was clinically
approved by the US FDA in 2012 for the
treatment of acute lymphoblastic leukemia
in second or greater relapses [5] . The phar-
macokinetic parameters and biodistribution
of liposomal VCR have been determined in
mice-bearing solid tumors, such as human
epidermoid carcinoma A431 [8] and MX-1
human mammary adenocarcinoma [9] . Fol-
lowing liposomal VCR injection, its circu-
lation time was prolonged resulting in sig-
nificantly higher VCR concentration in the
tumors for all time points tested. This can be
attributed to the enhanced permeability and
retention (EPR) effect [10] , a result of unique
pathophysiological features of some solid
tumors such as defective vascular architecture
and extensive angiogenesis [11] . Lower clear-
Prolonged circulation and increased tumor
accumulation of liposomal vincristine in a
mouse model of rhabdomyosarcoma
Maurizio Roveri
1,2,3
, Alice
Pfohl
1,2,3
, Patricia Jaaks
1,2
,
Nagjie Alijaj
1,2
, Jean-
Christophe Leroux
3
, Paola
Luciani*
,‡,3,4
& Michele
Bernasconi**
,‡,1,2
1
ExperimentalInfectiousDiseases&
CancerResearch,UniversityChildren’s
HospitalZurich,8008Zurich,Switzerland
2
Children’sResearchCenter,University
Children’sHospitalZurich,8032Zurich,
Switzerland
3
DepartmentofChemistry&Applied
Biosciences,InstituteofPharmaceutical
Sciences,ETHZurich,8093Zurich,
Switzerland
4
DepartmentofPharmaceutical
Technology,InstituteofPharmacy,
FriedrichSchillerUniversity,07743Jena,
Germany
*Authorforcorrespondence:
paola.luciani@uni-jena.de
**Authorforcorrespondence:
michele.bernasconi@kispi.uzh.ch
‡
Authorscontributedequally
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