The in vivo behavior and antitumor activity of doxorubicin-loaded
poly(γ-benzyl
L
-glutamate)-block-hyaluronan polymersomes in
Ehrlich ascites tumor-bearing BalB/c mice
Kamal Kumar Upadhyay, PhD
a,b,c
, Anil Kumar Mishra, PhD
d
, Krishna Chuttani, MSc
d
,
Ankur Kaul, MSc
d
, Christophe Schatz, PhD
a,b
, Jean-François Le Meins, PhD
a,b
,
Ambikanandan Misra, PhD
c
, Sebastien Lecommandoux, PhD
a,b,
⁎
a
Université de Bordeaux, Pessac-Cedex, France
b
CNRS, Laboratoire de Chimie des Polymères Organiques, Pessac, France
c
Pharmacy Department, Faculty of Technology and Engineering, Kalabhavan, Maharaja Sayajirao University of Baroda, Vadodara, Gujarat State, India
d
Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences (INMAS), Delhi, India
Received 25 November 2010; accepted 18 May 2011
Abstract
The in vivo efficacy of doxorubicin (DOX)-loaded poly(γ-benzyl
L
-glutamate)-block-hyaluronan (PBLG
23
-b-HYA
10
)-based
polymersomes (PolyDOX) was evaluated. Samples were efficiently labeled with technetium-99m radionuclide with good stability for in
vivo studies. PolyDOX enhanced circulation time compared to free DOX. Biodistribution studies revealed selective accumulation of
PolyDOX in the Ehrlich ascites tumor (EAT) as a result of passive accumulation and active targeting (CD44-mediated endocytosis) in EAT-
bearing mice. Toxicity studies demonstrated PolyDOX is a safe drug carrier, and no hemolysis was observed with PolyDOX equivalent to
200 μg/mL of free DOX. PolyDOX dominantly controlled tumor growth by delaying doubling time of EATs compared to free DOX over
30 days after treatment. PolyDOX also increased life span six times more than free DOX. Hence, it is reasonable to expect that higher DOX
levels attributable to PolyDOX improve the therapeutic index and reduce side effects due to site-specific drug accumulation.
From the Clinical Editor: In this preclinical project, doxorubicin loaded polymersomes enhanced intracellular uptake of doxorubicin in a
murine model of Ehrlich Ascites Tumor (EAT) through CD44 receptor mediated endocytosis, resulting in prolonged Tumor Doubling Time
and increase in life span of mice.
© 2012 Elsevier Inc. All rights reserved.
Key words: Polymersomes; Hyaluronan; Doxorubicin; Ehrlich ascites tumor (EAT); Antitumor activity
A major inherent limitation of current cancer chemotherapy
is the nonselectivity of anticancer drugs to tumor cells in vivo
and the nonspecific distribution of anticancer drugs in the body
after systemic administration, leading to serious side effects on
normal cells.
1-4
However, major efforts have recently been
made to improve the efficacy of anticancer drugs with simul-
taneous reduction of side effects, using targeted drug delivery
systems such as conjugates,
5-7
liposomes,
8-10
solid lipid nano-
particles,
11,12
and polymeric micelles or nanoparticles.
12-15
Supramolecular amphiphilic block co-polymers that self-
assemble into hollow spherical structures that structurally
resemble liposomes, named polymersomes, have been invented
as competent drug carriers with some remarkable features,
4,16,17
and have proved to be an emerging novel carrier for drug
delivery
18-21
and gene therapy.
22
Previously, we reported on self-targeted polymersomes-
loaded anticancer drugs toward CD44-expressing cancer
cells
19-21
based on poly(γ-benzyl
L
-glutamate)-block-hyaluronan
(PBLG
23
-b-HYA
10
). This new generation of polypeptide-block-
polysaccharide block co-polymers formed well-defined poly-
mersomes in aqueous buffer solution that efficiently loaded
doxorubicin (DOX)
19,20
and docetaxel.
21
In vitro cell line studies
demonstrated that hyaluronan (HYA)-based polymersomes
BASIC SCIENCE
Nanomedicine: Nanotechnology, Biology, and Medicine
8 (2012) 71 – 80
Research Article
nanomedjournal.com
This work was supported by a grant from the Science and Technology
Service, Embassy of France in India, India, internal funds from the Laboratoire
de Chimie des Polymères Organiques, and a National Doctoral Fellowship-All
India Council for Technical Education to K.K.U. The authors would also like to
thank the Technology Information, Forecasting and Assessment Council-
Centre of Relevance and Excellence in New Drug Delivery Systems, and the
director of the Institute of Nuclear Medicine and Allied Sciences for generous
funding and extension of laboratory facilities for the work.
⁎
Corresponding author: Université de Bordeaux, UMR5629, ENSCPB,
33607 Pessac-Cedex, France.
E-mail address: lecommandoux@enscbp.fr (S. Lecommandoux).
1549-9634/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.nano.2011.05.008
Please cite this article as: K.K., Upadhyay, et al, The in vivo behavior and antitumor activity of doxorubicin-loaded poly(γ-benzyl
L
-glutamate)-block-
hyaluronan polymersomes in Ehrlich ascites tumor-bearing BalB/c mice. Nanomedicine: NBM 2012;8:71-80, doi:10.1016/j.nano.2011.05.008