International
Journal
of
Pharmaceutics
460 (2014) 196–
204
Contents
lists
available
at
ScienceDirect
International
Journal
of
Pharmaceutics
journa
l
h
o
me
pag
e:
www.elsevier.com/locate/ijpharm
Pharmaceutical
Nanotechnology
Peptide
fragments
of
human
serum
albumin
as
novel
renal
targeting
carriers
Zhi-xiang
Yuan
a,∗,1
,
Xia-kai
He
b,1
,
Xiao-juan
Wu
c
,
Yuan
Gao
b
,
Mei
Fan
b
,
Lian-qiang
Song
b
,
Chao-qun
Xu
a
a
Institute
of
Pharmacy,
Sichuan
Academy
of
Chinese
Medicine
Sciences,
Chengdu,
Sichuan
610041,
PR
China
b
School
of
Pharmacy,
Chengdu
University
of
Traditional
Chinese
Medicine,
Chengdu,
Sichuan
610075,
PR
China
c
Integrative
Traditional
and
Western
Medicine
Hospital
of
Sichuan
Province,
Chengdu,
Sichuan
610041,
PR
China
a
r
t
i
c
l
e
i
n
f
o
Article
history:
Received
29
July
2013
Received
in
revised
form
8
October
2013
Accepted
17
October
2013
Available online 29 October 2013
Keywords:
Human
serum
albumin
Peptide
fragments
Renal
targeting
carrier
Optical
imaging
in
vivo
Cellular
uptake
a
b
s
t
r
a
c
t
To
develop
the
proper
renal
targeting
carrier
for
clinical
therapy,
human
serum
albumin,
as
starting
material,
was
firstly
cleaved
into
albumin
fragments
and
Superdex
75
and
CM-Sepharose
FF
were
used
to
separate
and
purify
the
degradation
products.
Consequently,
three
peptide
fragments
(PFs)
with
certain
sequence
named
PF-A
1–123
,
PF-A
124–298
and
PF-A
299–585
were
obtained
as
candidates
of
renal
targeting
carrier.
Then,
cytotoxicity
and
cellular
uptake
of
three
PFs
was
studied
preliminarily.
The
results
showed
that
three
PFs
had
no
adverse
effects
on
the
HeLa
and
MDCK
cell
even
up
to
5.00
mg/mL
and
PF-A
299–585
exhibited
highest
affinity
to
MDCK
cells.
After
that,
we
found
that
PFs
selectively
accumulated
in
the
kidneys,
especially
in
the
renal
tubules
after
intravenous
injection
in
mice
by
optical
imaging
study.
Finally,
Tissues
distribution
in
vivo
was
utilized
to
verify
the
renal
targeting
profiles
of
PFs.
Three
PFs
exhibited
renal
accumulation
characteristics.
In
particular,
about
40%
injected
doses
of
PF-A
299–585
were
specifically
distributed
into
kidneys
for
1
h.
The
mean
area
under
the
curve
(AUC)
of
PF-A
299–585
in
kidneys
increased
13
times
compared
with
those
of
PF-A
1–123
and
PF-A
124–298
.
Therefore,
PFs
can
be
applied
as
prospective
carriers
for
renal
targeting
and
PF-A
299–585
may
be
the
optimal
carrier.
© 2013 Elsevier B.V. All rights reserved.
1.
Introduction
The
kidneys
are
the
vital
organs
of
the
humoral
regulation
and
maintain
the
nutrients
and
metabolites
of
body
balanced.
Renal
dysfunction
may
lead
to
chronic
kidney
disease
(CKD),
which
has
been
generally
acknowledged
as
a
serious
problem
affecting
pub-
lic
health
(Chen
et
al.,
2005;
Stenvinkel,
2010;
Vassalotti
et
al.,
2007
).
As
the
pathogenic
condition
becomes
worse,
renal
replace-
ment
therapy
(RRT),
such
as
dialysis
or
renal
transplantation,
has
to
be
used
to
sustain
the
lives
of
patients.
However,
these
ther-
apies
are
generally
expensive
and
may
cause
various
severe
side
effects.
Meanwhile,
regular
drug
therapies
of
renal
diseases
often
induce
complicated
extrarenal
toxicity.
Therefore,
developing
new
therapeutic
strategies
for
treating
patients
with
renal
disease
was
necessary
and
crucial
(Kamada
et
al.,
2003;
Okamoto
et
al.,
2004).
Selective
targeting
of
drugs
to
kidneys
may
enable
an
increased
renal
effectiveness
combined
with
a
reduction
of
extra
renal
effects.
The
domestic
and
foreign
reports
showed
that
many
car-
riers
exhibited
the
fine
renal
targeting
profiles,
including
low
molecular
weight
chitosan
(He
et
al.,
2012;
Yuan
et
al.,
2007,
∗
Corresponding
author.
Tel.:
+86
28
85213973;
fax:
+86
28
85213973.
E-mail
address:
zhixiang
yuan@yahoo.cn
(Z.-x.
Yuan).
1
Both
are
equal
contribution
to
this
work.
2009,
2011
),
glycosyl
compound
(Suzuki
et
al.,
1999a,b)
and
poly(vinylpyrrolidone-co-dimethyl
maleic
acid)
(PVD)
(Kamada
et
al.,
2003;
Kodaira
et
al.,
2004;
Yamamoto
et
al.,
2004).
However,
these
strategies
have
some
serious
shortcomings,
such
as
strong
renal
toxicity,
cardiovascular
side
effects
and
poor
biocompatibility
and
biodegradation
(Begona
and
Ruth,
1997;
Kamada
et
al.,
2003;
Okamoto
et
al.,
2004).
In
addition,
domestic
research
on
renal
tar-
geting
was
a
weak
link
of
drug
delivery
field
and
only
a
few
of
research
paper
about
renal
targeting
carrier
were
reported.
There-
fore,
these
problems
seriously
hamper
the
development
of
renal
delivery
system.
It
was
previously
demonstrated
that
low
molecular
weight
pro-
tein
(LMWP,
M
w
≤
3000
Da),
such
as
lysozyme,
Cytochrome
C
and
aprotinin,
could
significantly
accumulate
in
the
kidney
and
was
reabsorbed
by
the
proximal
tubular
cells
after
glomerular
filtration
(
Eric
et
al.,
1993;
Haverdings
and
Haas,
2002).
The
studies
showed
that
80%
of
the
intravenously
injected
LMWP
was
finally
uptaken
by
kidneys
(Zhang
et
al.,
2009;
Zheng
et
al.,
2006,
2007).
However,
lysozyme,
Cytochrome
C
and
aprotinin
might
cause
immunological
rejection
and
renal
toxicity,
with
effects
on
blood
pressure
as
well
(
Haverdings
et
al.,
2001).
Therefore,
the
problem
of
biocompatibil-
ity
has
not
been
solved
yet.
Human
serum
albumin
(HSA),
the
most
abundant
protein
in
blood
plasma,
has
many
important
physiological
functions
as
well
as
excellent
properties
such
as
biocompatibility,
non-toxicity
and
0378-5173/$
–
see
front
matter ©
2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ijpharm.2013.10.041