Nano Res
1
Multifunctional electrospinning composite fibers for
orthotopic cancer treatment in vivo
Yinyin Chen1,2, Shi Liu2, †, Zhiyao Hou1, Pingan Ma1, Dongmei Yang1,2, Chunxia Li 1 () and Jun
Lin1()
Nano Res., Just Accepted Manuscript • DOI: 10.1007/s12274-014-0701-y
http://www.thenanoresearch.com on December 23 2014
© Tsinghua University Press 2014
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Nano Research
DOI 10.1007/s12274-014-0701-y
Multifunctional Electrospinning Composite Fibers for
Orthotopic Cancer Treatment in Vivo
Multifunctional Electrospinning Composite Fibers for
Orthotopic Cancer Treatment in Vivo
Yinyin Chen1,2, Shi Liu2, , Zhiyao Hou1, Pingan Ma1,
Dongmei Yang1,2, Chunxia Li 1*, and Jun Lin1*
1State Key Laboratory of Rare Earth Resource
Utilization, Changchun Institute of Applied Chemistry,
Chinese Academy of Sciences, Changchun 130024, P. R.
China
2 University of the Chinese Academy of Sciences Beijing
100049, P.R. China
State Key Laboratory of Polymer Physics and Chemistry,
Changchun Institute of Applied Chemistry, Chinese
Academy of Sciences
A multifunctional dual drug carrier platform
DOX-NaGdF4:Yb/Er@NaGdF4:Yb@mSiO2-PEG@MC-PG was
successfully assembled via electrospinning process. The resultant
multifunctional spinning pieces can be implanted directly to the tumor
site of mice by surgical procedures to fulfill the orthotopic
chemotherapy by the controlled release of DOX from mesoporous
SiO2 and the upconversion fluorescence/magnetic resonance dual
model imaging through NaGdF4:Yb/Er@NaGdF4:Yb embedded in
MC/UCNPS/DOX in vivo.
Multifunctional Electrospinning Composite Fibers for
Orthotopic Cancer Treatment in Vivo
Yinyin Chen1,2, Shi Liu2, †, Zhiyao Hou1, Pingan Ma1, Dongmei Yang1,2, Chunxia Li 1 () and Jun Lin1()
Received: day month year
Revised: day month year
Accepted: day month year
(automatically inserted by
the publisher)
© Tsinghua University Press
and Springer-Verlag Berlin
Heidelberg 2014
KEYWORDS
Electrospinning
Orthotopic, Treatment,
Controlled Release,
Multiple Structure
ABSTRACT
A multifunctional dual drug carrier platform was successfully assembled. The
antitumor drug doxorubicin (DOX) loaded core-shell structured
NaGdF4:Yb/Er@NaGdF4:Yb@mSiO2-polyethylene glycol (abbreviated as UCNPS)
nanoparticles were incorporated into antiphlogistic drug indomethacin (MC)
loaded poly(ε-caprolactone) (PCL) and galatin to form nanofibrous fabrics (labeled
as MC/UCNPS/DOX) via electrospinning process. The resultant multifunctional
spinning pieces can be implanted directly to the tumor site of mice by surgical
procedures to fulfill the orthotopic chemotherapy by the controlled release of DOX
from mesoporous SiO2 and the upconversion fluorescence/magnetic resonance dual
model imaging through NaGdF4:Yb/Er@NaGdF4:Yb embedded in
MC/UCNPS/DOX in vivo.
1. Introduction
Both unresectable tumors for example hepatocellular
carcinoma and metastases cancer such as breast
cancer, renal carcinoma, lung cancer and so on
represent a major clinical problem owing to the poor
prognosis. There are about 50–80% of patients
experiencing recurrence by 5 years after resection,
partly resulting from invisible intrahepatic
Nano Research
DOI (automatically inserted by the publisher)
Review Article/Research Article Please choose one
Address correspondence to Jun Lin. [email protected]; Chunxia Li. [email protected]
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2 Nano Res.
metastases during resection [1]. For the treatment of
unresectable cancer or for the prevention of
post-surgery tumor recurrence, chemotherapy will be
a good choice. The nonspecific systematic
distribution of the antitumor drugs is one of the main
disadvantages of the conventional tumor
chemotherapy [2-4]. In this case, orthotopic treatment
is an inevitable and promising approach. Although
many targeting therapeutic strategies have been
developed, due to the difficulty to transport
effectively the chemotherapy drugs to the specific
location in the context of multiple in vivo
physiological barriers [5, 6], the management of
malignant cancers still remains clinical challenge.
Thus, it will be necessary to prolong blood
circulation of antitumor drug. Owing to the excellent
character of mesoporous SiO2, such as good
biocompatibility, large specific surface area, tunable
mesoporous structure, and facile surface
functionalization and so on, it has recently acted as a
potential anticancer therapy, from which the
prolonged drug release with tunable drug release
kinetics could be achieved. Moreover, mesoporous
SiO2 could enhance the dissolution of the poorly
water-soluble drugs and increase their bioavailability,
and mesoporous SiO2 with small sizes preferably
accumulate at tumor sites caused by the enhanced
permeability and retention (EPR) effect [7, 8].
Electrospinning is a cutting edge technology for
producing continuous polymer fibers that has
recently attracted attention in the field of drug
delivery [9, 10]. Owing to their unique characteristics
such as extremely high surface area and excellent
pore interconnectivity, electrospun polymeric fibers
are particularly attractive for carriers for a series of
drugs and even can be engineered to smart delivery
drug in a controlled fashion [11-16]. More importantly,
the electrospun fibers as a kind of implant materials
can be exploited to site-specific delivery of drugs to
the body as well as wound healing or surgery
treatment.
Molecular imaging techniques, such as magnetic
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3 Nano Res.
resonance imaging (MRI) [17, 18], X-ray computed
tomography (CT), upconvension fluorescence
microscopy [19-22], and positron emission tomography
(PET) play an important role in medicine and
biomedical research [23, 24]. The information obtained
from single modal molecular imaging cannot satisfy
the higher requirements on the efficiency and
accuracy for clinical diagnosis and medical research
[25, 26]. Thus, multimodality imaging will provide more
complementary, effective and accurate information
on the physical anatomical structure and the
physiological function for diagnosis and treatment.
Resulting from their special 4f electron structure and
rich optical-magnetic properties [27-29],
lanthanide-based nano-probes have attracted
increasing attention in multimodal molecular
imaging. In particular, due to the existence of seven
unpaired electrons in 4f orbit of Gd3+ ions,
upconversion nanoparticles containing Gd3+ ions can
exhibit fluorescent and magnetic properties.
Therefore, such nanoparticle can be regarded as a
multimodal imaging biological probe for
simultaneous UCL and MRI.
So in this work, we put forward a
multifunctional anticancer drug carrier platform, in
which antitumor drug doxorubicin (DOX) loaded
core-shell structured
NaGdF4:Yb/Er@NaGdF4:Yb@mSiO2-polyethylene
glycol (abbreviated as UCNPS) nanoparticles were
incorporated into antiphlogistic drug indomethacin
(MC) loaded poly(ε-caprolactone) (PCL) and galatin
to form nanofibrous fabrics (labeled as
MC/UCNPS/DOX) via electrospinning process. The
resultant multifunctional spinning pieces can be
implanted directly to the tumor site of mice by
surgical procedures to fulfill the orthotopic
chemotherapy by the controlled release of DOX from
mesoporous SiO2 and the upconversion
fluorescence/magnetic resonance dual model
imaging through NaGdF4:Yb/Er@NaGdF4:Yb
embedded in MC/UCNPS/DOX in vivo.
2. Materials and methods
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4 Nano Res.
2.1. Materials
The rare earth chloride RECl3·6H2O (99.99%, RE=Y,
Yb and Er), oleic acid (90%, technical grade),
Octadecene (90%, technical grade),
Poly(ε-caprolactone) (PCL, Mw = 70,000-90,000),
Indomethacin (MC, 99%), Gelatin (pharmaceutical
grade) and 2,2,2-Trifluorothanol (TFE, 99.8%,
molecular biology grade) were purchased from
Aldrich. 2-[methoxy-(polyethyleneoxy)
propyl]trimethoxysilane (PEG500-silane, Mw = 460-590,
tech-90) was purchased from Gelest. Doxorubicin
hydrochloride (DOX) was purchased from Nanjing
Duodian Chemical Limited Company (China). Other
reagents including cetyltrimethylammonium
bromide (CTAB, ≥99%), tetraethylorthosilicate
(TEOS), ammonium fluoride (NH4F), sodium
hydroxide (NaOH, ≥98%) and ammonium nitrate
(NH4NO3, ≥99.0%) were purchased from Beijing Yili
Fine Chemical Regent Company (China). All the
chemical reagents were used as received without
further purification.
2.2. Preparation of
NaGdF4:Yb/Er@NaGdF4:Yb@mSiO2-PEG
(UCNP@mSiO2-PEG) nanoparticles
The preparation of NaGdF4:Yb/Er@NaGdF4:Yb
(UCNP for short) nanocrystals [Gd:Yb:Er=80:18:2
(mol ratio) in core and Gd:Yb=80:20 (mol ratio) in
shell] followed by mesoporous silica coating and
PEG modification was carried out according to our
previous approach [30-32]. The as-obtained
nanomaterials were labeled as UCNP@mSiO2-PEG.
2.3. Fabrication of drug delivery systems
2.3.1. DOX-loaded UCNP@mSiO2-PEG nanoparticles
10 mg of UCNPS sample dispersing in 2 mL of water
was mixed with 2 mL of DOX aqueous solution (1
mg/mL). After stirred for 24 h under dark conditions,
the DOX-loaded sample was collected by
centrifugation and denoted as UCNPS/DOX. The
as-obtained nanomaterials were denoted as
DOX-UCNP@mSiO2-PEG. To evaluate the
DOX-loading efficiency, the residual DOX content
(RDOX) in the supernatant and washed solutions was
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5 Nano Res.
obtained by UV-Vis measurement at a wavelength of
480 nm [33]. UV-Vis measurement of DOX at a
wavelength of 480 nm was used to evaluate the
DOX-loading efficiency by formula: [(ODOX -
RDOX)/ODOX]×100%, in which ODOX and RDOX is the
original DOX content and the residual DOX content
in the supernatant, respectively. The loading capacity
of DOX is 10.5%. Then, UCNPS/DOX samples were
immersed in 2 mL pH = 7.4 and 6.2 phosphoric acidic
buffer solutions (PBS) at 37 °C with gentle shaking.
At predetermined time intervals, PBS was taken by
centrifugation and replaced with an equal volume of
fresh PBS. The amount of released DOX in the
supernatant solutions was measured by UV-Vis
spectrophotometer at a wavelength of 480 nm.
2.3.2. DOX-loaded composite fibers (CFs)
Gelatin and PCL were dissolved separately in 2.5 mL
transparent DOX-TFE solution (1 mg/mL) under
stirring. The mass ratio of Gelatin and PCL was 1:1.
When Gelatin and PCL dissolved completely in
DOX-TFE solution, Gelatin and PCL were mixed
isometricly together and continued to stir for 30 min
to obtain a homogeneous precursor sol for further
electrospinning. The parameters adjustment of the
spinning equipment was based on our previous
method [11, 12]. The distance between the spinneret (a
metallic needle) and collector (a grounded conductor)
was fixed at 10 cm and the high-voltage supply was
maintained at 10 kV. The spinning rate was
controlled at 1.0 mL/h by a syringe pump
(TJ-3A/W0109-1B, Baoding Longer Precision Pump
Co., Ltd, China). The DOX-PG (labeled as DOX) CFs
was fabricated, dried and stored at 4 oC for further
using. Then, the DOX release experiments from
DOX-UCNP@mSiO2-PEG samples were similar to the
above procedures.
2.3.3. UCNP@mSiO2-PEG-loaded CFs
Gelatin and PCL were each dissolved separately in
2.5 mL UCNP@mSiO2-PEG-TFE solution (4 mg/mL,
20 mg UCNP@mSiO2-PEG dissolving in 5 mL TFE)
under stirring condition. The mass ratio of Gelatin
and PCL was 1:1. When Gelatin and PCL dissolved
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6 Nano Res.
completely in UCNP@mSiO2-PEG-TFE solution,
Gelatin and PCL were mixed isometricly together
and continued to stir for 30 min to obtain a
homogeneous precursor sol for further
electrospinning. The rest procedures for
UCNP@mSiO2-PEG@PG (labeled as UCNPS) CFs are
similar to those of DOX-loaded CFs.
2.3.4. DOX-loaded UCNP@mSiO2-PEG single drug
delivery system CFs
The DOX-loaded progress of UCNP@mSiO2-PEG was
implemented according to our previous operational
approach [11, 12]. 20 mg of UCNP@mSiO2-PEG was
dispersed and sonicated in 3 mL of DOX-TFE
solution (1 mg/mL). After stirred for 24 h under dark
and sealed conditions, the DOX-UCNP@mSiO2-PEG
nanoparticles were collected by centrifugation. These
DOX-loaded nanoparticles were dispersed and
sonicated in 5 mL TFE solution for 1 min, and then
0.25 g of PCL and 0.25 g of gelatin were added to the
suspension with continuous stirring for 3 h to form
electrospun precursor solution. The as-obtained
nanomaterials were denoted as
DOX-UCNP@mSiO2-PEG. Then the
DOX-UCNP@mSiO2-PEG nanoparticles were
dispersed and sonicated in 5 mL TFE solution to
obtain DOX-UCNP@mSiO2-PEG-TEF solution and
then Gelatin and PCL were added to above
suspension isometricly and continued to stir for 3 h
to obtain a homogeneous precursor sol for further
electrospinning. The rest procedures for
(DOX-UCNP@mSiO2-PEG)@PG (labeled as
UCNPS/DOX) CFs are similar to those of
DOX-loaded CFs.
2.3.5. DOX and MC co-loaded UCNP@mSiO2-PEG
dual drugs delivery system CFs
The DOX-loaded progress of UCNP@mSiO2-PEG was
implemented according to our previous operational
approach [11, 12]. 20 mg of UCNP@mSiO2-PEG was
dispersed and sonicated in 3 mL of DOX-TFE
solution (1 mg/mL). After stirred for 24 h under dark
and sealed conditions, the DOX-UCNP@mSiO2-PEG
nanoparticles were collected by centrifugation. These
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7 Nano Res.
DOX-loaded nanoparticles were dispersed and
sonicated in 5 mL of MC-TFE solution (20 mg/mL, 20
mg MC dissolving in 1 mL TFE) for 1 min, and then
0.25 g of PCL and 0.25 g of gelatin were added to the
suspension with continuous stirring for 3 h to form
electrospun precursor solution. The as-obtained
nanomaterials were denoted as
DOX-UCNP@mSiO2-PEG. Then the
DOX-UCNP@mSiO2-PEG nanoparticles were
dispersed and sonicated in 5 mL of MC-TFE solution
(20 mg/mL, 20 mg MC dissolving in 1 mL TFE) to
obtain DOX-UCNP@mSiO2-PEG-TEF-MC solution
and then Gelatin and PCL were added to above
suspension isometricly and continued to stir for 3 h
to obtain a homogeneous precursor sol for further
electrospinning. The rest procedures for
(DOX-UCNP@mSiO2-PEG)@(MC-PG) (labeled as
MC/UCNPS/DOX) CFs are similar to those of
DOX-loaded CFs.
2.4. In vivo UCL imaging of composite fibers
Kunming mice were purchased from Changchun
Institute of Biological Products Co. Ltd and all
animal procedures were approved by the University
Animal Care and Use Committee. The tumors were
established by subcutaneous injection of mouse
hepatoma H22 cells as described previously [34].
Briefly, hepatoma H22 cells, kindly gifted by
Chemical biology laboratory of Changchun Institute
of Applied Chemistry Chinese Academy of Sciences
(Changchun, China), were suspended in
physiological saline and injected intraperitoneally
into the mice for serial subcultivation. The mice with
viable H22 ascites tumors were sacrificed, and the
ascites were withdrawn and diluted with
physiological saline to modulate the cell density at 1
×107 cells/mL. The ascites was injected
subcutaneously to each mouse at the left axilla at a
dose of around 0.01 mL/g body weight. The tumors
were allowed to grow for several days to reach the
size of around 200 mm3. MC/UCNPS/DOX CFs mat
(about 15000 mm2) of required sizes (60-100 mm2/mat,
8 pieces/mouse), flexibly resized according to the
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8 Nano Res.
diameter of tumor nodules, was directly pasted on
the surface of the tumor of the tumor-bearing mice.
After 0 h, 24 h and 96 h, the UCL imaging
experiments were conducted by exposing the tumor
to a continuous semiconductor laser with an output
wavelength of 980 nm (1.2 W) and capturing
fluorescent signal by a camera.
2.5. In vivo MR imaging of composite fibers
MC/UCNPS/DOX CFs mat (about 15000 mm2) of
required sizes (60-100 mm2/mat, 8 pieces/mouse),
flexibly resized according to the diameter of tumor
nodules, was directly pasted on the surface of the
tumor of the tumor-bearing mice. After 2 days, MR
imaging studies were conducted on a 1.2 T clinical
MRI scanner [Atlas tong nuclear magnetic, shanghai,
China] equipped with a special coil designed for
small animal imaging.
2.6. In vivo therapy of composite fibers on
subcutaneous tumor model with composite fibers
When the size of tumors reach around 200 mm3, the
tumor-bearing mice were randomly divided into
groups with 5 animals in each group (n = 5). Then
DOX CFs mat, UCNPS CFs mat, UCNPS/DOX CFs
and MC/UCNPS/DOX CFs mat (about 15000 mm2) of
required sizes (60-100 mm2/mat, 8 pieces/mouse),
flexibly resized according to the diameter of tumor
nodules, was directly pasted on the surface of the
tumor (n = 5). The control group was without
administration. The body weights, tumor volumes,
and survival rate of animals were monitored every
other day after treatment. The length of the major
axis (longest diameter) and minor axis
(perpendicular to the major axis) of the tumor were
measured with a vernier caliper, and the tumor
volume was calculated as described previously. The
diameter of tumor was measured and the tumor
volume was calculated as described previously [35].
After 17 days treatment, all animals of each group
were euthanized to retrieve tumors and organs.
During the entire experiments, only a mouse in
control group died. To get a picture, we choose 4
tumors to take a photo after euthanizing all mice of
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9 Nano Res.
each group. The excised tumors and organs were
washed by deionized water and then were fixed by
4% (weight) paraformaldehyde solution. The tissues
were processed routinely, and sections were stained
with H&E [34]. Blood of experimental group and
control group was collected based on our previous
method. The collected blood samples were sended
for blood chemistry tests and complete blood panel
analysis [36].
2.7. MC in MC/UCNPS/DOX CFs helps to heal the
wounds
The tumors were allowed to grow for several days to
reach the size of around 200 mm3. 9 mice were
randomly divided into three groups. Then
UCNPS/DOX CFs and MC/UCNPS/DOX CFs mat
(about 15000 mm2) of required sizes (60-100 mm2/mat,
8 pieces/mouse,1 mg MC), were directly pasted on
the surface of the tumor (n = 3). Then the incision was
sutured. After 4 h, the blood of two animals in each
group was collected for blood routine examination.
And the remaining mice was kept growing in order
to observe their incision healing.
2.8. Biodistribution and release of drug in vivo
The tumors were allowed to grow for several days to
reach the size of around 200 mm3.The tumor-bearing
30 female Kunming mice in a weight range of 20-25 g
(8-12 weeks old) were divided into 10 groups with 3
mice in per group. These mice were used for the
study of drug release profile and the biodistribution
of MC/UCNPS/DOX CFs in vivo. MC/UCNPS/DOX
CFs mat (about 15000 mm2) of required sizes (60-100
mm2/mat, 8 pieces/mouse), flexibly resized according
to the diameter of tumor nodules were directly
pasted on the tumor. The animals were sacrificed at
0.5 h, 2 h, 8 h, 12 h, 24 h and 2, 3, 5, 7 days after
fiber-mat implantation and samples of tumor, liver,
kidneys, spleen lungs, and heart were harvested after
the remaining spinning pieces were removed by
surgical operation. The excised tissues and organs
were imaged by fluorescent imaging system (CRI
Maestro 500 FL) to follow the release of DOX from
the fiber-mat and its biodistribution in mice. Fixed
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10 Nano Res.
exposure time was adopted at all time points.
Semi-quantitative comparison between different
organs and different time intervals was also made by
means of commercial software (MaestroTM2.4).
2.9. Biodistribution measurement
The tumor-bearing 24 female Kunming mice in a
weight range of 20-25 g (8-12 weeks old) were
divided into 8 groups with 3 mice in per group.
These mice were implanted with MC/UCNPS/DOX
CFs mats. Then, the mice were sacrificed at 0 h, 0.5 h,
2 h, 8 h, 12 h, 24 h, 2 days and 7 days. Major organs
and tissues (tumor, heart, liver, spleen, lung, kidney)
were excised and collected after the remaining
spinning pieces were removed by surgical operation.
The excised organs and tissues wet weighed and
dissolved in digesting solutions (HNO3:H2O2 = 1:2 by
volume) [37]. The samples were heated at 70 oC for 4 h.
After cooling down to room temperature, the volume
of each sample solution was measured and
subsequently analyzed by ICP-AES to determine the
total amount of Gd3+ in each measured tissue. Three
animals per group were used in the biodistribution
measurement.
3. Results and discussion
3.1. Fabrication and characterization of the
materials
The working principle of our strategy is shown in
Scheme 1. Firstly, antitumor drug DOX delivery
carrier UCNP@mSiO2-PEG nanospheres were
fabricated according to a phase transfer assisted
surfactant-templating coating process reported
recently by us [30-32]. Subsequently, the as-obtained
DOX-UCNP@mSiO2-PEG were mixed with
electrospinning solution including PCL-gelatin (PG)
and anti-inflammatory MC so as to form dual
drugs-loaded multiple structure composite fibers
(DOX-NaGdF4:Yb/Er@NaGdF4:Yb@mSiO2-PEG)@(M
C-PG) (labeled as MC/UCNPS/DOX) via
electrospinning technique. The resultant
MC/UCNPS/DOX spinning piece can be implanted
directly to the tumor site of mice by surgical
procedures to fulfill the orthotopic efficient
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11 Nano Res.
chemotherapy by the controlled release of DOX from
mesoporous SiO2 and the upconversion
fluorescence/magnetic resonance dual model
imaging through NaGdF4:Yb/Er@NaGdF4:Yb
embedded in MC/UCNPS/DOX in vivo.
Fig. 1 shows the morphology of the
nanoparticles at the different synthesis stages. The
typical TEM image (Fig. 1(a)) indicates that
cetyltrimethylammonium bromide (CTAB)-stabilized
NaGdF4:Yb/Er@NaGdF4:Yb nanoparticles (labeled as
UCNP) in aqueous solution has uniform shape with
mean diameter of 25 nm. The high-resolution TEM
image has revealed the obvious crystal lattices with
interplanar distance of 0.30 nm (Fig. 1(b)), which can
be assigned to (110) plane of β-NaGdF4. After
mesoporous silica coating and PEG modification, the
as-obtained UCNP@mSiO2-PEG takes on obvious
core-shell structured morphology. Namely, the
mesoporous silica shell was coated on the surface of
single UCNP core in one-in-one fashion. The size of
UCNP@mSiO2-PEG nanospheres is about 86 nm. The
N2 adsorption/desorption isotherm and pore-size
distribution (Fig. S1, Supporting Information) of
UCNP@mSiO2-PEG indicates the mesoporous nature
of the materials, which is suitable for the loading of
drug molecules. Upon excitation with 980 nm
near-infrared laser, the resultant emission bands at
521 nm, 542 nm, and 652 nm can be ascribed to
2H11/2→4I15/2, 4S3/2→4I15/2, and 4F9/2→4I15/2 transitions of
activator Er3+ ions, respectively (Fig. 1(d)) [38].
In the subsequent preparation for
electrospinning composite fibers, PCL-gelatin (PG)
was chosen to modulate the viscoelasticity of the
precursor for electrospinning because PCL and
gelatin (PG) are recognized as safe and
biodegradable by the US FDA (Food and Drug
Administration) and CE (Conformit Europe) [39-41].
Furthermore, PG fibrous scaffold has promising
candidates in the fields of drug delivery and tissue
engineering [42-44]. In our current study, DOX-loaded
UCNP@mSiO2-PEG was encapsulated into PG
composite fibers including the other antiphlogistic
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12 Nano Res.
drug MC to form novel dual drugs carrier
MC/UCNPS/DOX. Fig. 2 has illustrated the shape of
the resultant MC/UCNPS/DOX composite fibers
(CFs). From Fig. 2(a), one can see that an enormous
amount of fibers can be clearly observed. The length
of fibers ranges from several tens to hundred
micrometers while the diameter is about 0.4-0.6 μm.
The TEM image (Fig. 2(b)) presents that the
DOX-UCNP@mSiO2-PEG spherical nanoparticles are
evenly distributed within the PG composite fibers.
Additionally, in order to carry out the contrast
experiments, the spinning pieces of pure drug DOX
CFs, pure materials UCNPS CFs, single drug-loaded
UCNPS/DOX CFs and dual drugs-loaded
MC/UCNPS/DOX CFs can be obtained under
appropriate electrospun conditions, respectively, as
shown in Fig. 2(c). From Fig. 2(c), it can be seen that
all kinds of the spinning pieces have flat surface and
uniform thickness.
3.2. DOX release properties of all kinds of CFs in
vitro
To examine the drug release properties of all kinds of
CFs, we comparatively have investigated their
release behaviors of an anti-cancer drug DOX.
Cumulative DOX release from
DOX-UCNP@mSiO2-PEG, DOX CFs, UCNPS/DOX
CFs and MC/UCNPS/DOX CFs at PBS buffer with
different pH is shown in Fig. 3. At pH 7.4, all samples
show similar release profile with lower DOX release
amount of only 7.5% (Fig. 3(a)). However, the DOX
release at pH 6.2 displays the fast rate in initial 4 h
and then a slow and continuous release in
DOX-UCNP@mSiO2-PEG, UCNPS/DOX CFs, and
MC/UCNPS/DOX CFs (Fig. 3(b)). This pH-responsive
DOX release profile can be explained as follows. The
lower pH value made surface zeta-potential of the
SiO2 layer more positive, which attenuated
electrostatic interaction between SiO2 and DOX
molecules with positive charges, leading to the faster
DOX release from carrier [45]. On the other hand, the
cumulative drug release behaviors for the
UCNPS/DOX CFs, MC/UCNPS/DOX CFs are
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13 Nano Res.
different from those of DOX-UCNP@mSiO2-PEG and
DOX CFs. Additionally, from Fig. 3(b), the release
behaviors of DOX from DOX-UCNP@mSiO2-PEG
nanoparticles and DOX CFs both have presented a
burst release. The DOX cumulative release amount is
48% for DOX-UCNP@mSiO2-PEG nanoparticles and
37% for DOX CFs within 12 h, then the drug release
reaches to a plateau after 24 h. In contrast, the DOX
in the UCNPS/DOX and MC/UCNPS/DOX CFs has
shown a persistent and long-term release behavior,
with a cumulative release amount of DOX up to
about 20% within 12 h and 34% after 128 h.
Compared with the burst release of
DOX-UCNP@mSiO2-PEG and DOX CFs, the
sustained releasing can last for more than 120 h. The
reasons for the starting burst release in UCNPS/DOX
and MC/UCNPS/DOX CFs can come down to both
the free distribution of DOX outside of
UCNP@mSiO2-PEG and the swelling of PG in fiber
matrices. Then the afterward process of sustained
releasing can attributed to the fact that in the
presence of UCNP@mSiO2-PEG a great majority of
DOX was encapsulated in the mesopores of SiO2. In
this situation, the DOX release has to traverse the two
barriers of both mesoporous SiO2 and PG. So the
DOX release from UCNPS/DOX and
MC/UCNPS/DOX CFs presented a persistent and
long-range behavior at pH 6.2 with a sluggish
releasing after 128 h. To sum up, this ingenious
architecture design of dual-drugs delivery system
can solve effectively the problem of drug burst
release to some extent in our previous systems [30-32].
3.3. The releases properties of MC and DOX in
MC/UCNPS/DOX CFs
To find out whether the DOX-UCNP@mSiO2-PEG
influenced the release of another drug MC in CFs, the
MC releasing behaviors of only MC loaded CFs
(labeled as MC) and MC/UCNPS/DOX CFs were
measured. The result is displayed in Fig. 4. Owning
to the random distribution of MC in the fiber
matrices, the MC in both MC CFs and
MC/UCNPS/DOX CFs has displayed a burst release
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14 Nano Res.
behavior in the starting 15 h. The cumulative release
amounts of MC after 64 h are about 62% and 57%,
respectively. The above outcomes suggest that
DOX-UCNP@mSiO2-PEG in the PG CFs has no
obvious effect on the release of MC. On the contrary,
the presence of MC also has little impact on the
release of DOX in the dual drugs delivery system
MC/UCNPS/DOX CFs comparing with single DOX
loaded UCNPS/DOX CFs (Fig. 3(b)). In other words,
the release behaviors of two drugs DOX and MC are
non-interfering. In this way, their respective
advantages can be very well displayed in tumor
therapy, which is very important for boosting the
sit-specific therapeutic efficacy and wound healing.
3.4. Up-conversion luminescence (UCL) and
magnetic resonance (MR) imaging effect of
MC/UCNPS/DOX CFs in vivo
The UCNP core in composite material endows it with
concurrent up-conversion luminescence and
magnetic properties, so we evaluate the application
of MC/UCNPS/DOX CFs in UCL/MRI dual modal
imaging in vivo. The MC/UCNPS/DOX CFs were
pasted on the surface of the tumor of the
tumor-bearing mice. The diffusion of nanoparticles
inside the tumor was monitored by the change of
upconversion luminescence in vivo. As shown in
Figure 5(b), the tumor site covered by
MC/UCNPS/DOX CFs has displayed red emission at
0 h, pink emission at 24 h and white-green emission
at 96 h under 980 nm laser excitation, respectively.
The above phenomenon can be explained as follows.
Since the UC emission bands in the green region
overlap with the broad absorbance of DOX centered
at about 480 nm, leading to occurrence of energy
transfer from UCNP to DOX. As such, the green
fluorescent of UCNPS in MC/UCNPS/DOX CFs was
quenched after loading DOX, and red emission was
obtained after the spinning piece was pasted on
tumor site. Subsequently, owing to the gradually
release of DOX from MC/UCNPS/DOX CFs with
extended time, the energy transfer from UCNP to
DOX has become weaker and weaker, which leads
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15 Nano Res.
directly to the change of luminescence color (Figure
5(b)).Thus, the green emission becomes stronger,
which is quite consistent to the change of the
spectrum in Fig. S2. (Supporting Information). This
outcome suggests that MC/UCNPS/DOX CFs can act
as a UCL imaging agent in vivo to monitor DOX
releasing. From the relaxation rate (Fig. 5(c)) R1
(1.80304) (1/T1) versus different mass concentrations
of UCNPS in MC/UCNPS/DOX CFs pieces at room
temperature and the obvious lighting effect (Fig. 5(d))
in the tumor, it can be demonstrated that the
composite materials can be used as a T1-weighted MR
contrast agent in vivo because of the presence of
paramagnetic Gd3+ ions. This signal is probably
because some of UCNPS have entered tumor tissue
underneath the fiber-piece by diffusion mechanism.
The multimodal UCL/MR imaging combines the
advantages of enhanced sensitivity of luminescence
imaging, and high spatial resolution of MR imaging,
which is paramount for real-time monitoring the
evolution of disease [46, 47].
3.5. In vivo antitumor efficacy of CFs
In our current study, a series of experiments were
conducted in order to verify the capability of
inhibiting tumor of MC/UCNPS/DOX CFs. In this
experiment, the control group received no further
treatment and other four groups were treated with
DOX CFs, UCNPS CFs, UCNPS/DOX CFs and
MC/UCNPS/DOX CFs, respectively. In our
experiments, it is found that the heavier mice with
similar tumor volume will grow much healthier in
the same group. The mice in control group without
any treatment will become unhealthier and are
more likely to die than those of treatment groups. In
this case, the heavier mice will be selected as control
group to make sure that they are live until the end
of the experiment. During the entire experiments,
only a mouse in control group died and other mice
appeared lively without the signs of decreased
activity. Fig. 6 has illustrated the antitumor efficacy
of CFs in vivo. From the photograph of tumors of
each group in Fig. 6(a), one can see that the tumor
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16 Nano Res.
sizes of MC/UCNPS/DOX group are smallest
among five groups. An even more important
finding is that the tumor of a mouse in
MC/UCNPS/DOX-treated group completely
disappeared at the end of experiment, as indicated
by the black circle. On the last day of experiment,
all of mice were executed. To assess the tumor sizes
and inhibition rates, the tumors were excised from
these mice and weighted. The mean tumor
inhibition (Fig. 6(b)) is about 96% for
MC/UCNPS/DOX CFs group and 95% for
UCNPS/DOX CFs group relative to the control
group, respectively, which is much higher than that
of pure DOX (61.8%) and our previous systems [34].
The enhanced tumor inhibition of the
MC/UCNPS/DOX CFs can be elucidated from two
aspects. On one hand, it is related to the sustained
DOX release from UCNP@mSiO2-PEG and as well
as the accumulation of DOX in the intratumor once
implanted administration. On the other hand, it
should be credited to the anti-inflammatory drug
MC in MC/UCNPS/DOX CFs which can suppress
the inflammatory efficacy of the wound after the
surgery. As can be seen from the representative
pictures of mice in Fig. 6(c), the wound in
MC/UCNPS/DOX group has been completely
healed while the wound for mice in other group has
become inflamed after the surgery. The weight of
all mice is growing stably with the time extension,
as shown in Fig. 6(d). However, the tumors in the
control, UCNPS and DOX groups keep growing
while MC/UCNPS/DOX and MC/UCNPS groups
show the dramatic inhibition of the tumor growth
(Fig. 6(e)).
Although UCNPS/DOX CFs and
MC/UCNPS/DOX CFs groups have displayed
comparable antitumor efficacy, the cure rate of the
wound is different after surgery procedures. The
wounds of 3 out of 5 mice are healed in
MC/UCNPS/DOX CFs group, however, the wound
of only 1 mouse is healed and the wounds of other 4
mice are suppurative and inflamed in UCNPS/DOX
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17 Nano Res.
CFs group. The unique role of anti-inflammatory
effect of MC is presented in Fig. 7. The routine
blood test has displayed that MC in
MC/UCNPS/DOX CFs can inhibit a surge of white
blood cell count (WBC) in quantity compared with
the UCNPS/DOX CFs group (Fig. 7(a)). Moreover,
from Fig. 7(b), one can also find that the wound of
the mouse in MC/UCNPS/DOX CFs group is in
better condition in contrast to that in UCNPS/DOX
CFs group with redness and inflammation after 5
days of the wound suture surgery. The above
results show that the MC in MC/UCNPS/DOX CFs
has significant effect on inhibiting inflammation of
wound after surgery. Thus this kind of dual drugs
delivery system will be perfectly fit for local
diagnosis and treatment, especially for those
patients receiving complete tumor resection or
cytoreductive surgery.
3.6. Toxicity assessment of UCNPS CFs, DOX CFs,
UCNPS/DOX CFs and MC/UCNPS/DOX CFs
The analysis results of gross anatomy and
pathomorphology examinations have suggested that
all of the organs, including heart, spleen, liver, and
kidney are health with no visible inflammation,
necrosis or lesion after the treatment of UCNPS CFs,
DOX CFs, UCNPS/DOX CFs and MC/UCNPS/DOX
CFs. The above result indicates that the CFs as drug
carrier have excellent in vivo biocompatibility. We
also test potential toxic of the CFs on the treated mice
by biochemical and hematological analyses of blood.
The result is displayed in Fig. 8. Different organs
function signals indicate that the functions of the
liver, spleen, kidneys, and heart are quite normal.
This is possibly because the great majority of UCNPS
is concentrated underneath the fiber-piece. The
reason is probably that UCNPS is too big to traverse
the histocyte to circulatory system. So, the UCNPS
concentration in other organs is quite low and not
enough to induce adverse effects. This implies that
the composite fibers can be served as an implant
material for effective treatment of intratumors while
minimizing side effects.
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18 Nano Res.
3.7. Biodistribution and release of drug in vivo
In order to research biodistribution of
MC/UCNPS/DOX CFs in vivo, the mice after pasting
MC/UCNPS/DOX fiber-pieces on the tumor were
sacrificed at different time intervals. Then the tumor
and major organs were collected and imaged by the
Maestro system. As shown in Fig. 9, ex vivo DOX
images of various organs have displayed high drug
accumulations in the tumor while weak signal is
observed in liver and kidney. Moreover, with the
extension of time, DOX fluorescence in the tumor
increases gradually and then decreases after 24 h. It is
because the great majority of DOX is concentrated
underneath the fiber-piece within the first 24 h, and
afterwards a part of DOX enters some organs
especially liver and kidney by blood circulation.
Since the DOX concentration in other organs is quite
low and not enough to induce adverse effects. These
findings indicate that the strategy for local
chemotherapy by implanting directly inside the solid
tumors provides alternative means for a safe,
efficient, and convenient chemotherapy. This style of
treatment can enhance the specificity of the drug
delivery, reduce the damage of the drugs to healthy
tissues and maximize the drug concentration at the
tumor site, leading to a greater inhibitory effect on
tumor growth.
3.8. Distribution of metabolic of
UCNP@mSiO2-PEG in MC/UCNPS/DOX CFs
To understand the biodistribution of
UCNP@mSiO2-PEG nanoparticles in CFs in vivo,
Kunming mice implanted with MC/UCNPS/DOX
were sacrificed at different time intervals. Then
tumors and principle organs were collected and
solubilized with HNO3 and H2O2 after the remaining
spinning pieces were removed by surgical operation.
From Gd3+ concentrations (Fig. 10) determined by
ICP-AES technique, it can be clearly seen that the
majority of UCNP@mSiO2-PEG nanoparticles are
concentrated at the tumor even after 7 days. The Gd3+
contents of organs nearly have kept unchanged. This
suggests that the UCNP nanoparticle embedded in
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19 Nano Res.
MC/UCNPS/DOX CFs almost can’t enter the
circulatory system. This is different from the
behavior of DOX biodistribution in Fig. 9, in which a
part of DOX enters some organs especially liver and
kidney by blood circulation. This is probablely
because the small molecule DOX can be much easy to
escape from the electrospinning composite
fiber-pieces by slowly swelled and broken in ambient
conditions and enter blood circulatory system [48, 49].
But Gd3+ contained in UCNP@mSiO2-PEG
nanoparticles is possiblely too big to traverse the
histocyte to circulatory system. The above result has
proved that concentration of UCNP@mSiO2-PEG is
quite low in organs and not enough to induce
adverse effects.
4. Conclusion
Electrospun upconversion composite fibers dual
drugs delivery system was successfully assembled.
DOX-loaded
NaGdF4:Yb/Er@NaGdF4:Yb@mSiO2-polyethylene
glycol nanoparticles were incorporated into
antiphlogistic drug MC loaded poly(ε-caprolactone)
(PCL) and galatin to form MC/UCNPS/DOX CFs by
electrospinning. The resultant multifunctional
spinning pieces can be implanted directly to the
tumor site of mice by surgical procedures to fulfill
the orthotopic chemotherapy by the controlled
release of DOX from mesoporous SiO2 and the
upconversion fluorescence/magnetic resonance
dual model imaging through
NaGdF4:Yb/Er@NaGdF4:Yb embedded in
MC/UCNPS/DOX in vivo. What’s more, the MC in
MC/UCNPS/DOX CFs can suppress the
inflammatory responses, which helped to heal the
wounds in vivo. These results provide an
encouraging prospect of using drug loaded
electrospun nanofibers in orthotopic diagnosis and
treatment combined with presently employed
treatment protocols, especially for those patients
suffering from unresectable tumors or metastases
cancer.
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20 Nano Res.
Acknowledgements
This project is financially supported by the National
Natural Science Foundation of China (NSFC
51332008, 51372243, 51422209), National Basic
Research Program of China ( 2014CB643803).
Supporting Information Available: N2
adsorption–desorption isotherms and mesopore size
distribution (the inset) of UCNP@mSiO2-PEG
nanocomposite (Fig. S1) UC emission spectra of
MC/UCNPS CFs and MC/UCNPS/DOX CFs under
980 nm laser excitation (Fig. S2). These material is
available free of charge via the Internet at
http://dx.doi.org.
References
[1] Cha, C. H.; Saif, M. W.; Yamane, B. H. Hepatocellular
carcinoma: current management. Curr Probl Surg. 2010, 47,
10-67.
[2] Toshkovaa, R.; Manolovab, N.; Gardevaa, E.; Ignatovab, M.;
Yossifovaa, L.; Rashkovb, I. Antitumor actinity of
quaternized chitosan-based electrospun implants against
graffi myeloid tumor. Int. J. Pharm. 2010, 400, 221-233.
[3] Yang, J. Stimuli-responsive drug delivery systems. Adv. Drug
Delivery Rev. 2012, 64, 965-966.
[4] Mura, S.; Nicolas, J.; Couvreur, P. Stimuli-responsive
nanocarriers for drug delivery. Nat. Mater. 2013, 12,
991-1003.
[5] Zhang, Y.; Qian, J.; Wang, D.; Wang, Y. L.; He, S. L.
Multifunctional gold nanorods with ultrahigh stability and
tunability for in vivo fluorescence imaging, SERS detection,
and photodynamic therapy. Angew. Chem. Int. Ed. 2013, 52,
1148-1151.
[6] Barreto, J. A. O.; Malley, W.; Kubeil, M.; Graham, B.;
Stephan, H.; Spiccia, L. Nanomaterials: applications in
cancer imaging and therapy. Adv. Mater. 2011, 23, 18-40.
[7] Yu, M. H.; Jambhrunkar, S.; Thorn, P.; Chen, J.; Gu, W.; Yu,
C. Hyaluronic acid modified mesoporous silica
nanoparticles for targeted drug delivery to
CD44-overexpressing cancer cells. Nanoscale 2013, 5,
178-183.
[8] Hoffman, A. S. The origins and evolution of "controlled"
drug delivery systems. J. Controlled Release 2008, 132,
153-163.
[9] Reneker, D. H.; Chun, I. Nanometre diameter fibres of
www.theNanoResearch.com∣www.Springer.com/journal/12274 | Nano Research
21 Nano Res.
polymer, produced by electrospinning. Nanotechnology 1996,
7, 216-223.
[10] Charernsriwilaiwat, N.; Opanasopit, P.; Rojanarata, T.;
Ngawhirunpat, T. Lysozyme-loaded, electrospun
chitosan-based nanofiber mats for wound healing. Int. J.
Pharm. 2012, 427, 379-384.
[11] Hou, Z. Y.; Li, X. J.; Li, C. X.; Dai, Y. L.; Ma, P. A.;
Zhang, X. Electrospun upconversion composite fibers as
dual drugs delivery system with individual release
properties. Langmuir 2013, 29, 9473-9482.
[12] Hou, Z. Y.; Li, C. X.; Ma, P. A.; Cheng, Z. Y.; Li, X. J.;
Zhang, X. Up-conversion luminescent and porous
NaYF4:Yb3+, Er3+@SiO2 nanocomposite fibers for
anti-cancer drug delivery and cell imaging. Adv. Funct.
Mater. 2012, 22, 2713-2722.
[13] Kenawy, E. R.; Bowlin, G. L.; Mansfield, K.; Layman, J.;
Simpson, D. G.; Sanders, E. H. Release of tetracycline
hydrochloride from electrospun
poly(ethylene-co-vinylacetate), poly(lactic acid), and a
blend. J. Controlled Release 2002, 81, 57-64.
[14] Luu, Y. K.; Kim, K.; Hsiao, B. S.; Chu, B. Development of
a nanostructured DNA delivery scaffold via
electrospinning of PLGA and PLA-PEG block copolymers.
J. Controlled Release 2003, 89, 341-353.
[15] Huang, C. B.; Soenen, S. J.; van Gulck, E.; Vanham, G.;
Rejman, J.; van Calenbergh, S. Electrospun cellulose acetate
phthalate fibers for semen induced anti-HIV vaginal drug
delivery. Biomaterials 2012, 33, 962-969.
[16] Wang, P.; Wang, Y. P.; Li, M. Functionalized polymer
nanofibers: a versatile platform for manipulating light at the
nanoscale. Light: Sci. Appl. 2013, 2, e102.
[17] Kuo, T. ; Lai, W. ; Li, C. ; Wun, Y. ; Chang, H. ; Chen, J. ;
Yang, P. ; Chen, C. AS1411 aptamer-conjugated Gd2O3:Eu
nanoparticles for target-specific computed
tomography/magnetic resonance/fluorescence molecular
imaging. Nano Res. 2014, 7, 658-669.
[18] Ju, Q.; Tu, D. T.; Liu, Y. S.; Li, R. F.; Zhu, H. M.; Chen, J.
C.; Chen, Z.; Huang, M. D.; Chen, X. Y.
Amine-functionalized lanthanide-doped KGdF4 nanocrystals
as potential optical/magnetic multimodal bioprobes. J. Am.
Chem. Soc. 2012, 134, 1323-1330.
[19] Liu, Y. S. ; Tu, D. T. ; Zhu, H. M. ; Li, R. F. ; Luo, W. Q. ;
| www.editorialmanager.com/nare/default.asp
22 Nano Res.
Chen, X. Y. A strategy to achieve efficient dual-mode
luminescence of Eu3+ in lanthanides doped Multifunctional
NaGdF4 nanocrystals. Adv. Mater. 2010, 22, 3266-3271.
[20] Fang, S. ; Wang, C. ; Xiang, J. ; Cheng, L. ; Song, X. J. ; Xu,
L. G. ; Peng, R. ; Liu, Z. Aptamer-conjugated upconversion
nanoprobes assisted by magnetic separation for effective
isolation and sensitive detection of circulating tumor cells.
Nano Res. 2014, 7, 1327-1336.
[21] Tu, D. T. ; Liu, L. Q. ; Ju, Q. ; Liu, Y. S. ; Zhu, H. M. ; Li, R.
F. ; Chen, X. Y. Time-resolved FRET biosensor based on
amine-functionalized lanthanide-doped NaYF4 nanocrystals.
Angew. Chem. Int. Ed. 2011, 50, 6306-6310.
[22] Tu, D. T.; Zheng, W.; Liu, Y. S.; Zhu, H. M.; Chen, X. Y.
Luminescent biodetection based on lanthanide-doped
inorganic nanoprobes. Coord. Chem. Rev. 2014, 273-274,
13-29.
[23] Liu, J. N.; Bu, J. W.; Bu, W.; Zhang, S. J.; Pan, L. M.; Fan,
W. P. Real-time in vivo quantitative monitoring of drug
release by dual-mode magnetic resonance and upconverted
luminescence imaging. Angew. Chem. Int. Ed. 2014, 53,
4551-4555.
[24] Zhou, J.; Liu, Z.; Li, F. Y. Upconversion nanophosphors for
small-animal imaging. Chem. Soc. Rev. 2012, 41, 1323-49.
[25] Louie, A. Y. Multimodality imaging probes: design and
challenges. Chem. Rev. 2010, 110, 3146-3195.
[26] Wang, C.; Cheng, L.; Liu Z. Upconversion nanoparticles for
photodynamic therapy and other cancer therapeutics.
Theranostics 2013, 3, 317-330.
[27] Shan, G. B.; Weissleder, R.; Hilderbrand, S. A.
Upconverting organic dye doped core-shell
nano-composites for dual-modality NIR imaging and
photo-thermal therapy. Theranostics 2013, 3, 267-274.
[28] Li, X. M.; Zhao, D. Y.; Zhang, F. Multifunctional
upconversion-magnetic hybrid nanostructured materials:
synthesis and bioapplications. Theranostics 2013, 3,
292-305.
[29] Debasu, M. L.; Ananias, D.; Pastoriza-Santos, I.;
Liz-Marzan, L. M.; Rocha, J.; Carlos, L. D. All-In-One
Optical Heater-Thermometer Nanoplatform Operative
From 300 to 2000 K Based on Er3+ Emission and
Blackbody Radiation. Adv. Mater. 2013, 25, 4868-4874.
[30] Li, C. X.; Hou, Z. Y.; Dai, Y. L.; Yang, D. M.; Cheng, Z. Y.;
www.theNanoResearch.com∣www.Springer.com/journal/12274 | Nano Research
23 Nano Res.
Ma, P. A. A facile fabrication of upconversion luminescent
and mesoporous core–shell structured β-NaYF4:Yb3+,
Er3+@mSiO2 nanocomposite spheres for anti-cancer drug
delivery and cell imaging. Biomater. Sci. 2013, 1, 213-223.
[31] Li, C. X.; Yang, D. M.; Ma, P. A.; Chen, Y. Y.; Wu, Y.; Hou,
Z. Y. Multifunctional upconversion mesoporous silica
nanostructures for dual modal imaging and in vivo drug
delivery. Small 2013, 9, 4150-4159.
[32] Zhang, X.; Yang, P. P.; Dai, Y. L.; Ma, P. A.; Li, X. J.; Cheng,
Z. Y. Multifunctional up-converting nanocomposites with
smart polymer brushes gated mesopores for cell imaging
and thermo/pH dual-responsive drug controlled release. Adv.
Funct. Mater. 2013, 23, 4067-4078.
[33] Janes, K. A.; Fresneau, M. P.; Marazuela, A.; Fabra, A.;
Alonso, M. J. Chitosan nanoparticles as delivery systems for
doxorubicin. J. Controlled Release 2001, 73, 255-267.
[34] Chen, Y. Y.; Ma, P. A.; Yang, D. M.; Wu, Y.; Dai, Y. L.; Li, C.
X. Multifunctional core–shell structured nanocarriers for
synchronous tumor diagnosis and treatment in vivo. Chem.
Asian J. 2014, 9, 506-513.
[35] Luo, X. M.; Xie, C. Y.; Wang, H.; Liu, C.; Yan, S.; Li, X.
Antitumor activities of emulsion electrospun fibers with core
loading of hydroxycamptothecin via intratumoral
implantation. Int. J. Pharm. 2012, 425, 19-28.
[36] Cheng, L.; Yang, K.; Shao, M. W.; Lu, X.; Liu, Z. In vivo
pharmacokinetics, long-term biodistribution and
toxicology study of functionalized upconversion
nanoparticles in mice. Nanomedicine 2011, 6, 1327-1340.
[37] Xiong, L.; Yang, T.; Yang, Y.; Xu, C.; Li, F. Long-term in
vivo biodistribution imaging and toxicity of polyacrylic
acid-coated upconversion nanophosphors. Biomaterials
2010, 31, 7078-7085.
[38] Wang, G. F.; Peng, Q.; Li, Y. D. Lanthanide-doped
nanocrystals: synthesis, optical-magnetic properties, and
applications. Acc. Chem. Res. 2011, 44, 322-332.
[39] Meek, M. F.; Coert, J. H. US food and drug administration
/conformit europe-approved absorbable nerve conduits for
clinical repair of peripheral and cranial nerves. Ann. Plast.
Surg. 2008, 60, 466-472.
[40] Kai, D.; Prabhakaran,M. P.; Stahl, B.; Eblenkamp, M.;
Wintermantel, E.; Ramakrishna, S. Mechanical properties
and in vitro behavior of nanofiber-hydrogel composites for
| www.editorialmanager.com/nare/default.asp
24 Nano Res.
tissue engineering applications. Nanotechnology 2012, 23,
095705.
[41] Hong, Y.; Huber, A.; Takanari, K.; Amoroso, N. J.;
Hashizume, R.; Badylak, S. F.; Wagner, W. R. Mechanical
properties and in vivo behavior of a biodegradable synthetic
polymer microfiber-extracellular matrix hydrogel biohybrid
scaffold. Biomaterials 2011, 32, 3387-3394.
[42] Chong, E. J.; Phan, T. T.; Lim, I. J.; Zhang, Y. Z.; Bay, B.
H.; Ramakrishna, S. Evaluation of electrospun
PCL/Gelatin nanofibrous scaffold for wound healing and
layered dermal reconstitution. Acta Biomater. 2007, 3,
321-330.
[43] Ghasemi-Mobarakeh, L.; Prabhakaran, M. P.; Morshed, M.;
Ramakrishna, S. Electrospun
poly(epsilon-caprolactone)/gelatin nanofibrous scaffolds
for nerve tissue engineering. Biomaterials 2008, 29,
4532-4539.
[44] Gautam, S.; Chou, C. F.; Dinda, A. K.; Potdar, P. D.;
Mishra, N. C. Fabrication and characterization of
PCL/Gelatin/Chitosan ternarynanofibrous composite
scaffold for tissue engineering applications. J. Mater. Sci.
2014, 49, 1076-1089.
[45] Tang, S. H.; Huang, X. Q.; Chen, X. L.; Zheng, N. F.
Hollow mesoporous zirconia nanocapsules for drug
delivery. Adv. Funct. Mater. 2010, 20, 2442-2447.
[46] Cheng, L.; Yang, K.; Li, Y. G.; Chen, J. H.; Wang, C.; Shao,
M. W. Facile preparation of multifunctional upconversion
nanoprobes for multimodal imaging and dual-targeted
photothermal therapy. Angew. Chem. Int. Ed. 2011, 50,
7385-7390.
[47] Chen, Y.; Chen, H. R.; Shi, J. L. In vivo bio-safety
evaluations and diagnostic/therapeutic applications of
chemically designed mesoporous silica nanoparticles. Adv.
Mater. 2013, 25, 3144-3176.
[48] Kai, D.; Prabhakaran, M. P.; Stahl, B.; Eblenkamp, M.;
Wintermantel, E.; Ramakrishna, S. Mechanical properties
and in vitro behavior of nanofiber-hydrogel composites for
tissue engineering applications. Nanotechnology 2012, 23,
095705.
[49] Hong, Y.; Huber, A.; Takanari, K.; Amoroso, N. J.;
Hashizume, R.; Badylak, S. F. Mechanical properties and in
vivo behavior of a biodegradable synthetic polymer
microfiber-extracellular matrix hydrogel biohybrid scaffold.
Biomaterials 2011, 32, 3387-3394.
Scheme 1. The schematic diagram of the multifunctional MC/UCNPS/DOX electrospinning composite fibers as dual drugs delivery
system for synchronous UCL/MR imaging and therapy of tumor in vivo.
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27 Nano Res.
Figure 1 TEM (a) and high-resolution (HR) TEM (b) images of NaGdF4:Yb/Er@NaGdF4:Yb (UCNP), TEM image of (c) and
up-conversion emission spectra (d) of UCNP@mSiO2-PEG as well as the corresponding digital luminescence photographs dispersed
in water under 980 nm laser excitation.
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28 Nano Res.
Figure 2 TEM images (a, b) of MC/UCNPS/DOX CFs, as well as the digital photographs (c) of UCNPS, UCNPS/DOX,
MC/UCNPS/DOX and DOX spinning pieces.
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29 Nano Res.
Figure 3 Cumulative DOX release from DOX-UCNP@mSiO2-PEG, DOX CFs, UCNPS/DOX CFs and MC/UCNPS/DOX CFs at pH
7.4 and pH 6.2 PBS buffer. Error bars were based on standard deviations (SD) of three times per group.
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30 Nano Res.
Figure 4 Cumulative MC release from MC CFs and MC/UCNPS/DOX CFs at pH=6.2. Error bars were based on standard deviations
(SD) of three times per group.
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31 Nano Res.
Figure 5 The schematic diagram (a) of in vivo up-conversion luminescence images and the corresponding luminescence colors (b) of
Kunming mice bearing tumors at different time point after in situ paste CFs patchs (60-100 mm2/mat, 8 pieces/mouse); relaxation rate
(c) R1 (1/T1) versus different mass concentrations of UCNPS in MC/UCNPS/DOX CFs pieces at room temperature using a 1.2 T
MRI scanner at different gadolinium concentrations; coronal MR images (d) of Kunming mice bearing tumors pre and post in situ
paste CFs patchs (60-100 mm2/mat, 8 pieces/mouse).
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32 Nano Res.
Figure 6 The photographs (a) and tumor weight (b) of excised tumors from euthanized mice on the last day of experiment, as well as
the images (c) of representative Kunming mice with tumors, the body weight (d) and the tumor volume (e) recorded for mice after
treatment with UCNPS CFs, DOX CFs, UCNPS/DOX CFs, MC/UCNPS/DOX CFs and control group, Error bars were based on
standard deviations (SD) of four mice per group (n=4).
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33 Nano Res.
Figure 7 White blood cell count (a) of MC/UCNPS/DOX CFs, UCNPS/DOX CFs and control groups as well as the photographs (b)
of wounds of MC/UCNPS/DOX CFs and UCNPS/DOX CFs 5 days after surgery. Error bars were based on standard deviations (SD)
of two mice per group (n=2).
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34 Nano Res.
Figure 8 Systematic toxicity of composite fibers marerials on healthy Kunming mice: hematoxylin and eosin stained images (a) of
major organs and blood analysis data (b) of mice 17 days after treatment with UCNPS CFs, DOX CFs, UCNPS/DOX CFs,
MC/UCNPS/DOX CFs and control group, respectively. Error bars were based on standard deviations (SD) of four mice per group
(n=4).
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35 Nano Res.
Figure 9 Biodistribution and in vivo drug (DOX) release of MC/UCNPS/DOX CFs. (a) Typical ex vivo images of the excised organs
examined by CRI Maestro 500 FL at 0.5 h, 2 h, 8 h, 12 h, 24 h, 2 d, 3 d, 5 d and 7 d after pasting MC/UCNPS/DOX fiber-pieces on
the tumor of Kunming mice. (b) Semi-quantitative fluorescence intensities of various organs determined at different time points.
Error bars were based on standard deviations (SD) of three mice per group (n=3).
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36 Nano Res.
Figure 10 Biodistribution of UCNP@mSiO2-PEG in mice at different time points after treatment with MC/UCNPS/DOX CFs by
ICP-AES (concentration of Gd3+). Error bars were based on standard deviations (SD) of three mice per group (n=3).
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Nano Res.
Electronic Supplementary Material
Multifunctional Electrospinning Composite Fibers for
Orthotopic Cancer Treatment in Vivo
Yinyin Chen1,2, Shi Liu2, †, Zhiyao Hou1, Pingan Ma1, Dongmei Yang1,2, Chunxia Li, 1 () and Jun Lin,1()
Figure S1 N2 adsorption–desorption isotherms and mesopore size distribution (the inset) of UCNP@mSiO2-PEG nanocomposite.
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Nano Res.
Figure S2. UC emission spectra of MC/UCNPS CFs and MC/UCNPS/DOX CFs under 980 nm laser excitation.
Address correspondence toJun Lin. [email protected]; Chunxia Li. [email protected]
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