Synthesis of light-induced expandable photoresponsive polymeric nanoparticles for triggered release

Article abstract of DOI:10.1002/cplu.201300212

High stability of drug-delivery nanocarriers during blood circulation is critical for effective drug delivery and low systematic toxicity, although destabilization of these nanocarriers is required for efficient release when they reach target sites. To develop efficient polymeric nanocarriers, we intended to synthesize and characterize a group of cross-linked, light-induced, expandable, polymeric nanoparticles through miniemulsion polymerization. These synthesized nanoparticles were stable in aqueous solutions, although light irradiation led to particle uncaging and further particle expansion up to 315-fold in volume. This resulted in the efficient release of the encapsulated contents in aqueous solutions and three cell lines (HeLa, RAW264.7, and MCF-7). Selective triggered release was also successfully achieved with spatial resolution in cell monolayers. In addition, curcumin encapsulation and photoregulation of its release were realized. Further cell viability of encapsulated curcumin was successfully achieved with light activation. Open the cage: A series of cross-linked photolabile polymeric nanoparticles are described. Light irradiation leads to the particle swelling 315-fold in volume and the efficient release of the encapsulated contents in both aqueous solutions and cells. Selective triggered release on a cell monolayer is achieved. Curcumin is efficiently encapsulated in particles and photoregulation of its release and cell viability is also successfully achieved. Copyright

Full text of DOI:10.1002/cplu.201300212

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DOI: 10.1002/cplu.201300212
Synthesis of Light-Induced Expandable Photoresponsive
Polymeric Nanoparticles for Triggered Release
[
a]
Zhen Wang, Peng Wang, and XinJing Tang*
High stability of drug-delivery nanocarriers during blood circu-
lation is critical for effective drug delivery and low systematic
toxicity, although destabilization of these nanocarriers is re-
quired for efficient release when they reach target sites. To de-
velop efficient polymeric nanocarriers, we intended to synthe-
size and characterize a group of cross-linked, light-induced, ex-
pandable, polymeric nanoparticles through miniemulsion poly-
merization. These synthesized nanoparticles were stable in
aqueous solutions, although light irradiation led to particle un-
caging and further particle expansion up to 315-fold in
volume. This resulted in the efficient release of the encapsulat-
ed contents in aqueous solutions and three cell lines (HeLa,
RAW264.7, and MCF-7). Selective triggered release was also
successfully achieved with spatial resolution in cell monolayers.
In addition, curcumin encapsulation and photoregulation of its
release were realized. Further cell viability of encapsulated cur-
cumin was successfully achieved with light activation.
Introduction
Many materials, such as lipids, carbohydrates, hydroxy acid
polymers, dendrimers, and diblock copolymers, have been ap-
plied to form micro- and nanoparticles for applications in
drug-delivery systems owing to their easy manipulation and
ation (o-nitrobenzyl, 4-hydroxylmethyl coumarin derivatives,
[17–22]
etc);
2) photoinduced segmentation of photolabile poly-
mers caused the dissociation of polymers into small fragments
through direct photocleavage of the polymer backbone or
[
1,2]
[23–26]
chemical modifications.
These kinds of polymeric particles
self-immolation based on the quinine–methide moiety.
are being intensively studied as drug capsules to increase drug
solubility and stability, enhance pharmacokinetics, and mini-
mize side effects. Although great improvements for drug deliv-
ery with these nanocarriers have been achieved, it is highly de-
sirable to control the release of encapsulated substances to
reach high enough drug concentrations and to mediate the ef-
fective therapeutic response through an external stimulus. Sev-
eral triggering events, such as chemical, thermal, electrical,
magnetic, biological, and photochemical methods, have been
Both kinds of polymers have shown good capabilities to self-
assembly into micelles for target encapsulation and photoin-
duced release of encapsulated targets. However, these self-as-
sembled micelles may suffer dissociation below their critical
micelle concentrations (CMCs), especially in blood vessels.
Thus, increasing the stability of polymeric particles is critical for
further in vivo applications. Cross-linked polymers show high
[27]
stability as drug nanocarriers. Several photolabile cross link-
ers (CLs) have been designed and synthesized. We recently de-
veloped a photocleavable CL by using 1-(2-nitrophenyl)ethane-
1,2-diol as the photolabile moiety, which was converted into
the bismethyl acrylate for cross linking of the internal core of
[
3,4]
widely applied.
However, most events based on these
mechanisms require variations in the internal environments,
which lead to limited spatiotemporal control of delivery.
Among these stimuli, light stands out as a clean and noninva-
sive one, and has the potential to overcome the above-men-
tioned limitations owing to the possibility of remote control
and manual manipulation of payload release at a specific time,
[28]
block copolymers. Further Nile red encapsulation and photo-
triggered release were realized. The groups of Anseth and
Kasko synthesized photosensitive PEGylated (PEG=polyethy-
lene glycol) CLs with o-nitrobenzyl moieties at both terminals
and further used these linkers to prepare photosensitive hy-
[
5–8]
position, and concentration.
[29,30]
Different photosensitive polymeric particle systems have
been designed and reported in the literature, and may be di-
vided into the following categories: 1) photoinduced structural
changes that lead to destabilization of micelles by photoiso-
drogels for live cell encapsulation and release.
Instead of
photosensitive CLs, photolabile cross-linked nanocarriers can
also be prepared by the application of photolabile subunits
and non-photolabile CLs. Anseth et al. applied photolabile
peptide subunits to synthesize click-based hydrogel and realize
photoreversible patterning of biomolecules for cell adher-
[
9–16]
merization (azobenzene, spiropyran, etc)
and photodissoci-
[29]
ence. Herein, we focus on cross-linked photolabile nanocarri-
ers that can be used for the full release of encapsulated sub-
stances upon light activation. Previously, an acid-sensitive poly-
meric particle with 2,4,6-trimethoxybenzaldehyde-protected
tris(hydroxymethyl)ethane and a CL (1,4-O-methacryloylhydro-
quinone) achieved acid-induced expandable particles for full
[
a] Z. Wang, P. Wang, Prof. Dr. X. Tang
State Key Laboratory of Natural and Biomimetic Drugs
School of Pharmaceutical Sciences, Peking University
No. 38 Xueyuan Rd., Beijing 100191 (P. R. China)
Fax: (+86)10-82805635
E-mail: xinjingt@bjmu.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cplu.201300212.
[31]
release.
Inspired by this study, we intended to design
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sponding carbamates and mask amine groups. We further es-
terified the obtained intermediates (3 and 6) with methacryloyl
chloride to give the photolabile monomers (M1 and M2). At
the same time, we also synthesized a photolabile monomer
(
Ma) and a nonphotolabile monomer (Mc) by direct esterifica-
[32]
tion of 2 and benzyl ethanol with methacryloyl chloride.
With these monomers in hand, we performed the syntheses of
polymeric particles through miniemulsion polymerization with
the addition of CL (ethylene glycol dimethacrylate) and initia-
tor (azodiisobutyronitrile (AIBN)), according to reported meth-
[31,33,34]
ods.
The synthesized particles were not soluble in organic sol-
vents, including DMSO, even though they could be dispersed
in deuterated water, so it was not possible to obtain NMR
spectra of particles or to perform gel permeation chromatogra-
phy (GPC). The synthesized nanoparticles were then character-
ized by dynamic light scattering (DLS), SEM, and UV/Vis and IR
spectroscopy (see Figures S1–4 in the Supporting Information).
Table 1 lists the diameters of the synthesized nanoparticles
with the encapsulation of different substances through DLS
Scheme 1. Above: Strategy for controllable release from light-induced ex-
pandable nanoparticles (eNPs). Below: Structures of photolabile monomers
(M1 and M2 for eNP1 and eNP2, respectively), and CL for particles synthe-
sized through miniemulsion polymerization.
a series of photosensitive expandable particles for nanocarriers
with photolabile monomers, as indicated in Scheme 1.
(
Cumulant method) by using the Zetasizer Nana-ZS instrument
from Malvern Instruments at 258C. For blank and substance-
Results and Discussion
encapsulated nanoparticles, the diameters were all around 80–
130 nm. Interestingly, when the particles (eNP1 and eNP2) with
Synthesis and characterization of light-induced expandable
nanoparticles
photolabile M1 and M2 were irradiated with light, the particle
sizes dramatically increased in aqueous solutions (Figure 1 and
Figure S3 in the Supporting Information). Light-induced swel-
ling ratios (LISRs) of these photoresponsive nanoparticles with
different encapsulated substances were up to about 315-fold
in volume in comparison to those of photolabile (NPa-CL-10%,
1.01) and non-photoresponsive (NPc-CL-10%, 0.99) nanoparti-
cles in aqueous solutions (Table 1). The size expansion of the
nanoparticles may be due to the formation of carbon diox-
To develop such photoresponsive nanoparticles, we first pre-
pared hydrophobic methacrylate monomers (M1 and M2 for
eNP1 and eNP2, respectively; Scheme 2). The photolabile moi-
eties of 1-(2-nitrophenyl)ethanol (2) and 7-diethylamino-4-hy-
droxymethylcoumarin (5) were synthesized according to litera-
[
17,32]
ture reports.
These two moieties were then converted into
N-hydroxysuccinimide (NHS) esters and the obtained inter-
[35]
mediates could react with aminoethanol to form the corre-
ide, which associates with amine instead of leaking out of
Scheme 2. Synthetic route to photolabile monomers M1 (above) and M2 (below). DSC=N,N’-disuccinimidyl carbonate.
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method does not allow the
evaluation of photocleavage of
a solution of eNP2-blk-10% par-
ticles because of the limited
change in UV/Vis absorbance
before and after light irradia-
tion. In addition to blank parti-
cles, we also determined the in
vitro releasing kinetics of cou-
Table 1. Size distribution and zeta potentials of particles before and after light irradiation, and light-induced
swelling ratios (LISRs) of nanoparticles with encapsulation of different substances.
[
a]
No UV
UV
LISR
3
Particle size
nm] (pdi)
Zeta potential [mV] Particle size
[nm] (pdi)
Zeta potential [mV] (dUV/dnouv)
[
eNP1-blk-10%
128.7 (0.112) ꢀ18.7
768.9 (0.284) +46.4
213.2
158.3
314.7
104.0
246.0
268.1
eNP1-coumarin6-10% 130.9 (0.084) ꢀ25.5
708.1 (0.223) +32.1
853.0 (0.263) +33.8
631.0 (0.191) +26.8
624.5 (0.174) +33.3
eNP1-FDA-10%
eNP1-curcumin-10%
eNP2-blk-10%
125.4 (0.140) ꢀ18.0
134.2 (0.127) ꢀ38.8
99.7 (0.177) ꢀ18.0
119.7 (0.212) ꢀ27.0
112.9 (0.164) ꢀ32.3
85.2 (0.238) ꢀ34.2
marin 6
from
coumarin 6
eNP2-FDA-10%
771.8 (0.115)
113.3 (0.142)
85.1 (0.200)
+18.9
ꢀ34.2
ꢀ33.8
loaded nanoparticles (eNP1-cou-
marin6-10%) by UV/Vis spectra.
The maximum release efficiency
was close to completeness in
150 s, according to the mea-
surement of precipitated cou-
marin 6 after UV irradiation (Fig-
[
b]
NPa-blk-10%
NPc-blk-10%
1.01
0.99
[
b]
[
(
a] blk refers to no encapsulation; FDA refers to fluorescein diacetate; 10% refers to the mole percentage of CL
ethylene glycol dimethacrylate) based on the monomers. [b] Control nanoparticles (photolabile; NPa-blk-10%;
nonphotolabile: NPc-blk-10%). See Figure S3 in the Supporting Information for the monomer structures.
the nanoparticles upon light activation of the eNPs. The reac-
ure S5 in the Supporting Information). In comparison to the
data for the photocleavage of eNP1-blk-10%, faster release of
coumarin 6 from nanoparticles indicated that it was not re-
quired for complete photocleavage of caging groups to reach
the full release of encapsulated substances in nanoparticles.
We also performed IR measurements on eNP1 and eNP2
nanoparticles before and after light irradiation. For eNP1 parti-
tion between amine and CO with the involvement of water
2
further solubilizes the internal core of eNPs. This observation is
[36]
similar to a previous report on CO -sensitive polymers. In ad-
2
dition, the zeta potentials of these nanoparticles were also in-
vestigated (Figure 1 and Figure S3 in the Supporting Informa-
ꢀ
1
cles, the absorption at n˜ =1527.8 cm was assigned to the
CꢀNO band, which disappeared with light irradiation. This ob-
2
[32,37,39]
servation was consistent with previous reports,
and con-
firmed photocleavage of the o-nitrobenzyl moiety and release
of the amine moiety. However, for eNP2 particles, the IR ab-
sorption of C=O of the carbamate was buried in that of the ab-
sorption for the C=O skeleton and light irradiation did not
induce clear changes in the C=O absorption in the IR spectra.
Instead, we observed a slightly shifted IR absorption peak, as
shown in Figure S1 in the Supporting Information.
Figure 1. Particle size variation of diameters and zeta potential changes of
eNP1-blk-10% before (red) and after (black) light irradiation.
Photoresponsive behavior of light-induced expandable
nanoparticles in solution and in cells
Coumarin 6, a hydrophobic fluorescence dye, was used as
a model to evaluate photocontrolled release in aqueous solu-
tion. The dye shows strong fluorescence in the hydrophobic
core of the nanoparticles and loses its emission when released
in aqueous solution, owing to low solubility. Coumarin 6 was
encapsulated in the core of the nanoparticles (eNP-coumarin6-
10%) when particles were synthesized through miniemulsion
polymerization with photolabile monomer M1. We measured
the fluorescence spectra of a solution of eNP-coumarin6-10%
with an excitation wavelength of l=460 nm. As shown in
Figure 2, the particle solution emitted strong fluorescence
when coumarin 6 was excited at l=460 nm before photoacti-
vation. However, a dramatic decrease in fluorescence intensity
was observed upon light irradiation. Fluorescence intensity of
tion). As listed in Table 1, the zeta potentials of eNP1 and eNP2
with the encapsulation of different substances were photo-
switched from negative (ꢀ18.0 to ꢀ38.8) to positive charges
(
+18.9 to +46.4), while there were almost no charge varia-
tions for either photosensitive NPa or nonphotosensitive NPc.
The dramatic changes in particle charge further indicated the
uncaging of photolabile particles (eNP1 and eNP2) and the re-
lease of the amine moiety.
To evaluate the time dependence of the photocleavage of
nanoparticles, an aqueous solution of eNP1-blk-10% was irradi-
ated with l=365 nm UV light. The UV/Vis absorbance spectra
of the particle solution were measured with different irradia-
tion times. We observed the appearance of a new absorbance
peak at l=310 nm, which belonged to the cleaved product, o-
ꢀ
1
200 mgmL of eNP-coumarin6-10% decreased about 85%
with 5 minutes irradiation. This result indicated photoswitching
of the hydrophobic environment of the internal core of the
nanoparticle and release of coumarin 6. A plot of fluorescence
intensity of an aqueous solution of eNP-coumarin6-10% versus
[
37–39]
nitrosophenoacetone.
By monitoring the absorbance at
l=310 nm, we observed no further increase in the UV/Vis
spectra after light irradiation for 20 minutes, which confirmed
the maximum conversion of photocleavage. However, this
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nonfluorescent, however, upon uptake by cells, intracellular es-
terases hydrolyze the acetate groups to produce a highly fluo-
rescent product (fluorescein). Although FDA-loaded nanoparti-
cles were taken up by cells, FDA was trapped in the hydropho-
bic core of the particles and could not be hydrolyzed by ester-
ases. However, once the internal hydrophobic core of the parti-
cles was damaged through light irradiation, FDA was quickly
released from the internal core of the particles and converted
into highly fluorescent fluorescein after hydrolysis. All three
kinds of cells were incubated with eNP1-FDA-10%
ꢀ
1
(
62.5 mgmL ) for 8 hours and then were thoroughly washed
with phosphate-buffered saline (PBS). The uptake of nanoparti-
cles (eNP1-FDA-10%) and triggered release of FDA in cells
were visualized directly by fluorescence microscopy. Figure 3a
shows fluorescent images of three cell lines under different
conditions. As expected, light irradiation lit up all three kinds
of cells, which indicated uptake and triggered release of FDA
in the cells. We further quantified the fluorescence intensity of
the triggered release of FDA before and after light irradiation
by measuring the fluorescence intensity of all three kinds of
cells in 96-well plates by using a microplate reader. Light irradi-
ation for 15 minutes led to 6–8-fold increase in fluorescence in-
tensity for all three cell lines that took up eNP1-FDA-10%
nanoparticles (Figure 3b). Because light and eNP1-FDA-10%
themselves did not lead to strong fluorescence emission,
eNP1-FDA-10% must have been photochemically uncaged and
FDA was released. We also evaluated another kind of photo-
sensitive nanoparticle (eNP2) with a photolabile coumarinyl
moiety instead of a 2-nitrobenzyl moiety according to a similar
procedure. The triggered release of FDA from eNP2-FDA-10%
was also successfully achieved in RAW264.7 and HeLa cells
with a large increase in fluorescence from hydrolyzed FDA (Fig-
ure S8 in the Supporting Information) of 11- and 7-fold for
RAW264.7 and HeLa cells, respectively. Because several reports
Figure 2. Fluorescence spectra of eNP1-coumarin6-10% upon light irradia-
ꢀ
2
tion (l=365 nm, 11 mWcm ) at an excitation wavelength of l=460 nm.
The inset shows the normalized fluorescence intensity at l=553 nm versus
irradiation time.
irradiation time is given as an insert in Figure 2. By fitting the
data with Equation (1), we obtained the characteristic time, t
(96.9 s), at which the fluorescence intensity decreased to
36.8% (1/e):
I=I ¼ ðI=I Þ þ ½1ꢀðI=I Þ ꢁexpðꢀt=tÞ
ð1Þ
0
0
m
0 m
For eNP2 nanoparticles, we directly measured the fluores-
cence spectra of the particle solutions owing to the inherent
fluorescence properties of the coumarin moiety. A strong fluo-
rescence emission of 5 in the hydrophobic core of eNP2-blk-
10% particles was observed, as expected. However, light irradi-
ation disrupted the hydrophobic properties of the core of the
particle, which led to a decrease in fluorescence intensity (Fig-
ure S6 in the Supporting Information). However, the maximum
decrease in fluorescence intensity was about 40% of its initial
value after irradiation for 400 s and no further change was ob-
served with longer irradiation. This is probably because 5 has
a higher solubility in aqueous solution than that of coumarin 6
and still has some fluorescence emission, even in aqueous so-
lution.
have demonstrated that the coumarinyl group can be uncaged
[17,25]
through two-photon excitation,
we expected that substan-
ces encapsulated in these coumarinyl-caged polymeric nano-
particles would also be released by two-photon activation.
Nanoparticles (eNP1-coumarin6-10%) were then tested for
uptake by three different cell lines (RAW264.7, HeLa, and MCF-
Light-induced patterned release in cells
7
). As illustrated in Figure S7A in the Supporting Information,
With these particles in place, we further tested their applicabili-
ty for making a simple pattern of FDA release in cell monolay-
ers. The ability to do this has the potential to make significant
contributions to the study of drug release with the spacing
and timing for a specific cell. We used the same nanoparticles
(eNP1-FDA-10% and eNP2-FDA-10%) as those described
above. Cells were first plated in 35 mm glass-bottomed dishes
and further incubated with these FDA-loaded nanoparticles for
12 hours and then thoroughly washed with PBS. Half of each
examined dish was masked from direct light exposure by stick-
ing the mask as close to the cells as possible. Because the light
source was not collimated, nor a point source, we still ob-
served some light leakage at the edge of the mask. The result-
ing patterned images are shown in Figure 4 and Figure S9 in
the Supporting Information. For both RAW264.7 and HeLa
cells, the irradiated cells lit up, while the other half of the cells
these three kinds of cells can take up nanoparticles that light
up the cells. We also quantified the uptake of the nanoparti-
cles by using cell flow cytometry for HeLa cells with or without
the incubation of eNP1-coumarin6-10%. Results shown in Fig-
ure S7B in the Supporting Information clearly demonstrate the
efficient uptake of eNP1-coumarin6-10% particles by the cells.
However, light irradiation did not induce detectable variation
in the fluorescence intensity of the cells because coumarin 6
released could also interact with hydrophobic proteins or
membranes to show strong fluorescence emission instead of
precipitation in the cells, as indicated in Figure S7 in the Sup-
porting Information for cell uptake of eNP1-coumarin6-10%
and free coumarin 6.
To further demonstrate the triggered release of encapsulat-
ed substances in cells, FDA was chosen because FDA itself is
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Figure 4. Patterning of the phototriggered release of FDA with photores-
ponsive eNP2-FDA-10% nanoparticles. In each image, the top half of the
cells were irradiated and showed fluorescence emission (scale bar=100 mm).
[40]
eases and viruses. Because of its limited solubility and insta-
bility, curcumin is difficult for the body to absorb. Nanocurcu-
min (a polymer nanoparticle encapsulated formulation of cur-
cumin) has the potential to bypass many of the disadvantages
[41]
associated with free curcumin. With a similar procedure of
miniemulsion polymerization as that mentioned above, we
solubilized curcumin through its encapsulation into the hydro-
phobic core of eNP1-curcumin-10%. Similar to coumarin 6 or
FDA-loaded nanoparticles, we also evaluated the triggered re-
lease of eNP1-curcumin-10% in aqueous solution. Curcumin
itself has almost no fluorescence emission in solution. In hydro-
phobic environment it emits fluorescence at l=505 nm with
excitation at l=420 nm. We measured the fluorescence spec-
tra of an aqueous solution of eNP1-curcumin-10% at different
irradiation times and monitored the intensity of the peak at
l=505 nm. Figure S11 in the Supporting Information shows
that the fluorescence intensity of a solution of curcumin-
loaded nanoparticles decreased to 20% of the initial fluores-
cence intensity within 600 s of light irradiation; this indicated
the efficient triggered release of curcumin from the internal
core of the nanoparticles in aqueous solutions.
Figure 3. a) Fluorescence images of RAW264.7, HeLa, and MCF-7 cells incu-
bated with eNP1-FDA-10% for 8 h followed by light irradiation for 15 min
and imaging. b) Enhancement ratios of the fluorescence intensity of three
cell lines after incubation with eNP1-FDA-10%. The fluorescence intensity
was measured before and after light activation by using a microplate reader.
Triggered release of curcumin from eNP1-curcumin-10% was
further evaluated in HeLa cells. First, the toxicity of these nano-
particles was studied by incubating cells with varying concen-
trations of these blank particles for 48 hours. No clear signs of
ꢀ
1
The concentration of particle solutions was 62.5 mgmL (scale bar=50 mm).
ꢀ
1
in the same dishes did not show fluorescence emission when
they were covered by the masks. All of these results indicate
that these photoresponsive eNPs are promising for use in the
photoregulation of drug release with spatial resolution.
toxicity were found up to 250 mgmL of eNP1-blk-10% with
or without exposure to light for 15 min and further incubation
for 48 hours (Figure S12 in the Supporting Information). Free
ꢀ
1
curcumin showed cell toxicity of IC =4.2 mgmL without irra-
50
ꢀ
1
diation and 3.6 mgmL with light irradiation for 15 min, as de-
termined by a sulforhodamine B (SRB) assay. The results
showed that light had little effect on the cytotoxicity of curcu-
min to HeLa cells (Figure S13 in the Supporting Information).
However, if curcumin was loaded into photoresponsive nano-
particles, it was trapped inside the hydrophobic core and did
not leak out. The entrapment efficiency of curcumin by the
particles was determined to be 71.5% by UV/Vis absorbance at
l=428 nm. According to the IC50 value of curcumin for HeLa
Drug loading and phototriggered release in HeLa cells
Instead of model chromophores, curcumin, which is a compo-
nent of Indian ayurvedic medicine, was chosen for further en-
capsulation and triggered release from the nanoparticles de-
scribed above (Figure S10 in the Supporting Information). Pre-
viously, in vitro and animal studies suggested that curcumin
had promising applications in the treatment of different dis-
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cells, we chose four different concentrations of aqueous solu-
tions of eNP1-curcumin-10% particle (100, 150, 200, and
may afford a new option for the photocontrollable treatment
of cancers and other diseases with spatiotemporal resolution.
ꢀ
1
2
50 mgmL , which corresponded to curcumin concentrations
ꢀ
1
of 3.14, 4.71, 6.28, and 7.85 mgmL , respectively) for the evalu-
ation of cell viability. As shown in Figure 5, the cell viability
was almost unchanged for cells treated with up to
Experimental Section
General methods
ꢀ
1
2
50 mgmL of eNP1-curcumin-10%, whereas light irradiation
All commercially solvents and reagents were used without further
purification except as noted below. Tetrahydrofuran, triethylamine
of cells treated with eNP1-curcumin-10% particles clearly trig-
gered cell death of up to 85%. Because there was no clear
light-induced cytotoxicity of eNP1-blk-10% (Figure S12 in the
Supporting Information), the dramatic variation in cytotoxicity
was assumed to be from curcumin released upon light activa-
tion.
(
TEA), and xylene were purified by distillation over CaH . 7-N,N-Di-
2
ethylamino-4-methylcoumarin, SeO , DSC, and coumarin 6 were
2
purchased from J&K Chemicals. Methacryloyl chloride was pur-
chased from TCI Shanghai. Ethanolamine, ethylene glycol dimetha-
crylate (CL) and trichloroacetic acid (TCA) were purchased from
Alfa Aesar. FDA was purchased from Alfa Aesar and stored at
ꢀ
208C. SRB was purchased from Sigma Aldrich (St. Louis, MO,
USA). Hexadecane (HD) was purchased from Haltermann in Germa-
ny. SDS and Tris base were purchased from Beijing Dingguo Bio-
technology Co. AIBN was purchased from Shanghai trial four
Hervey Chemical Co.
1
13
H and C NMR spectra were recorded on a Bruker AVANCEIII
00 MHz NMR spectrometer. Reported chemical shifts (ppm) were
relative to CDCl or [D ]DMSO and coupling constants were report-
4
3
6
ed in Hz. The diameters of nanoparticles were determined by DLS
at 258C with a Zetasizer Nana-ZS instrument from Malvern Instru-
ments. FTIR spectra were measured by using a Nicolet NEXUS-670
FTIR spectrometer. UV/Vis spectra were recorded on a DU800
UV/Vis spectrophotometer (Beckman, USA). Fluorescence spectra
were obtained by using a Cary Eclipse fluorometer (Varian, USA).
SEM (Hitachi S-4300) was used to observe the particles: typically
one drop of diluted nanoparticle solution was cast on silicon wafer,
and dried at 378C. FDA release in cells was detected with a FlexSta-
tion 3 Molecular Devices instrument. Cell uptake was observed
with an inverted fluorescence microscope (OLYMPUS, IX81). Pat-
terned cell experiments were acquired with a Zeiss Upright fluores-
cence microscope (Axio Imager A2). A B-100SP lamp (UVP, LLC)
Figure 5. The viability of HeLa cells exposed to different concentrations of
eNP1-curcumin-10% nanoparticles (with corresponding curcumin concentra-
ꢀ
1
tions of 3.14, 4.71, 6.28 and 7.85 mgmL , respectively). The UV exposure
was used as the light resource for irradiation (l=365 nm,
time was 15 min.
ꢀ2
1
1 mWcm ).
Synthesis
-(2-nitrophenyl)ethanol (2): Compound 2 was synthesized ac-
Conclusion
1
We synthesized a series of cross-linked, light-induced, expanda-
ble, polymeric particles with different photolabile monomers
[28]
cording to a literature procedure with minor modifications. An
aqueous solution of NaBH (34.4 mL, 10%) was added dropwise to
4
(nitrobenzyl and coumarinyl) through miniemulsion polymeri-
the solution of 1 (5 g, 30 mmol) in 1,4-dioxane (30 mL) at 08C. The
zation. The synthesized particles were stable in aqueous solu-
tions, however, light irradiation caused the release of the
amine moiety from internal hydrophobic core, which led to
the swelling of nanoparticles with LISR values of up to 315-fold
in volume and the efficient release of the encapsulated con-
tents. The release efficiency reached 85% based on the fluores-
cence intensity variations of coumarin 6. Uptake and triggered
release of the encapsulated substances from different cell lines
was observed with FDA-loaded nanoparticles. Selective trig-
gered release of cell monolayers was also successfully ach-
ieved. In addition, encapsulation of bioactive curcumin in pho-
toresponsive nanoparticles and light-triggered release of curcu-
min were realized. Further cell experiments showed that curcu-
mixture was stirred in an ice cold bath for 1 h and at room temper-
ature for an additional 30 min. Excess NaBH was then quenched
4
with acetone (20 mL). After removal of the solvents, the residue
was extracted with ethyl acetate, and the organic layer was dried
over anhydrous sodium sulfate. When ethyl acetate was removed,
the light-yellow oil obtained was used in the next step without fur-
1
ther purification (98%). H NMR (400 MHz, CDCl ): d=7.91 (d, J=
3
8
.1 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.66 (t, J=7.7 Hz, 1H), 7.42 (t,
J=7.7 Hz, 1H), 5.43 (q, J=6.4 Hz, 1H), 1.58 ppm (d, J=6.4 Hz, 3H);
13
C NMR (101 MHz, CDCl ): d=147.9, 141.0, 133.7, 128.2, 127.7,
3
1
24.4, 65.6, 24.3 ppm.
1
-(2-nitrophenyl)ethyl (2-hydroxyethyl)carbamate (3): DSC
(2.7 g,10.5 mmol) was added to a solution of 2 (1.1 g, 6.6 mmol) in
CH CN (60 mL), followed by the addition of TEA (2.7 mL,
3
ꢀ1
min released from a 250 mgmL solution of eNP1-curcumin-
0% particles caused cell death of up to 85% with 15 minutes
irradiation. This new light-triggered expandable particle system
1
8.6 mmol). The mixture was stirred overnight at room tempera-
1
ture. Ethanolamine (1 g, 16.4 mmol) was then added and the solu-
tion was stirred for another 6 h at room temperature. Solvents
ꢀ
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were evaporated to dryness and the residue was dissolved in
CH Cl , washed thoroughly with a saturated solution of NaHCO ,
1H), 6.54 (s, 1H), 5.98 (s, 1H), 5.21 (s, 2H), 4.69 (t, J=4.9 Hz, 1H),
3.42 (d, J=6.6 Hz, 6H), 3.09 (d, J=5.6 Hz, 2H), 1.11 ppm (t, J=
2
2
3
13
and then washed with brine. The organic layer was dried over an-
hydrous sodium sulfate. After removal of CH Cl , the residue was
6.5 Hz, 6H); C NMR (101 MHz, [D ]DMSO): d=160.9, 155.8, 155.6,
6
152.0, 150.5, 125.4, 108.8, 105.3, 104.4, 96.9, 60.9, 59.9, 44.1, 43.2,
2
2
+
purified by column chromatography over silica gel (petroleum
12.4 ppm; MS: m/z: 357.23 [M+Na] .
ether/ethyl acetate=2:1) to give 3 as a light-yellow oil (77.8%).
1
(7-Diethylamino-4-methylcoumarin-4-ylmethoxycarbonylami-
no)ethyl methacrylate (M2): Compound 6 (0.13 g, 0.39 mmol) and
dry TEA (0.17 mL, 1.17 mmol) were dissolved in dry CH Cl
(20.0 mL). The solution was then purged with nitrogen and allowed
to stir in an ice cold bath for 5 min. Methacryloyl chloride (0.10 mL,
1.04 mmol) was slowly added over a period of 10 min. The reaction
mixture was then warmed to room temperature and stirred over-
night. The reaction mixture was washed three times with a saturat-
H NMR (400 MHz, CDCl ): d=7.91 (d, J=8.2 Hz, 1H), 7.64–7.62 (t,
3
J=2.3 Hz, 3.6 Hz, 2H), 7.45–7.39 (m, 1H), 6.24 (q, J=6.4 Hz, 1H),
2
2
5
1
1
2
.41 (s, 1H), 3.63 (t, J=4.9 Hz, 2H), 3.26 (t, J=5.2 Hz, 2H), 2.56 (s,
13
H), 1.62 ppm (d, J=6.4 Hz, 3H); C NMR (101 MHz, CDCl ): d=
3
61.1, 152.6, 143.5, 138.6, 133.2, 132.2, 129.3, 73.8, 66.8, 48.3,
+
7.2 ppm; MS: m/z: 277.21 [M+Na] .
2
(
9
-({[1-(2-nitrophenyl)ethoxy]carbonyl}amino)ethyl methacrylate
M1): Compound 3 (0.8 g, 3.2 mmol) and dry TEA (1.4 mL,
.6 mmol) were dissolved in dry CH Cl (20.0 mL). The mixture was
ed solution of NaHCO and once with brine. The resulting organic
3
phase was dried over anhydrous sodium sulfate and concentrated
in vacuo. The residue was purified by column chromatography
over silica gel (CH Cl /acetone 20:1) to give M2 as a light-yellow
2
2
then purged with nitrogen and allowed to stir in an ice cold bath
for 5 min. Methacryloyl chloride (0.53 mL, 5.5 mmol) was slowly
added over a period of 10 min. The reaction mixture was then
warmed to room temperature and stirred overnight. After the reac-
tion was complete, the mixture was then washed three times with
2
2
1
solid (43.6%). H NMR (400 MHz, CDCl ): d=7.30 (d, J=9.0 Hz, 1H),
3
6.59 (dd, J=8.9, 2.0 Hz, 1H), 6.51 (d, J=2.1 Hz, 1H), 6.12 (d, J=
5.9 Hz, 2H), 5.61 (s, 1H), 5.34 (s, 1H), 5.23 (s, 2H), 4.27 (t, J=5.2 Hz,
2H), 3.56 (dd, J=5.6 Hz, 10.9 Hz, 2H), 3.40 (q, J=7.0 Hz, 4H), 1.96
a saturated solution of NaHCO and once with brine. The resulting
3
13
organic phase was dried over anhydrous sodium sulfate and then
concentrated in vacuo. The residue was purified by column chro-
matography over silica gel (petroleum ether/ethyl acetate=6:2) to
(s, 3H), 1.20 ppm (t, J=7.0 Hz, 6H); C NMR (101 MHz, CDCl ): d=
3
167.3, 162.0, 156.2, 155.6, 150.5, 150.2, 135.9, 126.3, 124.4, 108.7,
106.1, 97.8, 63.5, 61.9, 44.8, 40.4, 18.3, 12.4 ppm; MS: m/z: 425.27
1
+
give M1 monomer as a light-yellow oil (88.7%). H NMR (400 MHz,
[M+Na] .
CDCl ): d=7.93 (d, J=8.1 Hz, 1H), 7.61 (d, J=4.1 Hz, 2H), 7.44–7.38
3
(
m, 1H), 6.25 (q, J=6.5 Hz, 1H), 6.10 (s, 1H), 5.59 (d, J=1.4 Hz, 1H),
5
1
1
6
.02 (s, 1H), 4.19 (t, J=5.2 Hz, 2H), 3.49–3.40 (m, 2H), 1.93 (s, 3H),
13
.62 ppm (d, J=6.5 Hz, 3H); C NMR (101 MHz, CDCl ): d=172.3,
3
60.4, 152.5, 143.6, 140.9, 138.6, 133.2 132.1, 131.1, 129.3, 73.6,
Nanoparticle Synthesis
+
8.5, 45.0, 27.1, 23.2 ppm; MS: m/z: 345.20 [M+Na] .
Nanoparticles were prepared through miniemulsion polymerization
7
-Diethylamino-4-hydroxymethylcoumarin (5): A solution of SeO2
[31,33,34]
methods.
In a typical run, monomers (50 mg); ethylene
(
414 mg, 3.73 mmol) and 4 (570 mg, 2.63 mmol) in xylene (50 mL)
glycol dimethacrylate (CL, 10% mol of the monomers); coumarin 6
0.5 mg for coumarin 6 loaded particles), FDA (4 mg for FDA-
was heated at reflux under a nitrogen atmosphere. After 18 h, the
mixture was filtered and concentrated under the reduced pressure.
The dark-brown residual oil was dissolved in ethanol (50 mL), fol-
(
loaded particles), or curcumin (2.1 mg, for curcumin-loaded parti-
cles) in acetone (50 mL), 5% AIBN in CH Cl (10 mL, w/w), and co-
stabilizer HD (3.1 mg) were dissolved in CH Cl (500 mL). Distilled
2 2
2
2
lowed by the addition of NaBH (414 mg, 3.73 mmol). The reaction
4
mixture was stirred for 4 h at room temperature, and then carefully
hydrolyzed with 1m HCl. The reaction solution was concentrated
under reduced pressure to remove ethanol. The resulting mixture
water (5 mL) or pH 4 sodium acetate buffer solution (for FDA-
loaded particles, FDA is stable at pH 4 at 808C) containing sodium
dodecyl sulfate (SDS; 5 mg) was first purged by bubbling nitrogen
for 10 min, and was then added to the oil phase. The mixture was
sonicated in an ice bath for 5 min (JY92-IIN, Ningbo Scientz Bio-
technology Co., Ltd, 3 s pulses with 1 s delay) with 80 W of the
power. Following sonication, the solution was transferred to
a 25 mL sealed container purged with nitrogen. Polymerization
was performed at 808C in an oil bath for 18 h. After polymeri-
zation, the suspension was stirred overnight, which allowed CH Cl
was extracted with CH Cl and washed twice with a saturated solu-
2
2
tion of NaHCO . The organic phase was dried over MgSO and con-
3
4
centrated in vacuo. The resulting oil was purified by column chro-
matography over silica gel (CH Cl /acetone 20:1) to yield 5 as
2
2
1
a light-yellow solid (46.2% over two steps). H NMR (400 MHz,
CDCl ): d=7.30 (d, J=9.0 Hz, 1H), 6.55 (dd, J=8.9, 2.1 Hz, 1H),
3
6
.47 (d, J=2.0 Hz, 1H), 6.27 (s, 1H), 4.82 (d, J=3.6 Hz, 2H), 3.38 (q,
2
2
13
J=7.1 Hz, 4H), 1.18 ppm (t, J=7.1 Hz, 6H); C NMR (101 MHz,
to evaporate. The aqueous solutions were then dialyzed with a dial-
CDCl ): d=162.9, 156.1, 155.1, 150.5, 124.4, 108.7, 106.4, 105.3,
ꢀ1
3
ysis membrane (8000–14000 gmol ) against a 1% aqueous solu-
9
7.7, 60.9, 44.8, 12.5 ppm.
tion of DMSO and then with water for 2 days with replacement of
dialysis solution every several hours to remove excess surfactant.
7
-Diethylamino-4-methylcoumarin-4-yl methyl (2-hydroxyethyl)
carbamate (6): DSC (0.65 g, 2.63 mmol) was added to 5 (0.3 g,
.21 mmol) dissolved in CH CN (40 mL), followed by the addition
1
3
of TEA (0.67 mL, 4.61 mmol). The mixture was stirred overnight at
room temperature, then ethanolamine (250 mg, 4.10 mmol) was
added, and the reaction solution was stirred for another 6 h.
CH CN was removed in vacuo, and the residue dissolved in CH Cl
2
Characterization of particles
3
2
The mean particle size (diameter) and zeta potential of particles
were recorded by using a photon correlation spectroscopy tech-
nique in a particle size analyzer (Zetasizer Nano ZS, Malvern Instru-
ments, UK) at 258C. The morphological shape of a typical nanopar-
ticle was observed by SEM (Hitachi S-4300). For SEM analysis, the
sample was completely dried at 378C and coated with gold.
was washed thoroughly with a saturated solution of NaHCO then
3
brine. The organic layer was dried over anhydrous sodium sulfate.
Further purification with column chromatography over silica gel
1
(
CH Cl /acetone 5:1) gave 6 as a light-yellow solid (42.1%). H NMR
2
2
(
400 MHz, [D ]DMSO): d=7.48–7.43 (m, 1H), 6.69 (d, J=8.5 Hz,
6
ꢀ
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ꢀ
1
Encapsulation efficiency (EE) of curcumin-loaded particles
FBS and 100 IUmL penicillin–streptomycin. The cells were rou-
tinely passaged at 80–95% confluency. Prior to use, cells were har-
vested by trypsinization (0.25% trypsin–0.02% EDTA).
The EE of curcumin incorporated in the nanoparticles was deter-
mined by dispersing the drug-loaded nanoparticles (0.5 mg) in eth-
anol and sonication (JK-5200B, Hefei Kinnick Machinery Manufac-
turing Co., Ltd.) for 12 h to ensure curcumin was dissolved thor-
oughly, and the precipitated polymer was removed by centrifuging
the samples at 30000g for 20 min twice. The concentration of cur-
cumin was then determined by UV/Vis spectroscopy at l=428 nm.
The measurements were performed in duplicate. The calculated EE
was 71.5% from Equation (2), according to the standard curve (Fig-
ure S10 in the Supporting Information). Similar to the method de-
scribed above, the EE of eNP1-coumarin6-10% was 62.2% by
UV/Vis absorbance at l=460 nm, according to the standard curve
In vitro cellular uptake studies by fluorescence microscopy
The cellular uptake of coumarin 6 loaded nanoparticles was stud-
ied by fluorescence microscopy (IX-81, OLYMPUS Co., Tokyo,
Japan). Briefly, RAW264.7, HeLa, or MCF-7 cells were seeded into
six-well plates at a density of 5ꢁ10 cells per well and cultured at
78C for 12 h, 62.5 mgmL of coumarin 6 loaded nanoparticles
were added. After incubation for 8 h, the culture medium was re-
moved and the cells were rinsed twice with PBS for fluorescence
assessment.
4
ꢀ1
3
(
Figure S5 in the Supporting Information).
FDA-loaded particle uptake and release in cell study
amountofloadeddrugðmgÞ
amountofaddeddrugðmgÞ
FDA-loaded particles were incubated with RAW264.7 macrophage
cells, HeLa, or MCF-7 for 8 h. After incubation, cells were thorough-
ly washed with PBS and were then irradiated with l=365 nm UV
light for 15 min. The images were observed by means of an invert-
ed fluorescence microscope 10 min later, and the fluorescence in-
tensity of cells incubated with FDA-loaded particles either with or
without light irradiation were recorded by using a Molecular Devi-
ces instrument (FlexStation 3, excitation wavelength 488 nm, emis-
sion wavelength 530 nm).
Entrapmentefficiencyð%Þ ¼
ꢂ 100%
ð2Þ
Photodegradation and light-triggered release study
To study the photodegradation of the nanoparticles,
ꢀ
1
a 12.5 mgmL suspension of particles in a quartz cuvette was irra-
diated and UV/Vis absorption spectra were recorded after each ir-
radiation. Coumarin 6 and curcumin were used as hydrophobic flu-
orophores to study the triggered release in solutions and cells. The
in vitro release kinetics of coumarin 6 from the particles was deter-
Patterned imaging experiment
ꢀ1
mined. Briefly, a 200 mgmL
solution of eNP-coumarin6-10%
5
5
For patterned imaging, RAW264.7 (6ꢁ10 ) and HeLa cells (2ꢁ10 )
were plated in 35 mm glass-bottomed dishes overnight. After the
nanoparticles was irradiated with UV light (l=365 nm,
1 mWcm ). At predetermined time points, samples were mea-
sured by means of a fluorometer with an excitation wavelength of
l=460 nm and the emission spectra were recorded from l=500
to 750 nm. For curcumin-loaded nanoparticles (eNP-curcumin-
ꢀ2
1
ꢀ1
addition of 62.5 mgmL solutions of eNP1-FDA-10% or eNP1-FDA-
0%, the cells were cultured for another 24 h. Cells were washed
1
with PBS twice and refilled with PBS. Then half of the dish was
masked. The other half was illuminated for 15 min with an
upward-facing light-emitting diode (LED) array (Shenzhen Planck
1
0%), the emission spectra were recorded from l=450 to 700 nm
with an excitation wavelength of l=420 nm. All measurements
ꢀ
2
Photoelectric Co., Ltd, l=365 nm, 15 mWcm ). After 15 min,
images were acquired by using a Zeiss upright fluorescence micro-
scope (Axio Imager A2).
were performed in triplicate.
In addition to light-induced variation of fluorescence intensity, we
also quantified the released and precipitated coumarin 6 after light
activation, eNP1-coumarin6-10% (samples diluted 25-fold,
ꢀ1
2
00 mgmL ) was irradiated at l=365 nm at intervals. Aliquots
Cytotoxicity study on the particles
(
400 mL) from a solution of irradiated particles (4.0 mL) were re-
The cytotoxicity of nanoparticles was evaluated by using an SRB
moved at different irradiation times. The aliquots were centrifuged
at 1000g for 5 min to separate the precipitated coumarin 6 and
dried under vacuum. Then dried coumarin 6 was dissolved in di-
chloromethane (450 mL) and centrifuged at 30000g for 10 min. The
amounts of released coumarin 6 at different irradiated solutions
were determined by absorbance at a wavelength of l=460 nm.
assay. HeLa cells were seeded in 96-well plates at a density of 6ꢁ
4
1
0 cells per well. After proliferation for 12 h, cells were treated
with various amounts of particles (eNP1-blk-10%; 100 to
ꢀ1
2
50 mgmL ) and incubated for 12 h. The cells were divided into
two groups (“UV” and “no UV” group). The UV group was irradiat-
ed for 15 min. After incubation for another 48 h for both groups,
cellular protein was fixed by the addition of 10% TCA (200 mL) at
4
8C for 1 h, the 96-well plates were then washed five times with
1
Cell culture
ꢀ
deionized water and air dried. SRB solution (100 mL; 4 mgmL in
1% acetic acid) was added to each well and the cells were stained
for 30 min. Then, SRB solution was removed and the plates were
washed five times with 1% acetic acid. After air drying, 10 mm Tris
base solution (150 mL) was added to the 96-well plates to solubilize
the protein-bound dye on a gyratory shaker for 15 min. Absorb-
ance values were read on a microplate reader (Flexstation 3, Molec-
ular Devices) at a wavelength of l=540 nm.
Macrophage cell line (RAW264.7) was grown in Dulbecco’s modi-
fied Eagle cell culture medium (DMEM) containing 10% heat-inacti-
vated fetal bovine serum (FBS), 100 IUmL penicillin–streptomycin
ꢀ
1
in an atmosphere of 5% CO and 95% relative humidity. The cells
2
were routinely passaged at 80–95% confluency. Prior to use, cells
were harvested by trypsinization (0.125% trypsin/0.05% ethylene-
diaminetetraacetic acid (EDTA)).
Human uterine cervical cancer cells (HeLa) and MCF-7 were grown
For cell viability to curcumin, HeLa cells were seeded at a density
of 6ꢁ10 cellsmL in a 96-well plate and incubated overnight to
allow the cells to attach to the surface of the wells. The cells were
4
ꢀ1
at 378C in a humidified atmosphere with 5% CO in Roswell Park
2
Memorial Institute (RPMI) medium 1640, supplemented with 10%
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then exposed to nanoparticles (eNP1-curcumin-10%) with various
concentrations close to the IC50 value of curcumin for HeLa cells.
After incubation for 12 h, cells treated with eNP1-curcumin-10%
were thoroughly washed and cells in the UV group were then irra-
diated with l=365 nm light for 15 min. After incubation for anoth-
er 48 h, the cell viability was determined by SRB assay, as described
above, and IC50 values were calculated based on the percentage of
treatment over control. Experiments were repeated three times
and data were presented as meanꢃSD.
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