Redox-Hypersensitive Organic Nanoparticles for Selective Treatment of Cancer Cells

Article abstract of DOI:10.1021/acs.chemmater.6b01641

The diselenide-containing fluorescent molecules (SeBDP) and antitumor drug paclitaxel (SePTX) were synthesized and used for constructing SeBDP nanoparticles (SeBDP NPs) and SePTX NPs in aqueous solution through nanoprecipitation method. Both SeBDP NPs and SePTX NPs exhibit high stability and excellent reduction-sensitivity. More interestingly, SeBDP and SePTX could coassemble into uniform and spherical nanoparticles (co-NPs) with dual functions of fluorescence imaging and antitumor activity. These organic NPs could be internalized by different cells as revealed by confocal laser microscopy. Importantly, the co-NPs exhibited selectivity of cytotoxicities between cancerous and normal cells. The cellular proliferation inhibition toward tumor cells (including HeLa and MCF-7 cells) was obviously higher than that toward normal cells (BEAS-2B and L929 cells), which might be attributed to the increasing reactive oxygen species in cancer cells treated by diselenide-containing NPs. These results highlight the potential of developing diselenide-containing organic molecules as molecularly tunable and sensitive nanoplatform for cancer treatment.

Full text of DOI:10.1021/acs.chemmater.6b01641

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Article
Redox-Hypersensitive Organic Nanoparticles
for Selective Treatment of Cancer Cells
Wei Zhang, Wenhai Lin, Qing Pei, Xiuli Hu, Zhigang Xie, and Xiabin Jing
Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.6b01641 • Publication Date (Web): 01 Jun 2016
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Redox-Hypersensitive Organic Nanoparticles for Selective Treat-
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Wei Zhang,†,‡ Wenhai Lin,†,‡ Qing Pei,†,‡ Xiuli Hu,† Zhigang Xie, *,† and Xiabin Jing†
†State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese
Academy of Sciences, 5625 Renmin Street, Changchun, Jilin 130022, P. R. China
‡University of Chinese Academy of Sciences, Beijing 100049, P. R. China
ABSTRACT: The diselenide-containing fluorescent molecules (SeBDP) and antitumor drug paclitaxel (SePTX) were syn-
thesized and used for constructing SeBDP nanoparticles (SeBDP NPs) and SePTX NPs in aqueous solution through nano-
precipitation method. Both SeBDP NPs and SePTX NPs exhibit high stability and excellent reduction-sensitivity. More
interestingly, SeBDP and SePTX could co-assemble into uniform and spherical nanoparticles (co-NPs) with dual functions
of fluorescence imaging and antitumor activity. These organic NPs could be internalized by different cells as revealed by
confocal laser microscopy. Importantly, the co-NPs exhibited selectivity of cytotoxicities between cancerous and normal
cells. The cellular proliferation inhibition toward tumor cells (including HeLa and MCF-7 cells) was obviously higher than
that toward normal cells(BEAS-2B and L929 cells), which might be attributed to the increasing reactive oxygen species in
cancer cells treated by diselenide-containing NPs. These results highlight the potential of developing diselenide-
containing organic molecules as molecularly tunable and sensitive nanoplatform for cancer treatment.
lence state sulfur compounds. A series of selenium-
Owing to the advantages of precise molecular structure
containing compounds were reported in the pharmaco-
and multifarious synthesis chemistry, self-assembly of
chemistry as antioxidants and stimuli-sensitive drug de-
organic molecules has been used to fabricate various
livery carriers. For example, Xu’s group successfully intro-
functional materials.1-3 The assembly can be realized
duced diselenide bonds into a series of amphiphilic poly-
through supramolecular chemistry, such as hydrophobic
mers with different topology, which could self-assemble
interactions of amphiphilic small molecules and π-π in-
into micellar structures for drug delivery and enzyme
teractions between π-conjugated monomers.4,5 For exam-
mimics.18-21 However, there is few report about the
ple, Kasai et al. reported the fabrication of pure
diselenide-containing nanoparticles assembled from or-
nanodrugs from podophyllotoxin (PPT) dimer, which was
ganic molecules.
called carrier-free pure nanodrugs (PNDs).6 Since then,
increasing work about the dimer-induced self-assembly of
For the tumor treatment, it is challenging to develop
pure drugs has been reported.7-10 Recently, our group re-
drugs which can selectively kill cancer cells and show less
ported that a fluorescent dye of BODIPY (4, 4-difluro- 4-
toxicity towards normal cells. Scientists have made much
bora-3a,4a-diaza-s-indacence) dimer could self-assemble
effort to enhance tumor selectivity by using multifunc-
into nanoparticles for cellular imaging.11 Inspired by these
tional nanomedicines.22-24 The most widely used strategy
works, we hypothesized that the dimeric organic mole-
cules could form nanoparticles via self-assembly under
suitable conditions.
is the surface modification of vehicles with targeting moi-
eties including peptides (e.g. RGD),25 small molecules (e.g.
folate and galactose),26-28 and even short oligonucleotide
(aptamer).29-32 In general, tumor tissues and cells have
As a necessary microelement for human body, selenium
many unique characteristics, including lower pH values,
plays an important part in wide ranges of biological pro-
higher reduction potential and ROS levels (oxidative
cesses, such as the regulation of reduction and oxidation
stress), special biological enzymes, and tissue hypoxia,
processes which are of great importance to cancer preven-
etc.33-35 Thus, another strategy is using “smart nanocarri-
tion.12-16 Selenium possesses many unique chemical prop-
ers”, which can make quick response to relevant tumor
erties owing to its special electronegativity and atomic
microenvironment, such as lower pH value,36-39 high con-
radius. The bond energy of Se-Se is 172 KJ mol-1, which is
centration of glutathione (GSH)40,41 and enzyme.42,43 How-
weaker in comparison with that of C-C bond (364 KJ mol-
ever, all methods mentioned above usually need sophisti-
1) and S-S bond (240 KJ mol- 1).17 This difference makes it
cated and tedious synthesis and modification processes.
more sensitive to be oxidized and reduced than low va-
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Thus, it is challenging for researchers to develop smart and Figure S1C, all the protons and the peak at m/z 389.98
1
nanomaterials via a simple way.
were all agreed well with theoretical calculation.
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Figure 1. (A) DLS results and (B) TEM image of SeBDP
NPs. (C) Changes of the diameter and PDI as a function of
time measured by DLS. (D) TEM image of SeBDP NPs
after being stored for two weeks.
Scheme 1. A schematic illustration of (A) the dimer-
induced self-assembly of SeBDP, SePTX and the co-
assembly of the two dimers and (B) the cell endocytosis
and disassembly upon the intracellular GSH of the
nanoparticles.
Synthesis of SeBDP and SeBDP NPs. Passerini reaction
is a kind of three-component reactions involving carbox-
ylic acid, isocyanide, and aldehyde, which is highly effi-
cient and tolerant.45,46 Our group has reported the synthe-
sis of polymers via Passerini reaction.47,48 In this work, the
target diselenide-containing BDP molecules were synthe-
sized via the similar processes. 4,4-Difluoro-8-(4- isocy-
anophenyl)-3,5-dimethyl-4-bora-3a,4a-diaza-indacene
(NC-BDP) was made by following the literature meth-
ods.49 Then NC-BDP, 6,6'-diselanediyldihexanoic acid and
o-nitrobenzaldehyde were reacted in dichloromethane for
4 days at room temperature. The obtained SeBDP was
In the present work, reduction-sensitive diselenide-
containing fluorescent molecule SeBDP and antitumor
drug SePTX were synthesized, and these two molecules
could self-assemble into nanoparticles (SeBDP NPs and
SePTX NPs) or co-assembly into co-NPs in the absence of
any surfactants or adjuvants (Scheme 1). The co-NPs not
only possess dual functions of fluorescence imaging and
antitumor activity, but also exhibit high selectivity on
tumor cells (human cervical carcinoma (HeLa) cells and
human mammary tumor (MCF-7) cells).
1
characterized by H NMR and matrix-assisted laser de-
sorption/ionization time-of-flight mass spectrometry
(MALDI-TOF MS). As shown in Figure S2A, the signals at
8.57 ppm and 6.76 ppm for protons of imine and methane
indicated that NC-BDP was successfully incorporated into
SeBDP dimer. The peak at m/z 1309.4 in the MALDI-TOF
MS spectrum (Figure S2B) further confirmed the success-
ful synthesis of the fluorescent dimer.
RESULTS AND DISCUSSION
Synthesis of 6,6'-diselanediyldihexanoic acid. The
synthetic routes for the diselenide-containing acid were
shown in Figure S1A (Supporting Information). Disodium
diselenide (Na2Se2) was synthesized according to the lit-
erature methods.44 Then, Na2Se2 was treated with a tetra-
hydrofuran (THF) solution of 6-bromohexanoic acid un-
der inert atmosphere at 50 oC overnight. After purification
on a silica gel column, the 6,6'-diselanediyldihexanoic
acid was obtained and characterized by proton nuclear
magnetic resonance (1H NMR) and electrospray ioniza-
tion mass spectrometry (ESI-MS). As shown in Figure S1B
SeBDP could self-assemble into nanoparticles (SeBDP
NPs) in aqueous solution via nano-precipitation method.
The THF solution of SeBDP was added dropwise into de-
ionized water under stirring and then dialyzed to remove
the residual THF. The morphology and size distribution
of SeBDP NPs were characterized by transmission elec-
tronic microscopy (TEM) and dynamic light scattering
(DLS), respectively. As shown in Figure 1A, the average
diameter of SeBDP NPs measured by DLS was 158 nm,
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and the polydispersity index (PDI) was 0.12. The TEM
image (Figure 1B) indicated the isolated nanoparticles,
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whose size was close to the value obtained by DLS. The
diameter and PDI measured by DLS almost kept un-
changed even in two weeks (Figure 1C). Moreover, the
morphologies of SeBDP NPs were maintained even after
being stored for two weeks (Figure 1D). The results above
demonstrated that SeBDP NPs could keep their stability
in aqueous solution. As shown in Figure S3, SeBDP NPs
also exhibited favorable stability in physiological envi-
ronment as evidenced by the unchangeable particle size
and PDI for up to 24 h by incubating the SeBDP NPs in
PBS (pH 7.4) containing FBS (10 %) at 37 oC.
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Figure 3. (A) Size changes of SeBDP NPs (42.5 µg mL-1)
over time and (B) size distribution changes of SeBDP NPs
(42.5 µg mL-1) after 7 h determined by DLS in the
presence of different concentrations of GSH.
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with low concentration of reducing agents. As control, the
change of size was negligible over 7 h in the absence of
GSH, confirming the good stability of SeBDP NPs. These
results confirmed that SeBDP NPs were reduction-
sensitive and could disassemble in the presence of reduc-
ing agents. Meanwhile, we also monitored the zeta poten-
tial changes along with the size changes. As shown Figure
S4, the zeta potential of the nanoparticles gradually in-
creased along with the incubation time, changing from -
23.3 mV to -1.7 mV. Subsequently, we examined whether
the reductive behaviors could still be kept in serum con-
taining solution with GSH. As shown in Figure S5, the size
of NPs increased from 220 nm to 1718 nm and obvious
flocculent suspension could be found, which indicate the
efficient sensitivity of the formed NPs.
Figure 2. (A) UV-vis absorption and (B) fluorescence
spectra of SeBDP NPs in water and SeBDP in DMF:
H2O=1: 1 (v/v). Insets in (B) are photos of SeBDP in DMF:
H2O=1: 1 (v/v) solution (left) and SeBDP NPs in water
(right) under natural light and the illumination of UV
light (365 nm).
Cellular Uptake. The biocompatibility of nanomaterials
is vital for their biomedical applications. The in vitro cyto-
toxicities of SeBDP NPs toward HeLa cells were quantified
by methyl tetrazolium (MTT) viability assay. Figure S6
showed the viability of cells incubated with various con-
Figure 2 showed the UV-vis absorption and fluores-
cence spectra of the SeBDP NPs in water and SeBDP in
DMF:H2O = 1: 1 (v/v), respectively. The maximum absorp-
tion of SeBDP NPs in water was centered at 507.5 nm,
which was red-shifted by 7 nm relative to that of SeBDP.
Bathochromic shift absorption of SeBDP NPs was at-
tributed to the possible J-aggregate of SeBDP in aqueous
solution, as reported for the aggregation of BODIPY.50 In
Figure 2B, the maximum fluorescence wavelength was
seen at 515 nm for SeBDP, but almost no fluorescence was
seen for SeBDP NPs due to the aggregation-caused
quenching (ACQ).51 The phenomenon of ACQ could be
observed visually by photos under the 365 nm light irradi-
ation. As shown in Figure 2B, SeBDP in DMF: H2O=1: 1
(v/v) emitted a strong yellow-green fluorescence while no
fluorescence was observed for SeBDP NPs in water.
Redox Sensitivity. To demonstrate the reduction-
sensitive disruption of SeBDP NPs, the size changes of
SeBDP NPs were monitored by DLS in presence of GSH.
As shown in Figur 3A, the size of SeBDP NPs increased
from 157 nm to 2586 nm at 7 h with 10 mM GSH, which
was due to the disruption of diselenide bond and aggrega-
tion of hydrophobic fragments into large agglomerates.52
It is well known that the concentration of GSH is approx-
imately 1-10 mM in cytosol.53 Thus, we also tested the re-
duction-sensitive behaviors upon the treatment of 1 mM
GSH. The size of SeBDP NPs increased from 157 nm to
1149 nm, indicating efficient reduction-sensitivity even
Figure 4. Confocal microscopy images of HeLa cells (A)
pretreated with GSH (10 mM) for 2 h, (B) without any
pretreatment and (C) pretreated with NEM (1 mM) for 15
min, then treated with SeBDP NPs (2 µg mL-1) for 2 h. For
each panel, the images from left to right show cell nuclei
stained by DAPI (blue), BDP fluorescence in cells (green),
and overlays of both images. Scale bar: 20 μm.
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centrations of SeBDP NPs for 24 h. SeBDP NPs didn’t lecular weight of SePTX. SePTX also could self-assemble
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show obvious cytotoxicities on cell proliferation with the
concentration up to 25 μg mL-1. We could come to the
conclusion that SeBDP NPs could be used as safe nano-
materials for cell imaging.
into nanoparticles (SePTX NPs) in aqueous solution via
reprecipitation method. The SePTX NPs possessed spher-
ical morphology with diameter of 120 nm and low size
distribution as revealed by TEM and DLS in Figure S9A
and Figure S9B. The diameter and PDI of SePTX NPs
measured by DLS were almost unchanged over half a
month (Figure S9C). SePTX NPs also exhibited excellent
stability in PBS (pH 7.4) containing FBS (10 %) at 37 oC for
24 h (Figure S9D). The reduction-induced dissociation of
the SePTX NPs was confirmed in the presence of GSH as
shown in Figure S10.
The cellular uptake and reduction-response of SeBDP
NPs were carried out by confocal laser scanning micros-
copy (CLSM). HeLa cells were firstly pretreated with 10
mM GSH or 1 mM N-ethylmaleimide (NEM) according to
the reported protocol,54,55 and then incubated with 2 μg
mL-1 of SeBDP NPs for 2 h. The untreated cells incubated
with the same dose of NPs were used as control (Figure
4B). As expected, the strongest intracellular green fluo-
rescence was observed in the cytoplasm for the GSH pre-
treated cells in Figure 4A, indicating the effective inter-
nalization of SeBDP NPs. In contrast, little fluorescence
was observed in pretreated with NEM (Figure 4C), an effi-
cient modifier to react with biological thiol groups.55 This
results demonstrated that SeBDP NPs could rapidly disso-
ciate in cells in the presence of intracellular reducing
agents. We also used flow cytometry to quantitatively
examine the cellular uptake of the nanoparticles. As
shown in Figure S7, most of HeLa cells were able to inter-
nalize NPs because of the increased green fluorescence for
cells treated with SeBDP NPs.
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Due to the structural similarities of SeBDP and SePTX,
we speculated that they could co-assembled into nano-
particles containing both fluorescent chromophore (BDP)
and anti-tumor drug (PTX), which could be used as po-
tential imaging and therapeutic agents. The co-
assembling nanoparticles (co-NPs) were obtained after
the mixture of SeBDP and SePTX (SePTX: 1.4 mg and
SeBDP: 0.2 mg) in THF solution was dropped into water.
In order to further demonstrate the structure of the co-
assembly, we used the scanning electronic microscopy
(SEM) and energy dispersive spectrometer (EDS) to quali-
tatively analysis the distribution of the element (Se and B).
As shown in Figure S11A, spherical nanoparticles with the
diameter around 150 nm could be seen. Not all Se ele-
ments superpose with the B elements (Figure S11B). The
overlapping regions of Se and B are ascribed to the SeBDP
(containing both Se and B element), while the remaining
regions are assigned to the SePTX (only containing Se
element). These results validate partly the co-assembly of
the two small organic molecules (SeBDP and SePTX). The
final concentrations of SeBDP and SePTX were 118 μg mL-1
and 17.5 μg mL-1, respectively, which were determined by
high-performance liquid chromatography (HPLC) with
UV-vis spectrophotometer (as described in the Experi-
mental Section). Figure 5A showed isolated spherical par-
ticles with an average diameter of 190-200 nm. The aver-
age size of co-NPs measured by DLS was 195.2 nm and the
PDI was 0.087 (Figure 5B). The co-NPs also maintained
Synthesis of SePTX NPs and co-NPs NPs. Recently,
carrier-free pure nanodrugs have drawn much attention,
in which native pharmacological drugs are converted into
nanoscale formulation.56 Kasai’s group demonstrated that
prodrugs of the commercial antitumor agents (e.g. SN-38
and PPT) with dimeric structures could form stable nano-
particles.6,8 Inspired by their works, we synthesized the
diselenide-containing PTX dimer via the condensation
1
reaction, which was confirmed by H NMR (Figure S8)
and MALDI-TOF MS. The peak at 2061.62 was ascribed to
[M+H]+ of SePTX, which was close to the theoretical mo-
Figure 6. (A) Size and PDI changes of co-NPs resulting
from reduction-induced disassembly in the presence of 10
mM GSH. Inside: Photos of co-NPs in the absence and
presence of 10 mM GSH after 0.5 h. (B) The size changes
of co-NPs in the presence of different concentrations of
GSH. Inside: Changes of size distribution of co-NPs with
the treatment of GSH after 7 h.
Figure 5. (A) TEM image and (B) DLS results of co-NPs.
Changes of diameter and PDI of co-NPs (C) in water and
(D) in PBS with FBS (10 %) over different times measured
by DLS.
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cence from BDP and the red fluorescence from Lyso
the excellent stability in water (Figure 5C) or in PBS con-
1
2
taining FBS (10 %) (Figure 5D), indicating the co-
assembling did not affect the stability.
Tracker red, indicating the accumulation of co-NPs in
lysosomes.
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The reduction-sensitive behaviours of the co-NPs were
investigated through the changes of size and morphology.
As shown in Figure 6A, the increase in diameter of co-NPs
from 143 nm to 2261 nm was observed after adding GSH in
half an hour. The PDI also increased from 0.16 to 0.39,
which confirmed the disassembly of co-NPs. The co-NPs
solution changed from clear to muddy, and a large num-
ber of precipitates were found (photos in Figure 6A). Fur-
thermore, the spherical nanoparticles became irregular,
and large agglomerates could be seen after 0.5 h upon the
treatment of 10 mM GSH (Figure S12). Addition of differ-
ent concentrations of GSH could result in the disparate
size changes. As shown in Figure 6B, the size of co-NPs
increased from 145.6 nm to 2045 nm in the presence of 10
mM GSH for 7 h, and could increase from 145.6 nm to
308.6 nm with 1 mM GSH. These results confirmed that
reduction-sensitivity could still be maintained after co-
assembly.
Cytotoxicitieds of co-NPs toward the tumor cells (HeLa
and MCF-7 cells) and the normal cells (BEAS-2B and L929
cells) were evaluated by MTT assays. Comparing with the
free PTX, co-NPs have shown lower cytotoxicity as shown
in Figure 8A-C and Figure S10, which might be attributed
to the rapid diffusion of PTX into cytoplasm other than
endocytosis of co-NPs. Interestingly, obvious cell cytotox-
icities were induced by co-NPs toward cancer cells com-
pared with normal cells. More than 75 % of HeLa cells
and 60 % of MCF-7 cells were killed at the concentration
of 5 μg mL-1 of PTX. In contrast, no more than 25 % of
BEAS-2B cells and 20 % of L929 cells were dead, as shown
in Figure 8C and Figure S14. The IC50 values were about
0.83 μg mL-1 and 3.03 μg mL-1 toward HeLa cells and MCF-
7, which were actually much smaller than that of the
normal cells (Figure 8D and Table S2). These results indi-
cated the co-NPs possessed good selectivity on tumor
cells.
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Cellular uptake of nanoparticles is important for exert-
ing their function. The internalization of co-NPs by HeLa,
MCF-7, BEAS-2B and L929 cells were evaluated by CLSM.
These cells were incubated with co-NPs (SeBDP: 2 μg mL-1)
for 0.5 h and 2 h, respectively. The cell nuclei were dyed
with DAPI. As shown in Figure 7A and Figure S13, green
fluorescence was observed in the cell plasma, indicating
that the co-assembled nanoparticles could be endocy-
tosed by both cancer and normal cells. Moreover, the
green fluorescence in cells increased obviously along with
the increasing incubation time. The way of endocytosis
was studied by colocalization of the nanoparticles and
lysosomes labelled with red fluorescence (Lysosome
Tracker red). As shown in Figure 7B, the observed yellow
colocalization area was the overlay of the green fluores-
As an essential regulator of reactive oxygen species
(ROS) in vivo, selenium is considered that it will undergo
a series of sophisticated biological processes. It might be
reduced to low-valence-state (Se-2 or HSe-) by thiol-
containing compounds or be oxidized to high-valence-
state (SeO32- or SeO42-) by O2 and H2O2. During these pro-
cesses, ROS will be generated continuously, which are
crucial intermediates in selenium-induced apoptosis.57,58
Thus, in order to study the mechanism for selectivity of
the selenium-containing nanomedicines, the intracellular
concentration of ROS was quantified by using the 2’,7’-
dichlorofluorescence diacetate (DCFH-DA) fluorescence
Figure 8. In vitro cytotoxicities of different concentra-
tions of PTX and co-NPs toward (A) HeLa cells, (B) MCF-
7 cells and (C) BEAS-2B cells incubated for 48 h. (D)
Comparison of cytotoxicities in vitro toward tumor cells
(HeLa and MCF-7 cells) and normal cells (BEAS-2B cells)
after being incubated with co-NPs for 48 h. Statistical
significance analysis was assessed by SPSS via one-way
ANOVA test; P≤0.01 were considered statistically highly
significant and were denoted as “**”; P≤0.001 were con-
sidered statistically highly significant and were denoted as
“***”.
Figure 7. Representative CLSM images of (A) HeLa and
BEAS-2B cells incubated with co-NPs for 0.5 h and 2 h,
respectively. For each panel, the images from left to right
show cell nuclei stained by DAPI (blue), BDP fluores-
cence in cells (green), and overlays of both images. Scale
bar: 20 μm. (B) Colocalization images of HeLa cells treat-
ed with co-NPs for 2 h. The images from left to right show
cell nuclei stained by DAPI (blue), BDP fluorescence in
cells (green), Lyso Tracker fluorescence (red) in lyso-
somes and overlays of three images. Scale bar: 20 μm.
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(2) Ren, Y.; Hiszpanski, A. M.; Loo, Y.-L., Self-Assembly of Axial-
ly Functionalized Subphthalocyanines in Thin Films. Chem.
Mater. 2015, 27, 4008-4014.
method in HeLa and BEAS-2B cells. DCFH-DA is a com-
monly used fluorescence sensor for ROS, which can be
rapidly oxidized to 2’,7’-dichlorofluorescein (DCF) with
green fluorescence, and the fluorescence intensity is pro-
portional to the concentration of ROS.59 As shown in Fig-
ure S15-S17, the fluorescence intensity of HeLa and MCF-7
cells treated with the SePTX NPs are much stronger than
that of the control group. SePTX was used to instead of
co-NPs due to the same green fluorescence of co-NPs and
DCFH-DA under excitation at 488 nm. There are almost
no obvious changes of the DCF fluorescence intensity in
the normal cells (L929 or BEAS-2B cells), validating that
the selenium-containing nanoparticles could up-regulate
the intracellular ROS in cancer cells. Thus, we concluded
that the selectivity between normal cells and tumor cells
was mainly contributed to the higher selenium-induced
ROS in cancer cells, which was consistent with the results
of Xu’s group.60 Very recently, a similar strategy of reduc-
ing glutathione levels in cancer cells was used to enhance
the photodynamic therapy and preferential killing of can-
cer cells.61,62 This selenium bonds-based selective treat-
ment of cancer cells without any additional targeting
agents is valuable for the development of effective clinical
antitumor drugs.
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CONCLUSION
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Effect of Molecular Structure on the Anticancer Drug Release
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In this work, we reported the synthesis of reduction-
sensitive diselenide-containing dimers (SeBDP and SePTX)
and corresponding organic nanoparticles formed by su-
pramolecular self-assembly. It is the first example of di-
mer-induced self-assembly from selenium-containing
organic molecules. The obtained nanoparticles showed
excellent reductive sensitive behaviors and good selectivi-
ty between tumor cells and normal cells in absence of
targeting molecules. This highly selective cytotoxicities of
nanoparticles is promising in future cancer therapy. The
diselenide-based self-assembling nanoparticle represents
a new and important synthetic development in the design
of functional nanomaterials.
(10) Pei, Q.; Hu, X.; Li, Z.; Xie, Z.; Jing, X., Small Molecular Na-
nomedicines Made from a Camptothecin Dimer Containing a
Disulfide Bond. RSC Adv. 2015, 5, 81499-81501.
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dulterated BODIPY-dimer Nanoparticles with High Stability and
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enzymes: Designed and Redesigned. Chem. Soc. Rev. 2011, 40,
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ASSOCIATED CONTENT
Supporting Information. Experimental details and sup-
porting figures. This material is available free of charge via
the Internet at http://pubs.acs.org.
(14) Xu, H.; Gao, J.; Wang, Y.; Wang, Z.; Smet, M.; Dehaen, W.;
Zhang, X., Hyperbranched Polyselenides as Glutathione Peroxi-
dase Mimics. Chem. Commun. 2006, 7, 796-798.
(15) Rayman, M. P., Selenium in Cancer Prevention: a Review of
the Evidence and Mechanism of Action. Proc. Nutr. Soc. 2005,
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AUTHOR INFORMATION
Corresponding Author
(16) Preedy, V. R., Selenium: Chemistry, Analysis, Function and
Effects. Royal Society of Chemistry: 2015.
*
corresponding authors: xiez@ciac.ac.cn
(17) Kildahl, N. K., Bond Energy Data Summarized. J. Chem.
Educ. 1995, 72, 423-424.
Funding Sources
(18) Xu, H.; Cao, W.; Zhang, X., Selenium-containing Polymers:
Promising Biomaterials for Controlled Release and Enzyme
Mimics. Acc. Chem. Res. 2013, 46, 1647-1658.
This work was supported by the National Natural Science
Foundation of China (Project No. 51522307 and 51373167).
(19) Ma, N.; Li, Y.; Xu, H.; Wang, Z.; Zhang, X., Dual Redox Re-
sponsive Assemblies Formed from Diselenide Block Copolymers.
J. Am. Chem. Soc. 2009, 132, 442-443.
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