Selenol-Based Nucleophilic Reaction for the Preparation of Reactive Oxygen Species-Responsive Amphiphilic Diblock Copolymers

Selenide-containing amphiphilic copolymers have shown significant potential for application in drug release systems. Herein, we present a methodology for the design of a reactive oxygen species-responsive amphiphilic diblock selenide-labeled copolymer. This copolymer with controlled molecular weight and narrow molecular weight distribution was prepared by sequential organoselenium-mediated reversible addition fragmentation chain transfer (Se-RAFT) polymerization and selenol-based nucleophilic reaction. Nuclear magnetic resonance (NMR) and matrix-assisted laser desorption/ionization time-to-flight (MALDI-TOF) techniques were used to characterize its structure. Its corresponding nanomicelles successfully formed through self-assembly from the copolymer itself. Such nanomicelles could rapidly disassemble under oxidative conditions due to the fragmentation of the Se–C bond. Therefore, this type of nanomicelle based on selenide-labeled amphiphilic copolymers potentially provides a new platform for drug delivery.


Characterization
The number-average molecular weight (Mn) and molecular weight distribution (Ð) of the resulting polymers were determined by a TOSOH HLC-8320 size exclusion chromatograph (SEC) equipped with a TSKgel SuperMultiporeHZ-N column (3) (4.6 × 150 mm) at 40 °C. Tetrahydrofuran served as the eluent with a flow rate of 0.35 mL min -1 . SEC samples were injected using a TOSOH HLC-8320 SEC plus autosampler. The molecular weights were calibrated with polystyrene (PS) standards. 1 H (300 MHz) NMR spectra were recorded on a Bruker Avance 300 spectrometer. Chemical shifts are presented in parts per million (δ) relative to CHCl3 (7.26 ppm in 1 H NMR). Transmission electron microscopy (TEM) was performed with a HITACHI HT7700 microscope operating at a 120-kV accelerating voltage. The fluorescence emission spectra (FL) were obtained on a HITACHI F-4600 fluorescence spectrophotometer at room temperature. Hydrodynamic diameter (Dh) was determined by dynamic light scattering (DLS) using a Brookhaven NanoBrook 90Plus PALS instrument at 25 °C with a scattering angle of 90°. Fourier transform infrared spectroscopy (FT-IR) Scheme 1. Selenol-based nucleophilic reaction as a novel reaction forming amphiphilic diblock copolymers.

Characterization
The number-average molecular weight (M n ) and molecular weight distribution (Ð) of the resulting polymers were determined by a TOSOH HLC-8320 size exclusion chromatograph (SEC) equipped with a TSKgel SuperMultiporeHZ-N column (3) (4.6 × 150 mm) at 40 • C. Tetrahydrofuran served as the eluent with a flow rate of 0.35 mL min −1 . SEC samples were injected using a TOSOH HLC-8320 SEC plus autosampler. The molecular weights were calibrated with polystyrene (PS) standards. 1 H (300 MHz) NMR spectra were recorded on a Bruker Avance 300 spectrometer. Chemical shifts are presented in parts per million (δ) relative to CHCl 3 (7.26 ppm in 1 H NMR). Transmission electron microscopy (TEM) was performed with a HITACHI HT7700 microscope operating at a 120-kV accelerating voltage. The fluorescence emission spectra (FL) were obtained on a HITACHI F-4600 fluorescence spectrophotometer at room temperature. Hydrodynamic diameter (D h ) was determined by dynamic light scattering (DLS) using a Brookhaven NanoBrook 90Plus PALS instrument at 25 • C Polymers 2019, 11, 827 3 of 12 with a scattering angle of 90 • . Fourier transform infrared spectroscopy (FT-IR) was recorded with the Bruker TENSOR 27 FT-IR instrument using the conventional KBr pellet method. The elemental composition of the surfaces was measured with X-ray photoelectron spectroscopy (XPS) (Thermo Fisher Scientific ESCALAB 250 XI, Al KR source).

Typical Procedure of Organoselenium-Mediated Controlled Radical Polymerization
A dry 10-mL ampule was filled with styrene (8.0 mL, 80 mmol), Se-benzyl O-(4-methoxyphenyl) carbonodiselenoate (Se-CTA) (0.6147 g, 1.6 mmol), and AIBN (0.0788 g, 0.48 mmol). The solution was degassed using the standard freeze-pump-thaw method (at least 3 cycles). The ampule was flame-sealed and placed into an oil bath, which was thermoset at the desired temperature. At timed intervals, the ampule was immersed into iced water and then opened. The contents were dissolved in 3 mL of tetrahydrofuran (THF) and precipitated into 400 mL of methanol. Carbonodiselenoate-labeled polystyrene (PS-Se) was obtained by filtration and then dried to constant weight at room temperature under vacuum. The conversion of styrene was gravimetrically determined.

Typical Procedure of Selenol-Based Nucleophilic Addition of PS-Se to PEGMA
Without additional notes, a typical procedure for optimization of reaction time is given below as an example. A dry 5-mL ampule was filled with PS-Se-1 (M n,SEC = 1900 g mol −1 , 95 mg, 0.059 mmol), PEGMA950 (M n = 950 g mol −1 , 0.59 g, 0.59 mmol), and DMF (2.0 mL) with a stir bar. After being thoroughly bubbled with argon for 15 min to eliminate the dissolved oxygen, n-hexylamine (30 µL) was added. Then, the ampule was flame-sealed immediately. After stirring for 1 d at 60 • C, the solution was precipitated into 100 mL of methanol. The polymer was obtained by filtration and then dried to constant weight at room temperature under vacuum.

Fabrication of PS-Se-b-PEGMA Micelles
PS-Se-b-PEGMA (2 mg) was dissolved in DMF (2 mL), and then deionized water (0.3 mL) was added to the solution using a syringe pump at the rate of 0.2 mL h −1 at room temperature. After addition of the water, the suspension was stocked for 1 day to stabilize the aggregates. Then, the suspension was dialyzed in a dialysis bag (molecular weight cutoff: 1000 Da) against deionized water for at least 24 h to remove DMF. After dialysis, the suspension was added to deionized water until the volume increased to 2 mL with a concentration of 1 mg mL −1 for further tests.

Chemical Oxidation of PS-Se-b-PEGMA Micelles by H 2 O 2
In brief, 0.5 mL of PS-Se-b-PEGMA micelle suspension was kept in a 1-mL ampule and then placed into H 2 O 2 solution (33 mM). After stirring for 5 h, the micelle suspension was freeze-dried for TEM studies.

In Vitro Cytotoxicity Study of the Micelles
The samples were disinfected under ultraviolet light, and then five groups of extracts (2, 4, 6, 8, and 10 mg mL −1 ) were prepared. The blank group (culture medium) and the control group (culture medium and cells) were set up to compare with the experimental group. NIH-3T3 cells were inoculated on 96-well plates at a density of 8 × 10 4 mL −1 (8 × 10 3 well −1 ). Cells were cultured in incubators (at 37 • C and 5% carbon dioxide) to become adhered to the 96-well plates. After 24 h, the medium was removed and the extract was added to culture. Then, 24 h later, the extract was removed and 10 µL CCK-8 solution and 90 µL culture medium were added to each pore. Then, cells were incubated at 37 • C for 1 h. A microplate reader was used to measure the absorbance of the sample at 450 nm.

Drug Loading
The following process was carried out in the dark. A mixture of 5.0 mg DOX·HCl and 3.6 µL of triethylamine (TEA) in 1.0 mL of dimethyl sulfoxide (DMSO) was added to a 2-mL ampule. After stirring overnight, excess TEA was removed by rotary evaporation to give the hydrophobic DOX solution. Then, 4 mL of PBS solution (50 mM, pH 7.4) was added dropwise to the mixture of copolymer in DMF (1.0 mL, 1 mg mL −1 ) and DOX base solution (50 µL, 5.0 mg mL −1 ) with stirring at room temperature. Afterwards, in order to remove both unencapsulated DOX and the organic solvent, the mixture was dialyzed against PBS solution (50 mM, pH 7.4) for 24 h.
The amount of DOX was determined by fluorescence (FL4600) measurement (excitation at 480 nm). First, a calibration curve was obtained by measuring the fluorescence intensity of different concentration DOX/DMSO solutions. Second, the fluorescence intensity of DOX-loaded micelles dissolved in DMSO was analyzed. The amount of DOX loaded in the micelles could be determined using the calibration curve.

Oxidation-Responsive Drug Release
In brief, 33 mM H 2 O 2 was added into freshly prepared self-assembled solution (1.0 mL) of PS-Se-1-b-PEGMA 950 in PBS. The reaction mixture was stirred at 25 • C for 3 h.
Fluorescence spectrophotometry was then used to monitor the change in fluorescence intensity of the micelle solution.

Organoselenium-Mediated Controlled Radical Polymerization
The diselenocarbonate-end capped polymers were prepared through the organoselenium-mediated polymerization of styrene (St) according to our previous reports [33]. Two polymers, PS-Se-1 and PS-Se-2, with different molecular weights and narrow molecular weight distribution (<1.20) were prepared, as detailed in Table 1. The structure of PS-Se-1 was characterized by 1 H NMR. As shown in Figure 1, the signals at δ 3.78 ppm (3H, I 3.78 = 3.00) were ascribed to the protons of the methoxy group (-OMe), and the signals around δ 4.50 ppm (1H, I 4.43-4.68 = 1.06) were ascribed to the protons of CH-Se. The signals at around δ 7.00 ppm (5H, I 6.60-7.11 = 92.1) were ascribed to the protons of the phenyl group. Thus, the molecular weight (M n, NMR ) can be calculated to be 2100 g mol −1 by the equation M n, NMR = 104 × [(92.1 − 9) / 5] + 91 + 295. The polymers were also measured by using SEC with coupled refractive index (RI) and UV detectors ( Figure 2). The two curves almost coincide, and the molecular weight (M n,GPC = 1900 g mol −1 ) was close to the value obtained by 1 H NMR. All evidence proved the high chain end functionality of the diselenocarbonate-ended polystyrene (PS), which ensured further chain end modification.

Reaction Condition Optimization of Selenol-Based Nucleophilic Reaction
As in our previous reports, diselenocarbonate was expected to be converted to selenol by amine compounds [39]. In the present work, after the rapid aminolysis of PS-Se-1 (M n , SEC = 1900 g mol −1 ) by n-hexyl amine, the corresponding selenol reacted with PEGMA 950 (M n = 950 g mol −1 ) to make the block copolymers (Scheme 2). We initiated our studies by examining the effect of time on selenol-based nucleophilic reaction. The results are presented in Table 2. Screening experiments indicated that moderate conversion of PS-Se-1 could be obtained after four days (entries 1, 2, 3, and 4). An increase in temperature from 25 • C to 60 • C resulted in the increase of the conversion of PS-Se-1 from 22.4% to 50% (Table 2, entry 5). It was already found that Bu 3 P could act as a reducing agent to prevent Polymers 2019, 11, 827 6 of 12 oxidative coupling of selenol. Without Bu 3 P, the conversion of PS-Se-1 dropped to 14.6% (Table 2, entry 6). Bu 3 P also acts as a catalyst for the subsequent selenol-Michael addition reaction. Consequently, no more catalyst, such as DBU and Et 3 N, was needed to be added to this system (entries 7 and 8) [1]. Lastly, the effect of molar ratio on selenol-based nucleophilic reaction was examined. The reaction became more smooth as the amount of PEGMA (entries 9 and 10) increased. When the molar ratio of PS-Se-1:PEGMA = 1:10, the reaction reached the highest conversion rate of about 85% after separation. In contrast, the higher molar ratio of PS-Se-1:PEGMA (1:50) resulted in an extremely viscose solution, which may prevent further reaction. Moreover, purification loss also decreases the product yield.

Reaction Condition Optimization of Selenol-Based Nucleophilic Reaction
As in our previous reports, diselenocarbonate was expected to be converted to selenol by amine compounds [39]. In the present work, after the rapid aminolysis of PS-Se-1 (Mn, SEC = 1900 g mol −1 ) by n-hexyl amine, the corresponding selenol reacted with PEGMA950 (Mn = 950 g mol −1 ) to make the block copolymers (Scheme 2). We initiated our studies by examining the effect of time on selenol-based nucleophilic reaction. The results are presented in Table 2. Screening experiments indicated that moderate conversion of PS-Se-1 could be obtained after four days (entries 1, 2, 3, and 4). An increase in temperature from 25 °C to 60 °C resulted in the increase of the conversion of PS-Se-1 from 22.4% to 50% (Table 2, entry 5). It was already found that Bu3P could act as a reducing agent to prevent oxidative coupling of selenol. Without Bu3P, the conversion of PS-Se-1 dropped to 14.6% (Table 2,  entry 6). Bu3P also acts as a catalyst for the subsequent selenol-Michael addition reaction. Consequently, no more catalyst, such as DBU and Et3N, was needed to be added to this system (entries 7 and 8) [1]. Lastly, the effect of molar ratio on selenol-based nucleophilic reaction was examined. The reaction became more smooth as the amount of PEGMA (entries 9 and 10) increased. When the molar ratio of PS-Se-1:PEGMA = 1:10, the reaction reached the highest conversion rate of about 85% after separation. In contrast, the higher molar ratio of PS-Se-1:PEGMA (1:50) resulted in an extremely viscose solution, which may prevent further reaction. Moreover, purification loss also decreases the product yield.   The reaction was carried out at 60 • C with Bu 3 P. b The ratio of PS-Se-1 with PEGMA 950. c Conversion of PS-Se-1 determined after separation by NMR analysis with tetramethylsilane (TMS) as the internal standard for chemical shifts. d Ð was determined by SEC (THF as eluent, 1 mL min −1 , 40 • C) using polystyrene calibration. e The reaction was carried out at 25 • C with Bu 3 P. f The reaction was carried out at 60 • C without Bu 3 P.

Selenol-Based Nucleophilic Reaction of PS-Se-1 and PEGMAs with Different Molecular Weights
After studying reaction condition optimization for selenol-based nucleophilic reaction of PS-Se-1 with PEGMA 950 , PEGMAs with different molecular weights were examined. The results are listed in Table 3. PS-Se-1 reacted efficiently with PEGMA and the conversion rate of PS-Se-1 with PEGMA 320 peaked at 95.4%, and the conversion rate of PS-Se-1 decreased with the increase of molecular weight of PEGMA. The M n of copolymers was determined by SEC. As shown in Figure 3, the curves shifted significantly after the nucleophilic reaction, which evidenced the successful modification of PEGMA at the end of PS-Se-1. In the 1 H NMR spectra, the proton signals of the corresponding vinyl shifted from 6.10 and 5.54 ppm to 2.57 and 2.49 ppm, and the proton signals of CH groups close to Se shifted from 4.70 and 4.47 ppm to 2.84 ppm, indicating a complete conversion of PEGMA ( Figure 4). Also, MALDI-TOF mass spectrometry was used to further characterize the structure of the copolymer. As shown in Figure 5, the main population at the isotropic peak at 2340.428 m/z matched the theoretical calculation well (2340.152 m/z). Furthermore, two main sequence peaks are very close to the styrene (104.15 g mol −1 ) and CH 2 CH 2 O (44.03 g mol −1 ) units. All the evidence indicated the efficiency of this reaction. MALDI-TOF mass spectrometry was used to further characterize the structure of the copolymer. As shown in Figure 5, the main population at the isotropic peak at 2340.428 m/z matched the theoretical calculation well (2340.152 m/z). Furthermore, two main sequence peaks are very close to the styrene (104.15 g mol −1 ) and CH2CH2O (44.03 g mol −1 ) units. All the evidence indicated the efficiency of this reaction.           3.4. Self-Assembly of PS-Se-1-b-PEGMA 950 Before and After Oxidation Selenium-containing copolymers have shown redox responsiveness in many systems. Some selenide-containing aggregates can respond rapidly to external redox stimuli and subsequently release the incorporated species under mild conditions [26,28]. Here, self-assembly behavior of the three copolymers were investigated. It was found that PS-Se-1-b-PEGMA 950 could self-assemble spontaneously in aqueous solution through hydrophobic/hydrophilic interaction. As shown in Figure 6, the TEM measurement of PS-Se-1-b-PEGMA 950 micelles showed spherical aggregates with an average diameter of 30 nm. The DLS results are in accordance with the TEM results with an average diameter of 56 nm (Figure 7a). It is noteworthy that the micelles were quite stable in an ambient environment and could maintain their structures for at least one month. Then, H 2 O 2 solution was used as the oxidant to study the oxidation responsiveness of the selenide block copolymer aggregates. From the TEM images shown in Figure 6c,d, the micellar structure was converted to irregular aggregates after two hours of oxidation process, and these irregular aggregates were further decomposed for another three hours. The DLS results also proved that the morphology change of the aggregates occurred after adding H 2 O 2 solution. Furthermore, XPS was also used to analyze these micelles before and after oxidation treatment. As shown in Figure 7b, the binding energy of Se 3d 5 shifts from 56.22 eV to 60.81 eV, suggesting a higher valency of selenium which is close to the seleninic acid group [21]. All the results proved that oxidative cleavage of the selenide linkage leads to the morphology change of the micelle.
Polymers 2018, 10, x FOR PEER REVIEW 9 of 13 a Conversion of PS-Se-1 determined after separation by NMR analysis with reference to TMS as an internal standard. b Ð was determined by SEC (THF as eluent, 1 mL min -1 , 40 °C) using polystyrene calibration.

Self-Assembly of PS-Se-1-b-PEGMA950 Before and After Oxidation
Selenium-containing copolymers have shown redox responsiveness in many systems. Some selenide-containing aggregates can respond rapidly to external redox stimuli and subsequently release the incorporated species under mild conditions [26,28]. Here, self-assembly behavior of the three copolymers were investigated. It was found that PS-Se-1-b-PEGMA950 could self-assemble spontaneously in aqueous solution through hydrophobic/hydrophilic interaction. As shown in Figure 6, the TEM measurement of PS-Se-1-b-PEGMA950 micelles showed spherical aggregates with an average diameter of 30 nm. The DLS results are in accordance with the TEM results with an average diameter of 56 nm (Figure 7a). It is noteworthy that the micelles were quite stable in an ambient environment and could maintain their structures for at least one month. Then, H2O2 solution was used as the oxidant to study the oxidation responsiveness of the selenide block copolymer aggregates. From the TEM images shown in Figure 6c,d, the micellar structure was converted to irregular aggregates after two hours of oxidation process, and these irregular aggregates were further decomposed for another three hours. The DLS results also proved that the morphology change of the aggregates occurred after adding H2O2 solution. Furthermore, XPS was also used to analyze these micelles before and after oxidation treatment. As shown in Figure 7b, the binding energy of Se 3d 5 shifts from 56.22 eV to 60.81 eV, suggesting a higher valency of selenium which is close to the seleninic acid group [21]. All the results proved that oxidative cleavage of the selenide linkage leads to the morphology change of the micelle.

Cytotoxicity Test
The nanomicelles based on selenide-labeled amphiphilic copolymers potentially provide a new platform for targeted drug delivery. We examined the cytotoxicity of PS-Se-1-b-PEGMA (Mn,SEC = 3700 g mol −1 , Ɖ = 1.11, 1 × 10 −4 M). As shown in Figure 8, it can be seen that the PS-Se-b-PEGMA showed low cytotoxicity when compared with other selenide-containing polymers [40]. The obvious inhibitory effect on the NIH-3T3 cells was shown when the concentration of the micelles was high, at up to 1.6 mg mL −1 .

Drug Loading and Oxidation-Responsive Drug Release
The anticancer drug doxorubicin (DOX) was chosen as a model molecule for encapsulation. The self-assembly of PS-Se-1-b-PEGMA950 (1 mg mL −1 ) was conducted in DMF solution in the presence of DOX (0.1 mg mL −1 ), which has a characteristic maximum emission at 590 nm. The DOX-loading micelles were purified with dialysis membrane, and the DOX concentration was calculated by the fluorescence emission spectra. The drug loading content (DLC) was evaluated to be about 1.5%, and drug loading efficiency (DLE) was evaluated to be about 13.3%. Oxidation-triggered drug release studies in vitro were investigated at pH 7.4 and 25 °C by using H2O2. After oxidation for a specific time, the fluorescence emission of DOX was monitored, as shown in Figure 9a. The fluorescence

Cytotoxicity Test
The nanomicelles based on selenide-labeled amphiphilic copolymers potentially provide a new platform for targeted drug delivery. We examined the cytotoxicity of PS-Se-1-b-PEGMA (M n,SEC = 3700 g mol −1 , Ð = 1.11, 1 × 10 −4 M). As shown in Figure 8, it can be seen that the PS-Se-b-PEGMA showed low cytotoxicity when compared with other selenide-containing polymers [40]. The obvious inhibitory effect on the NIH-3T3 cells was shown when the concentration of the micelles was high, at up to 1.6 mg mL −1 .

Cytotoxicity Test
The nanomicelles based on selenide-labeled amphiphilic copolymers potentially provide a new platform for targeted drug delivery. We examined the cytotoxicity of PS-Se-1-b-PEGMA (Mn,SEC = 3700 g mol −1 , Ɖ = 1.11, 1 × 10 −4 M). As shown in Figure 8, it can be seen that the PS-Se-b-PEGMA showed low cytotoxicity when compared with other selenide-containing polymers [40]. The obvious inhibitory effect on the NIH-3T3 cells was shown when the concentration of the micelles was high, at up to 1.6 mg mL −1 .

Drug Loading and Oxidation-Responsive Drug Release
The anticancer drug doxorubicin (DOX) was chosen as a model molecule for encapsulation. The self-assembly of PS-Se-1-b-PEGMA950 (1 mg mL −1 ) was conducted in DMF solution in the presence of DOX (0.1 mg mL −1 ), which has a characteristic maximum emission at 590 nm. The DOX-loading micelles were purified with dialysis membrane, and the DOX concentration was calculated by the fluorescence emission spectra. The drug loading content (DLC) was evaluated to be about 1.5%, and drug loading efficiency (DLE) was evaluated to be about 13.3%. Oxidation-triggered drug release studies in vitro were investigated at pH 7.4 and 25 °C by using H2O2. After oxidation for a specific time, the fluorescence emission of DOX was monitored, as shown in Figure 9a. The fluorescence

Drug Loading and Oxidation-Responsive Drug Release
The anticancer drug doxorubicin (DOX) was chosen as a model molecule for encapsulation. The self-assembly of PS-Se-1-b-PEGMA 950 (1 mg mL −1 ) was conducted in DMF solution in the presence of DOX (0.1 mg mL −1 ), which has a characteristic maximum emission at 590 nm. The DOX-loading micelles were purified with dialysis membrane, and the DOX concentration was calculated by the fluorescence emission spectra. The drug loading content (DLC) was evaluated to be about 1.5%, and drug loading efficiency (DLE) was evaluated to be about 13.3%. Oxidation-triggered drug release studies in vitro were investigated at pH 7.4 and 25 • C by using H 2 O 2 . After oxidation for a specific time, the fluorescence emission of DOX was monitored, as shown in Figure 9a. The fluorescence intensity of DOX at 590 nm increased gradually, owing to the release of hydrophobic DOX from the drug carriers. The percentage release was calculated based on the fluorescence changes at 590 nm. The percentage release profile was plotted as a function of time, as shown in Figure 9b. intensity of DOX at 590 nm increased gradually, owing to the release of hydrophobic DOX from the drug carriers. The percentage release was calculated based on the fluorescence changes at 590 nm. The percentage release profile was plotted as a function of time, as shown in Figure 9b.

Conclusions
In conclusion, a straightforward protocol for the synthesis of an oxidation-sensitive selenidecontaining block copolymer has been developed on the basis of Se-RAFT. The diselenocarbonate termini of the polymers were readily converted to the selenide-containing block copolymer via aminolysis and selenol-based nucleophilic reaction. The present controlled radical polymerization (CRP)-based protocol offers a facile and straightforward fabrication of selenide-containing block copolymers that feature many monomer accessibilities, predictable MWs, and programmable polymeric architectures. These copolymers formed micelle-like nanoparticles of ~56 nm in diameter that show insignificant cytotoxicity of the micelles at high concentration and could be disrupted by H2O2. The biocompatibility and targeted cytotoxicity results suggest that these oxidation-sensitive selenide-containing block copolymers could be developed for controllable drug release.

Conclusions
In conclusion, a straightforward protocol for the synthesis of an oxidation-sensitive selenide-containing block copolymer has been developed on the basis of Se-RAFT. The diselenocarbonate termini of the polymers were readily converted to the selenide-containing block copolymer via aminolysis and selenol-based nucleophilic reaction. The present controlled radical polymerization (CRP)-based protocol offers a facile and straightforward fabrication of selenide-containing block copolymers that feature many monomer accessibilities, predictable MWs, and programmable polymeric architectures. These copolymers formed micelle-like nanoparticles of~56 nm in diameter that show insignificant cytotoxicity of the micelles at high concentration and could be disrupted by H 2 O 2 . The biocompatibility and targeted cytotoxicity results suggest that these oxidation-sensitive selenide-containing block copolymers could be developed for controllable drug release.