Selenium-Containing Polymers: Perspectives toward Diverse

Perspective Cite This: Macromolecules XXXX, XXX, XXX−XXX

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Selenium-Containing Polymers: Perspectives toward Diverse Applications in Both Adaptive and Biomedical Materials Jiahao Xia, Tianyu Li, Chenjie Lu, and Huaping Xu*

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Key Laboratory of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084, People’s Republic of China ABSTRACT: Selenium is a semimetallic element lying in group XVI of the periodic table with its chemical properties resembling sulfur. But owing to its relatively low electronegativity and large atomic radius compared with sulfur, selenium also shows unique properties. This feature endows selenium-containing compounds with high reactivity and sensitivity. Although organic selenium chemistry has been developing very fast, the successful introduction of selenium into polymer science is rather scarce. Fortunately, we have seen a drastic rising trend in the area of selenium-containing polymers over the past decade. In this Perspective, the synthetic routes of selenium-containing polymers are summarized, and their unique stimuli-responsive properties are elaborated on, together with their diverse applications in the field of adaptive and biomedical materials.

1. INTRODUCTION Selenium is a semimetallic element lying in group XVI of the periodic table with its chemical properties resembling sulfur. Selenium was first discovered by Jöns Jacob Berzelius in 1817 and was later proved to be a necessary trace element in mammals.1 Specifically, in 1973 Rotruck and co-workers found that the glutathione peroxidase (GPx) in blood cells of mice was a kind of selenium-containing enzyme and that selenium played an important role in the catalytic activity.2 GPx is responsible for catalyzing the decomposing of peroxides and thus maintaining the balance of redox equilibrium in the bodies of mammals. As a result, many efforts have been delegated to the research of selenium-containing small molecule drugs.3−7 Modern medical research has also reviewed that selenium is related to a list of human diseases such as cardiovascular disease, cancer, diabetes, and central nervous system diseases.5 According to the research from Long and co-workers, there is a very close relationship between the three major mass extinction events in history and the severe Se depletion in the oceans.8 This discovery showed the vital role Se has played in not only human health but also the evolution of life. Additionally, selenium is also unique in terms of chemical properties owing to its relatively low electronegativity and large atomic radius compared with sulfur. This feature endows selenium-containing compounds with high reactivity and sensitivity. Thus, it is believed that by incorporating selenium into polymers, new features and functions may be created. Although organic selenium chemistry has been developing very fast, the successfuk introduction of selenium into polymer science is rather scarce.9 Fortunately, we have seen a drastic rising trend in the area of selenium-containing polymers over the © XXXX American Chemical Society

past decade due to the contribution of many research fellows throughout the world.10 In this Perspective, the synthetic routes of selenium-containing polymers are summarized, and their unique stimuli-responsive properties are elaborated on, together with their diverse applications in the field of adaptive and biomedical materials.

2. SYNTHESIS OF SELENIUM-CONTAINING POLYMERS 2.1. Step Growth Polymerization. The traditional way of preparing selenium-containing polymer was via step growth polymerization. Prince and Bremer reported the synthesis of polyselenomethylene in 1967 by reacting sodium selenide with methylene bromide (Figure 1a).11 Kroll and co-workers reported the synthesis of a variety of selenium-containing polymers in 1970 including polyesters, polyureas, and polyurethanes.12 Selenium was introduced by the reaction of bis(2hydroxyethyl)selenide or bis(2-aminoethyl)selenide with different types of diisocyanate, terephthaloyl chloride, anhydride, and epoxy resins. Salzman and co-workers reviewed some of the preparation methods for polydiselenides in 1972.13 It should be noted that among those early stage selenium-containing polymers, polyselenophenes have been well investigated as an important conductive polymer and have shown potential applications as optoelectronic materials.14,15 But the development of alkyl-based selenium-containing polymers has since Received: July 25, 2018 Revised: September 11, 2018

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DOI: 10.1021/acs.macromol.8b01597 Macromolecules XXXX, XXX, XXX−XXX

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Figure 1. Step growth polymerization of selenium-containing polymers. (a) Synthesis of polyselenomethylene. (b) Synthesis of selenium-containing polyimide. (c) Synthesis of PEG-PUSeSe-PEG diselenide-containing polyurethane with good solubility in common organic solvents.

Figure 2. Radical polymerization to prepare selenium-containing polymers. (a) Selenium-containing vinyl free radical polymerization. (b) Diselenide compound used as photoiniferter in radical polymerization initiated by UV light irradiation.

canol. The long alkyl chain was designed to increase the solubility of the polymer. The diol was treated with 1.1 equiv of toluene diisocyanate to obtain linear diselenide-containing polyurethane (PUSeSe) with NCO groups at each end of the polymer chain. Finally, the NCO groups were terminated by poly(ethylene glycol) (PEG) monomethyl ether to obtain an ABA-type amphiphilic block polymer denoted as PEG-PUSeSePEG. The obtained polymer usually has a molecular weight around 10000 Da with the PDI close to 2 by the GPC test. In the meantime, monoselenide-containing polyurethane could be prepared in a similar way with disodium diselenide being replaced with sodium hydroselenide (NaHSe) in the first step,18 and the obtained polymer was denoted as PEG-PUSe-PEG. The obtained polymers are amphiphilic and could self-assemble to form aggregates in water. The diselenide bond is hydrophobic and was embedded in the core of the assemblies, thus preventing them from being oxidized in solution. This synthetic approach represents a successful example that solves both the solubility and stability problems and allows the selenium-containing polymer to be used as a novel stimuli-responsive biomaterial. Their response behavior will be elaborated on in the fourth section of the Perspective.

then been rather slow. In 2005, Turgay and co-workers synthesized a kind of selenium-containing polyimide to increase its solubility without sacrificing high thermal stability (Figure 1b).16 Bis(1,3-p-dimethylaminobenzylpyrimidyl-2-ylidene) was used to react with selenium element to obtain the selenium carbene-containing (CSe) monomer. This monomer was further reacted with various dianhydrides to obtain seleniumcontaining polyimides. But for most of the works mentioned above, molecular weights and other properties of the polymer obtained were not fully characterized. There were mainly two drawbacks of those traditional synthetic approaches that hindered the development of selenium-containing polymers. One is that the prepared polymer showed poor solubility in common organic solvents, thus prohibiting their further usage in real applications. The other problem is the stability of the polymer since both monoselenide and diselenide are very sensitive to oxidative agents like oxygen in air. In 2010, our group first proposed a diselenide-containing polyurethane with good solubility in common organic solvents like THF, DMF, DCM, etc. (Figure 1c).17 The diselenide group was first introduced to a diol through the reaction of disodium diselenide and a long alkyl chain alcohol like 11-bromoundeB


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Figure 3. Selenium-containing compounds used in controlled polymerization. (a) Structure of phosphinodiselenoic acid esters used in polymerization. (b) A new type of phosphinodiselenoic acid ester (DPPSB) for controlled polymerization. (c) The iniferter polymerization mechanism of DPPSB. (d) RAFT polymerization mechanism by cyclic selenium-containing RAFT agent RAFT-Se.

tional phenyl selenide photoiniferter in 2003.22 The molecular weight could reach Mw of 153.9 kDa though the dispersity was pretty high at 3.24. In general, using diaryl diselenide as a photoiniferter to initiate the polymerization was the first try to synthesize selenium-containing polymer by radical polymerization. However, being a photoiniferter means that selenide is not only responsible for initiation but also works as an effective chain transfer agent, which would inevitably increase the dispersity. Reversible addition−fragmentation chain transfer polymerization (RAFT) is widely accepted as a versatile technique to perform living radical polymerization.23,24 Thiocarbonylthio chain transfer agents, which are sulfur-containing organic compounds, play a vital role in controlling the polymerization process.25 Because selenium resembles sulfur in terms of chemical properties, it may also be employed to mediate RAFT polymerization. In 2008, Lee and co-workers introduced a series of phosphinodiselenoic acid esters into the thermally initiated styrene polymerization (Figure 3a).26 During the polymerization the number-average molecular weight (Mn) increased almost linearly with degree of monomer conversion and time, showing the features of living polymerization. However, the dispersity increased with the growth of molecular weight, ranging from 1.6 to 2.5. Later on, Zhu and co-workers synthesized a new type of phosphinodiselenoic acid ester (DPPSB) and used it to mediate the polymerization of styrene

2.2. Radical Polymerization. Apart from step growth polymerization, selenium-containing polymer could also be prepared by radical polymerization. In 1996. Kondo and coworkers found that p-methylselenostyrene and p-phenylselenostyrene could be polymerized to afford polymers with molecular weights ranging from 20000 to 150000 (Figure 2a).19 The reaction was based on the free radical polymerization mechanism in which the vinyl groups were polymerized by radical initiators like AIBN or BPO. One year later they discovered that diaryl diselenide could be used as a photoiniferter to perform living radical polymerization (Figure 2b).20 Specifically, the diselenide bond could be homolytically dissociated to generate phenylseleno radicals under a 100 W high-pressure mercury lamp, which accounts for the initiation of the polymerization process. The polymerization was proved to follow a living radical mechanism with a relatively small dispersity at 1.6−2.1. The prepared polymer has arylseleno groups at both chain ends, which could be transformed to become hydrogen by reductive elimination or carbon double bond by oxidation. In 1999, Yuki and co-workers used this polymerization method to synthesize a grafting polymer with PS as the backbone and PMMA as the branches.21 The PS backbone with phenyl selenide structure was first synthesized by radical polymerization, which was followed by polymerizing MMA under strong UV light. Later on, they further used this reaction to synthesize a star-shape polystyrene from a tetrafuncC


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Figure 4. Diselenide-containing polymers prepared by (a) aminolysis−oxidation reaction and (b) ATRP.

Figure 5. Synthesis of dendrimer and hyperbranched selenium-containing polymers. (a) Fréchet-type dendrimers terminating in phenylselenide and phenylseleninic acid groups. (b) Synthesis of a hyperbranched polymer by self-condensing vinyl polymerization. (c) Structure of a three-generation poly(aryl ether) dendrimer with a diselenide core. (d) A hyperbranched polyselenide prepared by 1,3,5-tris(bromomethyl)-2,4,6-trimethylbenzene with NaHSe.

under UV irradiation (Figure 3b).27 It was found that a linear polymerization kinetics was observed, and the molecular weight increased linearly with the consumption of monomers. The dispersity of the obtained polymer was from 1.5 to 2.0. Further study of the end groups revealed that this polymerization underwent an iniferter mechanism. In 2013, they synthesized a cyclic selenium-containing RAFT agent and compared its function with the sulfur counterpart (Figure 3d).28 It turned out that the RAFT-Se showed a better control in terms of molecular weights compared with RAFT-S in the synthesis of poly(vinyl acetate). Besides, it is believed that RAFT-Se was not only in the ending groups but also incorporated into the backbone of PVAc. They have also synthesized diselenocarbonates as a new type of RAFT agent.29 The PVAc was obtained with controlled molecular weight. But the dispersity rises with the increase of molecular weight, from 1.3 to more than 1.7.

In 2015, Pan and Zhang and co-workers reported a facile transformation from diselenocarbonate-mediated RAFT polymer to diselenide-containing polymer via an efficient aminolysis followed by a spontaneous oxidation coupling reaction (Figure 4a).30,31 Specifically, diselenocarbonate could react with amines to produce selenol, which could be oxidized by oxygen in air to obtain diselenide bonds. This reaction could be monitored by UV−vis, 1H NMR, and GPC. Atom transfer radical polymerization (ATRP) is another wildly used method to prepare polymers with controlled structures and dispersity.32−34 However, the traditional ATRP usually requires cuprous ions as the mediator, which would be coordinated with selenium-containing compounds and lost its function. Fortunately, polymers prepared via ATRP usually leave a halogen element like Br in the end of the chain, which could be efficiently coupled by NaHSe and Na2Se2 to form D


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Figure 6. Selenium-containing polymers obtained from ring-opening polymerization. (a) Selenolactone used as the precursor to prepare diselenidecontaining polymers. (b) Selenic cyclic carbonate dimer used to prepare selenium-containing aliphatic polycarbonates.

selenium-containing polymers. In 2014, our group first reported this strategy to synthesize diselenide-containing polystyrene (PSSe)2.35 In 2015, Zhang and Zhu and co-workers demonstrated this approach in great details (Figure 4b).36 First, polystyrene was synthesized by ATRP; then the terminal Br was reacted with Na2Se2 through nucleophilic attack to obtain PSSeSe-PS. The Mn of the polymer was 4000 Da, and the dispersity was only 1.07 from GPC results. The structure of the polymer was testified by GPC, NMR, MALDI-TOF, and oxidation test. From these characterization results it was concluded that almost all of the PS-Br reacted to generate PS-SeSe-PS. However, when other commonly used monomers like methyl methacrylate were employed, the coupling reaction showed less efficiency, which implied the reaction yield depends on the structure of the polymer to some extent and that further purification may be required to separate the final product. 2.3. Synthesis of Dendrimer and Hyperbranched Selenium-Containing Polymer. Dendrimers and hyperbranched polymers have been extensively used as catalysts, drug delivery vehicles, self-assembly monolayer, etc., due to their precise structures and high functionalities.37 In 2003, Detty and co-workers synthesized Fréchet-type dendrimers terminating in phenylselenide and phenylseleninic acid groups.38,39 This type of dendrimer could be used to catalyze the oxidation of bromide with hydrogen peroxide (Figure 5a). In 2004, Takagi and coworkers synthesized a hyperbranched selenium-containing polystyrene via self-condensing vinyl polymerization (Figure 5b). Specifically, p-(phenylselenomethyl)styrene, which has both a vinyl group and selenium in the same molecule, could be photopolymerized to generate hyperbranched selenium-containing polystyrene under ultraviolet irradiation.40 In 2004, Zhang and co-workers synthesized a three-generation poly(aryl ether) dendrimer with a diselenide core (Figure 5c).41 In 2006, Smet and Zhang and co-workers prepared a hyperbranched polyselenides simply by reacting 1,3,5-tris(bromomethyl)-2,4,6trimethylbenzene with NaHSe (Figure 5d).42 The dendrimer and hyperbranched polymer could be used as glutathione peroxidase (GPx) mimics with high catalytic efficiency. 2.4. Ring-Opening Polymerization. Except for step growth polymerization and radical polymerization, recent studies have revealed that selenium-containing polymer could also be prepared by ring-opening polymerization. In 2017, Pan

and Du Prez and co-workers reported the use of selenolactone as the precursor of the polymerization and thus obtained a series of diselenide-containing polymers with different topologies (Figure 6a).43 Selenolactone could be easily synthesized via the reaction of sodium hydrogen selenide (NaHSe) and 4chlorobutanoyl chloride. Selenolactone could be opened by diamine like 4,9-dioxadodecanediamine to form selenol structures, which could be further oxidized to become diselenide bond, thus obtaining the diselenide-containing polymer with a molecular weight Mn of 5.0 kDa and a dispersity of 1.75 according to the SEC test. In 2018, Lang and co-workers developed an approach to synthesize well-defined seleniumcontaining aliphatic polycarbonates via the ring-opening polymerization of a selenic cyclic carbonate dimer monomer (MSe) (Figure 6b).44,45 This monomer was prepared by intermolecular cyclization of di(1-hydroxyethylene)selenide and diphenyl carbonate catalyzed by lipase CA. Then the monomer was employed to undergo ring-opening polymerization to obtain selenium-containing aliphatic polycarbonates under the same catalyst lipase CA. The obtained polymer has a Mn of 35.9 kDa and a dispersity of 1.30. There was a linear relationship between time and ln([M]0/[Mt]), indicating the living feature of the polymerization. Besides, this approach is universal as this monomer could copolymerize with other carbonate monomers to prepare polycarbonates with different chemical structures. In conclusion, selenium-containing polymers could be prepared by a series of polymerization methods including step growth polymerization, radical polymerization, and ring-opening polymerization. Different synthesis routes lead to polymers with various structures and functions. We believe in the future more monomers and polymerization techniques will be designed to facilitate the synthesis of selenium-containing polymers, and the successful preparation of those polymers can provide new building blocks for further applications.

3. SELENIUM-CONTAINING DYNAMIC COVALENT CHEMISTRY AND THEIR APPLICATIONS IN SELF-ADAPTIVE MATERIALS The dynamic covalent bond (DCB) is a kind of special covalent bond that can cleave, re-form, and exchange under certain stimulus.46,47 The concept of DCB was first put forward by Prof. E


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Figure 7. (a) Diselenide metathesis under visible light irradiation. (b) Peak shift in 1H NMR monitored during metathesis. (c) Two new peaks showed up after diselenide metathesis indicating the appearance of the exchange product. (d) Radical scavengers like TEMPO significantly prohibit the reaction, proving the radical mechanism of the reaction. Reproduced with permission from ref 35. Copyright 2014 Wiley-VCH.

Figure 8. (a) Diselenide metathesis at the oil/water interface. (b) Pendant drop model; the decrease of the surface energy indicated the occurrence of the dynamic diselenide metathesis. (c) DLS results and (d) TEM image of the micelles formed by amphiphilic diselenide-containing polymer. Reproduced with permission from ref 56. Copyright 2016 Royal Society of Chemistry.

sensitive DCB.55 We therefore demonstrated that the Se−Se bond is indeed another type of selenium-containing DCB.35 Two symmetric diselenide-containing molecules could undergo exchange reaction to generate an asymmetric diselenidecontaining molecule when exposed to visible light (380−780 nm) without adding any catalysts or reactants (Figure 7a). The final composition is 25% of each reactant and 50% of exchanged product due to the chemical equilibrium. The metathesis reaction could be easily followed by 1H NMR, and the reaction kinetics could be investigated via the changes of the integration of the distinct peaks adjacent to selenium atoms based on spectrum (Figure 7b). 77Se NMR also offers a unique perspective to illustrate the diselenide metathesis reaction. The new peaks evolved after metathesis clearly indicated the occurrence of the reaction and the asymmetric exchanged product (Figure 7c). Apart from visible light stimuli, it is found that the metathesis reaction could happen simply by heating over 70 °C. The reaction was proved to undergo a radical mechanism as the radical scavenger like TEMPO could significantly prohibit the reaction (Figure 7d). It is worth noting that diselenide metathesis does not show solvent selectivity and

J. M. Lehn in 1999 and has since then draw much attention due to its dynamic and adaptive features.48 Many classic dynamic covalent chemistries like the Diels−Alder reaction, amide formation/exchange, acylhydrazone formation/exchange, and disulfide exchange have been well studied and applied in a series of research areas.49−53 As a matter of fact, every discovery of a new dynamic covalent bond would create a hot spot in the field of supramolecular chemistry and smart responsive materials. Therefore, it is of significant importance to develop new DCB with mild and unique response properties. Herein, we will report the recent progresses our research group as well as some other research groups have made in terms of selenium-containing dynamic covalent bonds and their applications in some appealing fields. 3.1. Selenium-Containing Dynamic Covalent Bond. The disulfide bond has long been known as a type of DCB and has been applied to many interesting areas.54 The disulfide exchange reaction is usually trigged by either UV irradiation or catalytic reductants. It should be noted that the bond energy of S−S is 240 kJ mol−1 while that of the Se−Se bond is only 172 kJ mol−1, which implies that the Se−Se bond may be a more F


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Macromolecules can extend to polymer systems as well. Two polystyrenes with different molecular weight could exchange to obtain middlemolecular-weight polystyrene following the same mechanism mentioned above though it takes a longer time to reach equilibrium due to the entanglement of the long polymer chains. We then sought to investigate whether the diselenide metathesis could be performed at the oil/water interface (Figure 8a).56 An interface model was designed based on the pendant drop test. The oil drop containing hydrophobic dibenzyl diselenide was hung inside the water phase containing hydrophilic ditetraglycol diselenide. When visible light (380− 780 nm) irradiation was used, a dramatic decrease of the surface energy could be spotted as two diselenide molecules exchanged at the interface to give the amphiphilic diselenide product. The latter served as surfactants which helped to stabilize the oil/ water interface (Figure 8b). We believe this discovery opened up new avenues for the combination of interface chemistry with diselenide dynamic chemistry. Moreover, the mixture of hydrophilic diselenide polymer (mPEGSe2) and hydrophobic diselenide polymer (PSSe2) was used to generate amphiphilic block polymer (mPEGSeSePS) after the exchange reaction, which could self-assemble into micelles in water (Figure 8c). The unreacted mPEGSe2 could be removed by dialysis, and the remaining PSSe2 precipitate could be removed by filtration. Although some of the unreacted PSSe2 tend to coassemble into the hydrophobic core of the micelles. Further experiments proved that the resulting micelles showed light stability even though the composition is not at its stable stage. This means the micelle-induced stabilization could serve as an alternative way to shift the dynamic equivalence of the diselenide metathesis reaction. According to the Pauling equation, the estimated bonding energies of Se−N, Se−S, and Se−O are 193, 203, and 233 kJ/ mol;57 all of them are weaker than S−S bond, which implies that all three selenium-containing bonds could potentially be dynamic covalent bonds. Our discovery of the Se−N dynamic covalent bond started with the well-known Se−N noncovalent interaction which plays an important role in glutathione peroxidase (GPx, an antioxidant selenoenzyme in mammal).58 Se−N noncovalent interaction was used as a driving force to fabricate well-defined azacalix[6]pyridine (APy6) nanosheets in an aqueous solution (Figure 9a). APy6 alone could only form irregular aggregates since it is hydrophobic, but when mixed with a three-armed selenium containing amphiphile (SeG) at a ratio of 4:1, well-defined nanosheets with which are 1−2 mm long and 300−500 nm wide can be obtained (Figure 9b). TEM-EDS results clearly indicated the existence of selenium element in the nanosheet. The blue-shift of the C−Se bond from 561 to 568 cm−1 in the FT-IR spectrum together with the XPS spectrum of Se 3d experiencing a downward shift from 51.80 to 50.82 eV highlighted the importance of Se−N interaction in the assembly of the nanosheet. Further experiments proved that the nanosheet structures could be destroyed by adding acids or oxidants simply due to the protonation from N to NH+ or the oxidation from Se to SeO. After the above work, we proposed the discovery of the Se−N DCB.59 The bond energy of Se−N is estimated to be 193 kJ mol−1 based on the Pauling equation. It is found that Se of phenylselenyl halogen species (PhSeBr) and N of pyridine derivative could form Se−N DCB under sonication within 1 min. The formed Se−N DCB could be efficiently cleaved by heating, adding acid, or replacing by stronger electron-donating pyridine derivatives (Figure 10a). The formation of the Se−N

Figure 9. (a) Fabrication of well-defined azacalix[6]pyridine (APy6) nanosheets in an aqueous solution by Se−N noncovalent interaction. (b) TEM image of the nanosheets. (c) AFM image of the nanosheets. (d) Micelles formed by SeG in aqueous solution. (e) Irregular aggregates formed by insoluble APy6 in water. Reproduced with permission from ref 58. Copyright 2012 Royal Society of Chemistry.

Figure 10. (a) Se−N covalent bond formed by pyridine derivatives and PhSeX. (b) Structure of the polymer and pyridine derivatives used in this work. (c) UV−vis spectra of PhSeBr with pyridine derivatives. The signal at 470 nm decreased as electron-donating ability of the N atoms in the model molecules get stronger. Reproduced with permission from ref 59. Copyright 2013 Wiley-VCH.

G


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Figure 11. Formation of a novel selenium-containing macrocycle and the transformation between different types of selenium-containing DCBs.

Figure 12. (a) Formula of the diselenide-containing polyurethane elastomer. (b) Visual proof of the self-healing property of the polymer; the red part was stained with Nile Red for clarity. (c) Healing behavior under pressure; the crack disappeared after 24 h light irradiation. (d) Mechanical properties of the polymer before and after self-healing. (e) Self-healing behavior under laser irradiation. Reproduced with permission from ref 64. Copyright 2015 Wiley-VCH.

well. Then the cleavage of the Se−N DCB was investigated. It was found that when adding stronger electron-donating pyridine derivatives, the weaker one could be replaced. For example, DMAP could be used to replace PS-b-P4VP to form Se−N DCB which would lead to the disassembly of the polymeric micelles. Besides, from the FT-IR results the cleavage could occur when temperature was increased to the range 80−120 °C. PhSeBr offers a unique UV/vis absorption at 470 nm due to the

DCB was achieved by sonication of a 1:1 mixture of PhSeX (X = Br or Cl) and polystyrene-b-poly(4-vinylpyridine) (PS-bP4VP). The shift of 77Se NMR signals from 868.7 ppm into 1180.3 ppm before and after reaction indicated the chemical environment of selenium atoms has changed. A new peak accounting for Se−N covalent bond was also observed in the FT-IR spectrum. Apart from that evidence of XPS, TEM, 1H NMR, and DLS have confirmed the formation of Se−N DCB as H


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Figure 13. (a) Stress relaxation and (b) strain fixation behavior of elastomer with different contents of diselenide bonds. (c) Shape memory cycles and visible light-induced transition of the permanent shape. Scale bar: 2 cm. (d) Visible light patterning based on a commercialized projector. Reproduced with permission from ref 65.

dithiothreitol (DTT) was added into the DMSO solution of M1, the Se−N bond could be transformed to the Se−S bond and formed a novel selenium-containing macrocycle. Carboxylate groups were further added as a guest template, facilitating the transformation from a Se−S bond into Se−Se bond; thus, a diselenide-containing macrocycle was formed (Figure 11). This work demonstrated that those selenium-containing dynamic covalent bonds can transform from one to another under certain stimuli. 3.2. Selenium-Containing DCC Used in Self-Adaptive Materials. With the unique mild response of the diselenide DCB, it was successfully incorporated into the fabrication of selfhealing materials with visible light healing property (Figure 12a).64 A series of polyurethanes (PU) with different diselenide bond contents were synthesized by different ratios of toluene diisocyanate (TDI), poly(tetramethylene glycol) (PTMG), and di(1-hydroxyundecyl) diselenide (DiSe). A visual proof of the self-healing property was first demonstrated. PU was cut and attached together, which was followed by 24 h visible light irradiation giving by a common table lamp (Figure 12b). The healed PU was able to bear a weight of 200 g, which was calculated to be 0.22 MPa in terms of tensile strength. Then the mechanical properties of PUs were further tested to quantitatively study the self-healing behavior (Figure 12d). According to the strain−stress tests, the original breaking strain and stress of PU was 380% and 1.31 MPa, respectively. After visible light irradiation for 24 and 48 h, the breaking stress could reach 45% and 72% of its original figure. Because it is the dynamic diselenide metathesis that accounts for the healing process, the entanglement of polymer chains is unable to be fully recovered, which explains the breaking stress difference before and after cutting−healing treatment. However, the Young’s

auxochrome group of selenyl bromide, which could be utilized to monitor the concentration of PhSeBr in solution (Figure 10c). This absorption changed with the adding of CF3COOH and pyridine in sequence for several cycles, which proved its reversibility under pH stimuli. The Se−N DCB was used to adjust the amphiphilicity of the polymer PS-b-P4VP and further achieved the one-step double emulsion in the DCM/H2O system.60 The PhSeBr could react with P4VP segment to obtain the Se−N cation and Br counterion, thus enhancing the hydrophilicity to the polymer. When tuning the ratio of pyridine group to PhSeBr, a series of particles with different morphologies could be prepared. Because all of these particles had selenium-containing active centers, they could be used as glutathione peroxidase (GPx) mimics to catalyze the reduction of hydroperoxides. Because the porous structures provided high specific surface areas, the catalytic behavior was accelerated to some extent, with the most porous one possessing the highest catalytic activity. This was the very first example of the application of selenium-containing DCB. Apart from Se−N DCB, it is predicted that Se−S may also act as DCB.61 Prof. Michael Pittelkow’s group established a dynamic combinatorial library (DCL) where diselenides, disulfides, and selenenyl sulfides coexist.62 The DCL was constructed by mixing a bis-diselenide macrocycle and a bisdisulfide cycle together in the presence of 5-mercaptoisophthalic acid acting as the catalyst. Additionally, diselenide was proved to accelerate the formation of disulfide based dynamic combinatorial libraries at physiological pH. Ebselen is an antiinflammatory, antioxidant drug that contains a Se−N bond in the molecular structure.6,7 In our group, a monomer composed of two ebselen moieties was synthesized.63 When DLI


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Figure 14. One-pot surface modification of graphene oxide by diselenide-containing molecules. Reproduced with permission from ref 66.

sample, the stress relaxed area bulged to give the patterning of the projected images (Figure 13d). Because of the unique oxidation response and visible light response features, the diselenide DCB could be applied to the surface functionalization of two-dimensional materials like graphene oxide (GO) (Figure 14).66 GO is an important member of two-dimensional materials and has been widely applicable to many research fields. Yet the current existing covalent surface functionalization methods usually requires harsh conditions, long reaction time, and low reactivity, while the noncovalent methods are inevitably unstable with amounts of competitive species in the physiological environment. Because GO is oxidative and radical attackable due to its unique chemical structure, it was found that diselenide-containing molecules could react with GO to realize the in situ covalent surface functionalization in a relatively mild way. The chemical structure of the obtained GOSe was characterized by FT-IR, ToF-SIMS, AFM, etc. The reaction mechanism was deduced to involve both redox reaction and radical addition reaction as the XPS Se 3d results showed two peaks after surface functionalization. The Raman spectrum and atomic emission spectroscopy results also confirmed the proposed mechanism. Then GO was modified by a diselenide-containing polymer (mPEGSe2), and the obtained material was proved to be capable of modulating the balance of reactive oxygen species as a result of the selenium active center. Because of the unique properties of selenium, it can be anticipated that more of the selenium-containing bonds like Se− O and Se−Te may also serve as DCBs, yet their response behavior may vary from bond energy differences. It is of vital importance to understand the response condition and behavior of each selenium-containing DCBs, together with the dynamic transformation from one to another. This series of research will provide with promising applications in polymer and smart material science.

modulus was almost fully recovered, from 2.79 MPa for original to 2.44 MPa after 24 h healing and 2.75 MPa after 45 h healing. To optimize the self-healing performance, a blue laser was employed to replace the table lamp. By doing so, the healing period was significantly shortened from 48 h to 30 min; meanwhile, the healing effect was further enhanced to 84% high recovery rate compared with the original material (Figure 12e). Additionally, using laser as the light source allows the potential for remote healing as the laser is spatial controllable and light intensive. The groups of Prof. Haritz Sardon and Prof. Jian Zhu also reported a kind of self-healing material based on the diselenide DCB. The obtained PU was found to be able to selfheal under room temperature and showed enhanced reprocessing characteristics compared with the disulfide counterpart. Furthermore, the commonly used catalyst dibutyltin dilaurate (DBTDL) for PU preparation was found to boost the diselenide exchange rate, thus accelerating the self-healing process. Apart from self-healing materials, the diselenide DCB was also employed in shape memory materials with visible light induced plasticity.65 Di-(1-hydroxylundecyl)diselenide (DiSe), poly(tetramethylene glycol) (PTMG), 4,4′-diphenylmethane diisocyanate (MDI), and cross-linker glycerol were used in different ratios to fabricate thermoset PUs with different diselenide bond contents varies from 0% to 100%. It was found that the shape memory efficiency increased with the rise of the diselenide bond content. However, since the diselenide metathesis could slowly happen when the temperature was above 60 °C, a certain amount of stress was released before temperature rise; thus, the recovery step from temporary shape back to permanent shape cannot be fully achieved. Subsequently, the visible light induced plasticity was investigated. As expected, a higher diselenide bond content led to better stress relaxation behavior (Figure 13a). The strain fixation was determined to increase with the increase of diselenide bond content, which was consistent with the stress relaxation behavior (Figure 13b). The mechanism behind it is the diselenide metathesis reaction triggered by visible light. For most of the thermoset shape memory materials the permanent shape was fixed once it was fabricated. But the combination of shape memory property and light-induced plasticity allowed the transition from a temporary shape to a permanent shape simply by visible light irradiation during the shape memory cycles (Figure 13c). To demonstrate the unique application of visible light induced plasticity, certain images were projected on the previously stretched materials by a commercialized projector. The projected area underwent stress relaxation while the other parts remained intact. When the stretch was released from the

4. SELENIUM-CONTAINING POLYMERS AS PROMISING BIOMATERIALS Inorganic and organic small molecular selenium-containing compounds have been investigated to treat cancers over the past few decades. However, selenium-containing polymers were not realized as promising biomaterials for controlled drug release until the report of Xu and Zhang and co-workers in 2010.67 Recently, more and more selenium-containing polymers have J


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Figure 15. Diselenide-containing polymers exhibit dual redox response. The PEG-PUSeSe-PEG micelles can be broken by H2O2 or GSH in very low concentration. Reproduced with permission from ref 69.

Figure 16. Dual redox-responsive coassemblies composed of diselenide-containing polymers and polymer lipids. Reproduced with permission from ref 80.

copolymer PEG-PUSeSe-PEG could self-assemble into spherical micelles in water, which improved the stability of diselenide bonds buried inside the hydrophobicity part (Figure 15). Owing to the diselenide bonds, the diselenide-containing polymer showed sensitive dual redox responsive property, which disassembled under treatment of 0.01% H2O2 or 0.03 mM GSH. This unique property endows diselenide-containing polymers with the potential for becoming smart drug delivery vehicles, which release the loading drug molecules in response to redox stimuli in the tumor microenvironment. After this study of diselenide-containing polymer, more diselenide-containing drug delivery systems were developed,

been developed due to their high redox sensitivity or potential anticancer activity.68 4.1. Diselenide-Containing Materials. Redox responsiveness is a vital property of diselenide-containing polymers. The low binding energy of diselenide bonds (172 kJ mol−1) endows them with high sensitivity to both oxidation and reduction stimuli. Under oxidative conditions, diselenide bonds can be oxidized to seleninic acids or selenonic acids, while under reductive conditions, they can be reduced to selenols. In 2010, we reported the first diselenide-containing block copolymer with good stability and solubility, which opened a new avenue for the research of selenium-containing polymers.69 The block K


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Figure 17. Red light-responsive diselenide-containing polymer system. (a) Schematic illustration of red light-induced oxidation and drug release. (b) Release profile of Dox under red light irradiation with or without porphyrin. (c) MTT assays showing biocompatibility of diselenide-containing polymers. Reproduced with permission from ref 81. Copyright 2013 Royal Society of Chemistry.

Figure 18. A γ-radiation responsive hydrogel formed by complexation of a positively charged diselenide-containing polymer with a peptide amphiphile. Reproduced with permission from ref 84. Copyright 2013 Wiley-VCH.

biocompatibility of polymer lipids, the coassemblies exhibit great potential for further applications in physiological environment. Besides the redox responsiveness, diselenide-containing polymers were also reported to be responsive to light. We developed diselenide-containing polymers that responded to red light in the presence of photosensitizers like porphyrin (Figure 17).81 Under irradiation of red light (600−780 nm), porphyrin could generate singlet oxygen, which subsequently oxidized the diselenide bonds and led to disruption of the polymer micelles. In this way, red light triggered drug release was achieved. Because red light is a safe light source with deep penetration in tissue, the light responsive diselenide-containing polymers can be an ideal system for controlled drug release in cancer treatment. To increase the responding efficiency to light, a positively charged diselenide-containing polymer was deposited alternatively with a porphyrin-loaded polyanion using the layerby-layer (LBL) method.82 In this circumstance, diselenide bonds were close to porphyrins, which provided more

including micelles, hydrogels, and metal−organic frameworks (MOFs), which released drugs in response to oxidation,70,71 reduction,72−75 or dual redox stimuli.76−78 Zhang and coworkers reported the fabrication of diselenide-containing supramolecular polymers, which were synthesized by mixing diselenide-containing monomer (FGGC11Se) 2 with cucurbit[8]uril (CB[8]).79 The monomer was composed of a diselenide bond linked with two undecyl chains and two tripeptides of Phe-Gly-Gly (FGG) as end groups. The host− guest interactions between (FGGC11Se)2 and CB[8] drove the formation of the diselenide-containing supramolecular polymer. It could release the loading molecule under mild oxidation and reduction conditions. We constructed coassembly systems via self-assembly between diselenide-containing polymers and polymer lipids (Figure 16).80 With a little amount of diselenide-containing polymers (∼10%), the lipid system obtained good redox responsiveness. The coassemblies could disrupt in the presence of 0.1% H2O2 or 0.05 mM GSH and release drug molecules. Taking advantage of the good L


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Figure 19. Diselenide-containing hyperbranched polymers used as a self-delivery anticancer drug and a drug carrier for hydrophobic anticancer drugs. Reproduced with permission from ref 91. Copyright 2012 Elsevier.

exposed in an aqueous solution. According to this hypothesis, we prepared diselenide-containing polymers that self-assembled into micelles in water phase. Anticancer drugs like Dox could be loaded into the polymeric micelles and released under γradiation as low as 5 Gy (Figure 2).85 TEM and Dox release experiments showed that the sizes of micelles increased slightly and about 45% Dox was released in 6 h when exposed to 5 Gy γradiation. The results confirmed that diselenide-containing polymers in solution were more sensitive to γ-radiation. Such ultrasensitive systems exhibited great potential for clinical radiotherapy and chemotherapy. The redox-responsive diselenide-containing polymers were not only used for controlled drug release but also applied in construction of gene delivery vehicles. Gu and co-workers developed diselenide-containing polycationic gene carriers (OEI-SeSe) by cross-linking of branched oligoethylenimine (OEI) with diselenide-containing esters.86−88 Because DNA carries a negative charge, the OEI-SeSe could efficiently compact with plasmid DNA based on the electrostatic interaction. After entering into cells, the diselenide bonds of OEI-SeSe would be cleaved by high concentration of GSH in cytoplasm. The gene carrier would subsequently disrupt and release the loading DNA, which promoted DNA transcription. Wang and co-workers reported the synthesis of diselenide-containing PEGylated polyethylenimine as gene carrier.89 The size of the diselenidecontaining carrier increased more dramatically under the treatment of GSH compared with that of disulfide-containing carrier. The diselenide-containing carrier also showed higher transcription efficiency. ROS responsive gene carriers were also developed by cross-linking of polyethylenimine with a diselenide-containing linker.90 The high-molecular-weight gene carrier would degrade to low-molecular-weight segments under ROS treatment and release the loading DNA. High transcription efficiency was achieved in this system. In addition to the redox responsiveness, diselenide-containing molecules were also reported to show anticancer activity by themselves. Huang and Yan and co-workers designed hyperbranched polymers consisting of hydrophobic diselenide bonds and hydrophilic phosphate segments in the backbone (Figure 19).91,92 The hyperbranched polydiselenide exhibited potential to inhibit proliferation of various kinds of cancer cells. In contrast, disulfide-containing hyperbranched polymers showed little anticancer activity, which demonstrated the crucial role of diselenide bonds. The amphiphilic hyperbranched polydisele-

opportunities for singlet oxygen to oxidize the diselenide bonds. Porphyrins in this LBL film exhibited a 100-fold improvement in the efficiency of singlet oxygen production compared with those free porphyrins in solution. If porphyrins can be directly incorporated into polymers, the efficiency will be further improved. Recently, we designed a diselenide-containing hyperbranched polymer with porphyrins incorporated in the backbone.83 Under visible light irradiation, porphyrins in polymer chains would produce singlet oxygen, which oxidized diselenide bonds into seleninic acids. Cell viability tests revealed excellent anticancer activity of seleninic acids. Therefore, the selenium/porphyrin-containing hyperbranched polymer exhibited light-responsive anticancer activity on its own, which may achieve the combination of chemotherapy and photodynamic therapy. γ-Radiation is an ionizing radiation widely applied in radiotherapy, which kills cancer cells by causing DNA damage and generating free radicals. Exposure to γ-radiation will lead to ROS production and then induce cell apoptosis. Diselenide bonds are sensitive to oxidation stimuli including ROS. Thus, it is anticipated that diselenide-containing polymers can be used as a γ-radiation responsive controlled release system and combine radiotherapy with chemotherapy to achieve better efficacy in cancer treatment. We developed a γ-radiation responsive hydrogel by complexation of a positively charged diselenide-containing polymer with a peptide amphiphile (Figure 18).84 The hydrogel was composed of long cross-linked nanofiber networks. Exposed to 0.5 kGy γ-radiation, diselenide bonds on the backbone of the polymer would be cleaved by radiation produced ROS, which led to disruption of long fibers networks into short fragments. A γ-radiation-induced gel−sol transition subsequently happened. Compared with the diselenide-containing hydrogel, a disulfidecontaining polymer hydrogel with similar structure was exposed to γ-radiation. It kept intact under even 5 kGy γ-radiation, which exhibited the ultrasensitivity of diselenide bonds. However, the dosage of γ-radiation in clinical radiotherapy is still lower than 0.5 kGy, calling for drug delivery systems that are more sensitive to γ-radiation. Hydrogels consist of densely cross-linked nanofiber networks, which can restrict ROS diffusion and make it hard to break diselenide bonds in the hydrogels. Thus, the diselenidecontaining hydrogel is less sensitive to γ-radiation. A more sensitive system may be developed if diselenide bonds are M


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Figure 20. An oxidation responsive monoselenide-containing polymer PEG-PUSe-PEG. (a) Schematic illustration of Dox loading and release behaviors of PEG-PUSe-PEG. (b) XPS figure showing the valence change of selenium after oxidation. (c) Dox release profile of PEG-PUSe-PEG before and after oxidation. Reproduced with permission from ref 18. Copyright 2010 Royal Society of Chemistry.

Figure 21. Side-chain monoselenide-containing polymer exhibiting reversible oxidation and reduction property. Reproduced with permission from ref 95. Copyright 2012 Royal Society of Chemistry.

nide could self-assemble into nanoparticles with an average diameter of 50 nm, thus achieving self-delivery based on the EPR effect. Moreover, the polydiselenide could also encapsulate hydrophobic anticancer drugs and release them under redox stimuli as a drug carrier for combination chemotherapy. 4.2. Monoselenide-Containing Materials. While diselenide bonds exhibit ultrasensitivity to redox stimuli, monoselenide-containing compounds can also respond to dual redox stimuli. Different from diselenide bonds, redox processes of monoselenide do not involve bond cleavage. Monoselenide can be oxidized to form selenoxide or selenone, which can be reversely transferred to monoselenide under reduction stimuli. Because selenoxide and selenone have better hydrophilicity than monoselenide, self-assembly behaviors of monoselenide-con-

taining polymers can be regulated by change of redox conditions. This property makes monoselenide-containing polymers possible for construction of redox-responsive materials. We designed and synthesized a monoselenide-containing polymer PEG-PUSe-PEG with high sensitivity to oxidation stimuli (Figure 20).18 Similar to diselenide-containing polymers PEG-PUSeSe-PEG, PEG-PUSe-PEG could self-assemble into spherical micelles in water and encapsulate hydrophobic anticancer drugs, such as Dox. The micelles would disassemble under treatment of 0.1% H2O2 and release the encapsulated Dox because selenium was oxidized to selenoxide and selenone with better hydrophilicity, which weakened the amphiphilicity of PEG-PUSe-PEG. The oxidation responsive drug release rate of a N


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Figure 22. Monoselenide-containing peptides exhibiting redox regulated self-assembly behaviors and catalytic activity. Reproduced with permission from ref 96. Copyright 2013 Wiley-VCH.

Figure 23. Coordination responsive drug delivery system constructed by coordination between cisplatin and selenium-containing polymer could load Dox. In the presence of GSH, both Pt2+ and Dox could be released. Reproduced with permission from ref 100. Copyright 2012 Royal Society of Chemistry.

smart system showed potential applications for responsive drug delivery and antioxidation studies. In addition, the reversible redox responsive system can be applied to regulate biological activities. We synthesized monoselenide-containing functional polypeptides with reversible redox responsive self-assembly behaviors and catalytic activities (Figure 22).96 In the reduced state, monoselenidecontaining peptides self-assembled into long fibers and entangled into 3D networks; while in the oxidized state, the selenoxide-containing peptides would form spherical micelles. The peptides in oxidized state could be slowly transformed into hydrogel by vitamin C, which was involved in the transformation from selenoxide to selenide. Histidine with catalytic activity was attached to the selenium-containing peptide, which endowed the peptide with ability to catalyze the hydrolysis of acetate. Selfassembly behaviors of the peptides showed great influence on the catalytic activity. The activity of peptides in oxidized state was 10 times higher than that of peptides in reduced state, which demonstrated the redox controlled catalytic activity of monoselenide-containing peptides. Monoselenide-containing polymers were also reported to show anticancer activity. Huang and Yan and co-workers developed an amphiphilic hyperbranched polymer with alternative monoselenides and phosphate groups in the backbone.97 The hyperbranched polymer exhibited anticancer activity without loading any cargo. It could inhibit proliferation of cancer cells via inducing cell apoptosis. In contrast, if the

monosulfide-containing polymer PEG-PUS-PEG was much lower than that of PEG-PUSe-PEG, which demonstrated the sensitivity of monoselenides to oxidation stimuli. Zhang and coworkers further investigated the disassembly process of PEGPUSe-PEG using atomic force microscopy (AFM)-based singlemolecule force spectroscopy (SMFS).93 The difference between force−extension curves of the monoselenide-containing polymer in water and in DMSO revealed the disassembly process under oxidation stimuli, which resulted from the change of amphiphilicity. A monoselenide-containing supramolecular amphiphile was developed based on the electrostatic interaction between a selenium-containing surfactant (SeQTA) and a hydrophilic polymer of poly(ethylene glycol)-b-acrylic acid (PEG-b-PAA).94 The supramolecular amphiphile could also self-assemble in water and exhibited oxidation responsive disassembly behavior. Therefore, it was suitable for the construction of controlled release systems. Taking advantage of the reversible redox property of monoselenide-containing molecules, we developed side-chain monoselenide-containing poly(ethylene oxide-b-acrylic acid) block copolymers PEO-b-PAA-Se (Figure 21).95 PEO-b-PAASe self-assembled into spherical micelles in water. Under mild oxidation stimuli, monoselenide was oxidized to selenoxide and the micelles would disassemble. The selenoxide could be reversibly reduced to monoselenide under mild reduction stimuli and recover to form spherical micelles. This reversible redox process could be repeated more than seven times. Such a O


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Figure 24. Small molecular assembly with selective anticancer activity constructed by coordination between selenium-containing molecule EGSe and platinum. (a) Chemical structure of the coordination complex. (b) MTT assay results showing selective anticancer activity. (c) Confocal microscopy figures indicating production of high level of ROS in cancer cells. (d) Tumor volumes and weight changes of mice during in vivo experiments. Reproduced with permission from ref 104. Copyright 2014 Wiley-VCH.

combining GSH response with spermine response to develop synergetic multiresponsive smart systems. Similarly, a seleniumcontaining thermogel with coordination responsiveness was developed by Yu and Ding and co-workers for controlled drug delivery.103 It is worth noting that the selenium−platinum coordination complexes can exhibit anticancer activity as the contents of selenium and platinum increase. We developed seleniumcontaining dendrimers and small molecular assemblies, which showed anticancer activity after coordination with platinum.104−107 A selenium-containing small molecule EGSe was coordinated with platinum to form a coordination complex, which exhibited selective anticancer activity (Figure 24). MTT assays showed low viability (4%) of cancer cells and high viability (72%) of normal cells under treatment of the coordination complex. However, both cancer cells and normal cells showed low viability under treatment of cisplatin. The mechanism was reported to be involved with the concentration of ROS in cells. The coordination complex could induce higher level of ROS in cancer cells than that in normal cells, which led to higher toxicity to cancer cells. In vivo experiments revealed high antitumor efficacy and low side effects of the coordination complex. This selenium−platinum coordination assembly exhibited great potential for clinical applications in cancer treatment.

selenium was replaced to oxygen or carbon, the hyperbranched polymer showed little anticancer activity. Additionally, the monoselenide-containing hyperbranched polymer could act as a hydrogen peroxide-responsive drug delivery vehicle, which loads and releases Dox in a controlled manner. This type of therapeutic nanocarrier with both anticancer activity and drug delivery ability provides a new platform for combined therapy. 4.3. Coordination Materials. Selenium can act as a ligand to coordinate with different metals.98,99 Complexes formed by coordination between selenium and metals showed special chemical and biological properties. We studied the coordination between selenium-containing polymer and platinum and introduced the competitive coordination mechanism into the construction of drug delivery systems.100 Competitive coordination processes are widespread in metabolism of human bodies. They play crucial roles in regulating physiological activities, such as the function of G protein-coupled receptors and the immune processes between antigen and antibody.101 Making use of the biological ligands, coordination responsive systems can be developed for controlled drug release in cancer treatment. A coordination responsive system for controlled drug release was constructed by coordination between cisplatin and selenidecontaining polymer (Figure 23). The coordination complex could self-assemble into spherical micelles with good biocompatibility and stability in water. GSH could replace the selenium-containing ligands and competitively coordinate with platinum. Because GSH had a high concentration of 1−10 mM in cells but a low concentration of ∼2 μM outside cells, it is regarded as a promising stimulus to trigger drug release from delivery vehicles. In the presence of GSH, platinum cations would be extracted from the micelles. Dox could also be loaded in the micelles. The release of platinum cations would cause partial disassembly of the micelles, which further triggered the release of Dox. This system showed advantages in achieving combination therapy with different kinds of drugs. Besides GSH, other ligands of platinum, such as DTT and spermine, were also found to have the ability of competitive coordination.102 Spermine is a polyamine existing widely in human bodies, which acts as a biomarker in a rapidly growing tumor. Therefore, the coordination responsive polymer opens a new avenue of

5. CONCLUSION AND OUTLOOK The unique chemical properties of selenium element have endowed selenium-containing polymer a series of fascinating features. Those features allow them to be employed as both selfadaptive materials and biomaterials. The methods to synthesize selenium-containing polymer has been widely expanded in recent years. Step growth polymerization allows an efficient way to obtain polymers with a relatively high content of selenium because selenium was incorporated into each repeating unites. However, the shortcoming of this method is pretty obvious; the structure and the dispersity cannot be precisely controlled. As for radical polymerization, where selenium-containing compounds were used as initiator or RAFT agents, there are only limited amount of selenium-containing residual groups left in the polymer chain, P


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which may limit their application in certain areas. Additionally, selenium-containing monomers are usually not compatible with living radical polymerization like ATRP and RAFT since selenium-containing groups may react with initiator, metal catalysts (ATRP) and sulfur-containing RAFT agents via radical reactions or coordination reactions. Ring-opening polymerization seems to offer a balance between the selenium content and controllable polymer structures. Yet there are only limited monomers to be selected. We expect that the challenge of controlled radical polymerization of selenium-containing monomer could be overcome in the future, which may provide with a universal preparation method that can offer structure controllable polymers with high selenium contents. Selenium-containing dynamic covalent bond is a new area full of opportunities. We have mentioned that not only Se−Se, Se− N, and Se−S bonds are DCBs, Se−O and even Se−Te could also potentially be DCBs. In the future, more selenium-containing DCBs should be discovered, and their internal transformation rules should be established. In the meantime, the thermodynamic and kinetic process of the dynamic covalent reactions should be thoroughly investigated. Moreover, this new DCB family could be widely applied in a series of self-adaptive materials like self-healing materials, reprocessable polymer materials, etc. It is worth noting that the combination of two or more types of selenium-containing DCBs in a single system may generate multiresponsive reversible materials. Besides, it has been proved that selenium-containing DCBs could perform easily at the interface; hence, it could be employed into the field of surface chemistry. Because many enzymes and proteins contain a S−S bond, the Se−S DCB could offer opportunities to modify those biomacromolecules into surfaces. In recent years selenium-containing polymers, including diselenides, monoselenides, and selenium−platinum coordination complexes, were realized to be promising biomaterials as well. Taking advantages of the stimulus-responsive property and the anticancer activity of selenium, these materials were used to construct smart drug delivery systems with controlled release manners. We anticipate that various types of seleniumcontaining molecules can be synthesized besides those highlighted above. Although selenium-containing biomaterials have been rapidly developed in recent years, there is still a large gap between smart systems reported in journals and commercially available nanomedicine for clinical use. The anticancer mechanism of selenium should be clarified more clearly. The biosafety of selenium-containing materials need to be further evaluated in big animal models and clinical trials. The immunogenicity of selenium-containing materials should also be noted. Because selenite was reported to show cancer immunological activity, we prospect that selenium-containing polymers will show potentials for cancer immunotherapy. With rational design, these systems may achieve the combination of immunotherapy with chemotherapy and radiotherapy in cancer treatment. Additionally, biological systems desire stimulusresponsive materials even more sensitive than seleniumcontaining polymers in some special situations. Telluriumcontaining materials can be a good candidate for developing such smart systems responding to biomolecules in low concentration.

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Chenjie Lu: 0000-0002-3000-1835 Huaping Xu: 0000-0002-7530-7264 Author Contributions

J.X. and T.L. contributed equally to this work. Notes

The authors declare no competing financial interest. Biographies

Jiahao Xia received a B.Eng. in Polymer Materials and Engineering from Sichuan University in 2011 and is currently a Ph.D. student under the supervision of Prof. Huaping Xu at Tsinghua University. His research focuses on the selenium-containing dynamic covalent bonds and their applications in dynamic materials.

Tianyu Li received his B.S. degree in Chemistry from Tsinghua University in 2014. He is currently a Ph.D. graduate student under the supervision of Prof. Huaping Xu at Tsinghua University. His research focuses on the development of selenium-containing assemblies for cancer treatment.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (H.X.). Q


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Lottermoser, B. Severe Selenium Depletion in the Phanerozoic Oceans as a Factor in Three Global Mass Extinction Events. Gondwana Res. 2016, 36, 209−218. (9) Kishore, K.; Ganesh, K. Polymers Containing Disulfide, Tetrasulfide, Diselenide and Ditelluride Linkages in the Main-Chain. Polymer Synthesis/Polymer Engineering 1995, 121, 81−121. (10) Xu, H.; Cao, W.; Zhang, X. Selenium-Containing Polymers: Promising Biomaterials for Controlled Release and Enzyme Mimics. Acc. Chem. Res. 2013, 46 (7), 1647−1658. (11) Prince, M.; Bremer, B. Preparation of Hexagonal Polyselenomethylene. J. Polym. Sci., Part B: Polym. Lett. 1967, 5 (9), 843−845. (12) Kroll, H.; Bolton, E. F. Synthesis of Selenium Condensation Polymers Using Bis(2-Hydroxyethyl) Selenide and Bis(2-Aminoethyl) Selenide. J. Appl. Polym. Sci. 1970, 14 (9), 2319−2325. (13) Gunther, W. H. H.; Salzman, M. N. Methods in Selenium Chemistry. 4. Synthetic Approaches to Polydiselenides. Ann. N. Y. Acad. Sci. 1972, 192 (17), 25−43. (14) Glenis, S.; Ginley, D. S.; Frank, A. J. Solid-State and Electrochemical Properties of Polyselenophene. J. Appl. Phys. 1987, 62 (1), 190−194. (15) Yoshino, K.; Kohno, Y.; Shiraishi, T.; Kaneto, K.; Inoue, S.; Tsukagoshi, K. Electrical and Optical-Properties of Electrochemically Prepared Polyselenophene Film. Synth. Met. 1985, 10 (5), 319−326. (16) Koytepe, S.; Seckin, T.; Cetinkaya, E.; Gok, Y. Synthesis and Properties of Novel Selenium Containing Polyimides with Various Dianhydrides. J. Inorg. Organomet. Polym. Mater. 2005, 15 (2), 269− 279. (17) Ma, N.; Li, Y.; Xu, H. P.; Wang, Z. Q.; Zhang, X. Dual Redox Responsive Assemblies Formed from Diselenide Block Copolymers. J. Am. Chem. Soc. 2010, 132 (2), 442−443. (18) Ma, N.; Li, Y.; Ren, H.; Xu, H.; Li, Z.; Zhang, X. SeleniumContaining Block Copolymers and Their Oxidation-Responsive Aggregates. Polym. Chem. 2010, 1 (10), 1609−1614. (19) Ando, T.; Kwon, T. S.; Kitagawa, A.; Tanemura, T.; Kondo, S.; Kunisada, H.; Yuki, Y. Synthesis and Free Radical Polymerization of PMethylseleno- and P-Phenylselenostyrenes. Macromol. Chem. Phys. 1996, 197 (9), 2803−2810. (20) Kwon, T. S.; Kumazawa, S.; Yokoi, T.; Kondo, S.; Kunisada, H.; Yuki, Y. Living Radical Polymerization of Styrene with Diphenyl Diselenide as a Photoiniferter. Synthesis of Polystyrene with CarbonCarbon Double Bonds at Both Chain Ends. J. Macromol. Sci., Part A: Pure Appl.Chem. 1997, 34 (9), 1553−1567. (21) Kwon, T. S.; Kondo, S.; Takagi, K.; Kunisada, H.; Yuki, Y. Synthesis and Radical Polymerization of P-Phenylselenomethylstyrene and Applications to Graft Copolymers. Polym. J. 1999, 31 (6), 483− 487. (22) Kwon, T. S.; Takagi, K.; Kunisada, H.; Yuki, Y. Synthesis of Star Polystyrene by Radical Polymerization with 1,2,4,5-Tetrakis(P-TertButylphenylselenomethyl)Benzene as a Novel Photoiniferter. Eur. Polym. J. 2003, 39 (7), 1437−1441. (23) Chiefari, J.; Chong, Y. K.; Ercole, F.; Krstina, J.; Jeffery, J.; Le, T. P. T.; Mayadunne, R. T. A.; Meijs, G. F.; Moad, C. L.; Moad, G.; Rizzardo, E.; Thang, S. H. Living Free-Radical Polymerization by Reversible Addition-Fragmentation Chain Transfer: The Raft Process. Macromolecules 1998, 31 (16), 5559−5562. (24) Moad, G.; Rizzardo, E.; Thang, S. H. Radical AdditionFragmentation Chemistry in Polymer Synthesis. Polymer 2008, 49 (5), 1079−1131. (25) Keddie, D. J. A Guide to the Synthesis of Block Copolymers Using Reversible-Addition Fragmentation Chain Transfer (Raft) Polymerization. Chem. Soc. Rev. 2014, 43 (2), 496−505. (26) Moon, J.; Nam, H.; Kim, S.; Ryu, J.; Han, C.; Lee, C.; Lee, S. Synthesis of Phosphinodiselenoic Acid Esters and Their Application as Raft Agents in Styrene Polymerization. Tetrahedron Lett. 2008, 49 (35), 5137−5140. (27) Zeng, J.; Zhu, J.; Zhang, Z.; Pan, X.; Zhang, W.; Cheng, Z.; Zhu, X. New Selenium-Based Iniferter Agent for Living Free Radical Polymerization of Styrene under Uv Irradiation. J. Polym. Sci., Part A: Polym. Chem. 2012, 50 (11), 2211−2218.

Chenjie Lu studied chemistry at Hangzhou Normal University Qianjiang College as an undergraduate student. He received M.S. in Polymer Chemistry & Physics from Hangzhou Normal University in 2018 under the direction of Dr. Shouchun Yin. His current research interest is focused on fluorescent supramolecular polymers.

Huaping Xu received his Bachelor degree in 2001 and Ph.D. degree in 2006 in Jilin University, China, under the supervision of Prof. Xi Zhang. In 2006, he joined Prof. David N. Reinhoudt and Prof. Jurriaan Huskens’s group at University of Twente, The Netherlands, as a postdoc. Since July 2008, he has worked at Department of Chemistry, Tsinghua University, China. He was promoted to full professor in 2014. In 2014, he received the Natural Science Fund for Outstanding Young Scholars from NSFC. In 2017, he was enrolled in Leading Talent of National High-level personnel of special support program (“people plan”). He has served for Associate Editor of ACS Biomaterials Science & Engineering since January 2017. His current research is focused on selenium/tellurium-containing polymers.

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ACKNOWLEDGMENTS This work was financially supported by the National Science Foundation for Distinguished Young Scholars (Grant 21425416), the National Natural Science Foundation of China (Grant 21734006), and the National Basic Research Plan of China (2018YFA0208900).

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REFERENCES

(1) Boyd, R. Selenium Stories. Nat. Chem. 2011, 3 (7), 570. (2) Rotruck, J. T.; Pope, A. L.; Ganther, H. E.; Swanson, A. B.; Hafeman, D. G.; Hoekstra, W. G. Selenium-Biochemical Role as a Component of Glutathione Peroxidase. Science 1973, 179 (4073), 588−590. (3) Mugesh, G.; Singh, H. B. Synthetic Organoselenium Compounds as Antioxidants: Glutathione Peroxidase Activity. Chem. Soc. Rev. 2000, 29 (5), 347−357. (4) Mugesh, G.; du Mont, W. W.; Sies, H. Chemistry of Biologically Important Synthetic Organoselenium Compounds. Chem. Rev. 2001, 101 (7), 2125−2179. (5) Cai, X.; Wang, C.; Yu, W.; Fan, W.; Wang, S.; Shen, N.; Wu, P.; Li, X.; Wang, F. Selenium Exposure and Cancer Risk: An Updated MetaAnalysis and Meta-Regression. Sci. Rep. 2016, 6, 19213. (6) Muller, A.; Cadenas, E.; Graf, P.; Sies, H. A Novel BiologicallyActive Organoselenium Compound 0.1. Glutathione Peroxidase-Like Activity Invitro and Antioxidant Capacity of Pz-51 (Ebselen). Biochem. Pharmacol. 1984, 33 (20), 3235−3239. (7) Wendel, A.; Fausel, M.; Safayhi, H.; Tiegs, G.; Otter, R. A Novel Biologically-Active Organoselenium Compound 0.2. Activity of Pz-51 in Relation to Glutathione-Peroxidase. Biochem. Pharmacol. 1984, 33 (20), 3241−3245. (8) Long, J. A.; Large, R. R.; Lee, M. S. Y.; Benton, M. J.; Danyushevsky, L. V.; Chiappe, L. M.; Halpin, J. A.; Cantrill, D.; R


Perspective

Macromolecules (28) Zhan, Y.; Zhang, Z.; Pan, X.; Zhu, J.; Zhou, N.; Zhu, X. A Cyclic Selenium-Based Reversible Addition-Fragmentation Chain Transfer Agent Mediated Polymerization of Vinyl Acetate. J. Polym. Sci., Part A: Polym. Chem. 2013, 51 (7), 1656−1663. (29) Ma, F.; Zhu, J.; Zhang, Z.; Pan, X.; Zhou, N.; Zhu, X. SelenoContaining Poly(Vinyl Acetate) Prepared by DiselenocarbonatesMediated Controlled Free Radical Polymerizations. J. Polym. Sci., Part A: Polym. Chem. 2013, 51 (15), 3159−3165. (30) Gao, F.; Pan, X.; Zhu, J.; Zhang, Z.; Zhang, W.; Zhu, X. Facile Synthesis of Well-Defined Redox Responsive Diselenide-Labeled Polymers Via Organoselenium-Mediated Crp and Aminolysis. Polym. Chem. 2015, 6 (8), 1367−1372. (31) Cai, Z. X.; Lu, W. H.; Gao, F.; Pan, X. Q.; Zhu, J.; Zhang, Z. B.; Zhu, X. L. Diselenide-Labeled Cyclic Polystyrene with Multiple Responses: Facile Synthesis, Tunable Size, and Topology. Macromol. Rapid Commun. 2016, 37 (10), 865−871. (32) Wang, J. S.; Matyjaszewski, K. Controlled Living Radical Polymerization - Halogen Atom-Transfer Radical Polymerization Promoted by a Cu(I)Cu(Ii) Redox Process. Macromolecules 1995, 28 (23), 7901−7910. (33) Wang, J. S.; Matyjaszewski, K. Controlled Living Radical Polymerization - Atom-Transfer Radical Polymerization in the Presence of Transition-Metal Complexes. J. Am. Chem. Soc. 1995, 117 (20), 5614−5615. (34) Matyjaszewski, K. Atom Transfer Radical Polymerization (Atrp): Current Status and Future Perspectives. Macromolecules 2012, 45 (10), 4015−4039. (35) Ji, S. B.; Cao, W.; Yu, Y.; Xu, H. P. Dynamic Diselenide Bonds: Exchange Reaction Induced by Visible Light without Catalysis. Angew. Chem., Int. Ed. 2014, 53 (26), 6781−6785. (36) Fan, C. W.; Ding, C. L.; Pan, X. Q.; Zhang, Z. B.; Zhu, J.; Zhu, X. L. A Straightforward Method for Preparing Well-Defined Responsive Diselenide-Containing Polymers Based on Atrp. Macromol. Rapid Commun. 2015, 36 (10), 903−908. (37) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. About Dendrimers: Structure, Physical Properties, and Applications. Chem. Rev. 1999, 99 (7), 1665−1688. (38) Drake, M. D.; Bright, F. V.; Detty, M. R. Dendrimeric Organochalcogen Catalysts for the Activation of Hydrogen Peroxide: Origins of the “Dendrimer Effect” with Catalysts Terminating in Phenylseleno Groups. J. Am. Chem. Soc. 2003, 125 (41), 12558−12566. (39) Francavilla, C.; Drake, M. D.; Bright, F. V.; Detty, M. R. Dendrimeric Organochalcogen Catalysts for the Activation of Hydrogen Peroxide: Improved Catalytic Activity through Statistical Effects and Cooperativity in Successive Generations. J. Am. Chem. Soc. 2001, 123 (1), 57−67. (40) Takagi, K.; Nishikawa, Y.; Kwon, T. S.; Kunisada, H.; Yuki, Y. Synthesis of Branched Polystyrene by Photopolymerization of Selenium-Containing Styrene Monomer. Polym. J. 2000, 32 (11), 970−973. (41) Zhang, X.; Xu, H. P.; Dong, Z. Y.; Wang, Y. P.; Liu, J. Q.; Shen, J. C. Highly Efficient Dendrimer-Based Mimic of Glutathione Peroxidase. J. Am. Chem. Soc. 2004, 126 (34), 10556−10557. (42) Xu, H. P.; Gao, J.; Wang, Y. P.; Wang, Z. Q.; Smet, M.; Dehaen, W.; Zhang, X. Hyperbranched Polyselenides as Glutathione Peroxidase Mimics. Chem. Commun. 2006, 0 (7), 796−798. (43) Pan, X. Q.; Driessen, F.; Zhu, X. L.; Du Prez, F. E. Selenolactone as a Building Block toward Dynamic Diselenide-Containing Polymer Architectures with Controllable Topology. ACS Macro Lett. 2017, 6 (2), 89−92. (44) Wei, C.; Zhang, Y.; Yan, B.; Du, Z.; Lang, M. A Versatile Strategy to Main Chain Sulfur/Selenium-Functionalized Polycarbonates by Macro-Ring Closure of Diols and Subsequent Ring-Opening Polymerization. Chem. - Eur. J. 2018, 24 (4), 789−792. (45) Wei, C.; Xu, Y.; Yan, B.; Hou, J.; Du, Z.; Lang, M. Well-Defined Selenium-Containing Aliphatic Polycarbonates Via Lipase-Catalyzed Ring-Opening Polymerization of Selenic Macrocyclic Carbonate Monomer. ACS Macro Lett. 2018, 7 (3), 336−340.

(46) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart, J. F. Dynamic Covalent Chemistry. Angew. Chem., Int. Ed. 2002, 41 (6), 898−952. (47) Corbett, P. T.; Leclaire, J.; Vial, L.; West, K. R.; Wietor, J.-L.; Sanders, J. K. M.; Otto, S. Dynamic Combinatorial Chemistry. Chem. Rev. 2006, 106 (9), 3652−3711. (48) Lehn, J. M. Dynamic Combinatorial Chemistry and Virtual Combinatorial Libraries. Chem. - Eur. J. 1999, 5 (9), 2455−2463. (49) Von Delius, M.; Geertsema, E. M.; Leigh, D. A. A Synthetic Small Molecule That Can Walk Down a Track. Nat. Chem. 2010, 2 (2), 96− 101. (50) Wilson, A.; Gasparini, G.; Matile, S. Functional Systems with Orthogonal Dynamic Covalent Bonds. Chem. Soc. Rev. 2014, 43 (6), 1948−1962. (51) Hou, H.; Yin, J.; Jiang, X. Reversible Diels-Alder Reaction to Control Wrinkle Patterns: From Dynamic Chemistry to Dynamic Patterns. Adv. Mater. 2016, 28 (41), 9126−9132. (52) Herrmann, A. Dynamic Combinatorial/Covalent Chemistry: A Tool to Read, Generate and Modulate the Bioactivity of Compounds and Compound Mixtures. Chem. Soc. Rev. 2014, 43 (6), 1899−1933. (53) Moulin, E.; Cormos, G.; Giuseppone, N. Dynamic Combinatorial Chemistry as a Tool for the Design of Functional Materials and Devices. Chem. Soc. Rev. 2012, 41 (3), 1031−1049. (54) Black, S. P.; Sanders, J. K. M.; Stefankiewicz, A. R. Disulfide Exchange: Exposing Supramolecular Reactivity through Dynamic Covalent Chemistry. Chem. Soc. Rev. 2014, 43 (6), 1861−1872. (55) Kildahl, N. K. Bond-Energy Data Summarized. J. Chem. Educ. 1995, 72 (5), 423−424. (56) Xia, J.; Ji, S.; Xu, H. Diselenide Covalent Chemistry at the Interface: Stabilizing an Asymmetric Diselenide-Containing Polymer Via Micelle Formation. Polym. Chem. 2016, 7 (44), 6708−6713. (57) The bond energy of the Se−X covalent bond is calculated according to the Pauling equation: DA−B = (DA−ADB−B)1/2 + 96.5(XA − XB)2 in which D is bond energy and X is electronegativity of the element. (58) Yi, Y.; Fa, S.; Cao, W.; Zeng, L.; Wang, M.; Xu, H.; Zhang, X. Fabrication of Well-Defined Crystalline Azacalixarene Nanosheets Assisted by Se Center Dot Center Dot Center Dot N Non-Covalent Interactions. Chem. Commun. 2012, 48 (60), 7495−7497. (59) Yi, Y.; Xu, H.; Wang, L.; Cao, W.; Zhang, X. A New Dynamic Covalent Bond of Se-N: Towards Controlled Self-Assembly and Disassembly. Chem. - Eur. J. 2013, 19 (29), 9506−9510. (60) Huang, X.; Fang, R.; Wang, D.; Wang, J.; Xu, H.; Wang, Y.; Zhang, X. Tuning Polymeric Amphiphilicity Via Se-N Interactions: Towards One-Step Double Emulsion for Highly Selective Enzyme Mimics. Small 2015, 11 (13), 1537−1541. (61) Ji, S.; Xia, J.; Xu, H. Dynamic Chemistry of Selenium: Se-N and Se-Se Dynamic Covalent Bonds in Polymeric Systems. ACS Macro Lett. 2016, 5 (1), 78−82. (62) Rasmussen, B.; Sorensen, A.; Gotfredsen, H.; Pittelkow, M. Dynamic Combinatorial Chemistry with Diselenides and Disulfides in Water. Chem. Commun. 2014, 50 (28), 3716−3718. (63) Ji, S.; El Mard, H.; Smet, M.; Dehaen, W.; Xu, H. Selenium Containing Macrocycles: Transformation between Se−N/Se−S/Se− Se Bonds. Sci. China: Chem. 2017, 60 (9), 1191−1196. (64) Ji, S.; Cao, W.; Yu, Y.; Xu, H. Visible-Light-Induced Self-Healing Diselenide-Containing Polyurethane Elastomer. Adv. Mater. 2015, 27 (47), 7740−7745. (65) Ji, S.; Fan, F.; Sun, C.; Yu, Y.; Xu, H. Visible Light-Induced Plasticity of Shape Memory Polymers. ACS Appl. Mater. Interfaces 2017, 9 (38), 33169−33175. (66) Xia, J.; Li, F.; Ji, S.; Xu, H. Selenium-Functionalized Graphene Oxide That Can Modulate the Balance of Reactive Oxygen Species. ACS Appl. Mater. Interfaces 2017, 9 (25), 21413−21421. (67) Xu, H.; Cao, W.; Zhang, X. Selenium-Containing Polymers: Promising Biomaterials for Controlled Release and Enzyme Mimics. Acc. Chem. Res. 2013, 46 (7), 1647−1658. S


Perspective

Macromolecules (68) Cao, W.; Wang, L.; Xu, H. Selenium/Tellurium Containing Polymer Materials in Nanobiotechnology. Nano Today 2015, 10 (6), 717−736. (69) Ma, N.; Li, Y.; Xu, H.; Wang, Z.; Zhang, X. Dual Redox Responsive Assemblies Formed from Diselenide Block Copolymers. J. Am. Chem. Soc. 2010, 132 (2), 442−443. (70) Sun, T.; Jin, Y.; Qi, R.; Peng, S.; Fan, B. Post-Assembly of Oxidation-Responsive Amphiphilic Triblock Polymer Containing a Single Diselenide. Macromol. Chem. Phys. 2013, 214 (24), 2875−2881. (71) Deepagan, V. G.; Kwon, S.; You, D. G.; Nguyen, V. Q.; Um, W.; Ko, H.; Lee, H.; Jo, D. G.; Kang, Y. M.; Park, J. H. In Situ DiselenideCrosslinked Polymeric Micelles for Ros-Mediated Anticancer Drug Delivery. Biomaterials 2016, 103, 56−66. (72) Zeng, X.; Zhou, X.; Li, M.; Wang, C.; Xu, J.; Ma, D.; Xue, W. Redox Poly(Ethylene Glycol)-B-Poly(L-Lactide) Micelles Containing Diselenide Bonds for Effective Drug Delivery. J. Mater. Sci.: Mater. Med. 2015, 26 (9), 234. (73) Wei, C.; Zhang, Y.; Xu, H.; Xu, Y.; Xu, Y.; Lang, M. Well-Defined Labile Diselenide-Centered Poly(E-Caprolactone)-Based Micelles for Activated Intracellular Drug Release. J. Mater. Chem. B 2016, 4 (29), 5059−5067. (74) Wei, C.; Zhang, Y.; Song, Z.; Xia, Y.; Xu, H.; Lang, M. Enhanced Bioreduction-Responsive Biodegradable Diselenide-Containing Poly(Ester Urethane) Nanocarriers. Biomater. Sci. 2017, 5 (4), 669−677. (75) Xue, Y.; Xia, X.; Yu, B.; Tao, L.; Wang, Q.; Huang, S. W.; Yu, F. Selenylsulfide Bond-Launched Reduction-Responsive Superparamagnetic Nanogel Combined of Acid-Responsiveness for Achievement of Efficient Therapy with Low Side Effect. ACS Appl. Mater. Interfaces 2017, 9 (36), 30253−30257. (76) Zhou, W.; Wang, L.; Li, F.; Zhang, W.; Huang, W.; Huo, F.; Xu, H. Selenium-Containing Polymer@Metal-Organic Frameworks Nanocomposites as an Efficient Multiresponsive Drug Delivery System. Adv. Funct. Mater. 2017, 27 (6), 1605465. (77) Sun, T.; Zhu, C.; Xu, J. Multiple Stimuli-Responsive SeleniumFunctionalized Biodegradable Starch-Based Hydrogels. Soft Matter 2018, 14 (6), 921−926. (78) Zhai, S.; Hu, X.; Hu, Y.; Wu, B.; Xing, D. Visible Light-Induced Crosslinking and Physiological Stabilization of Diselenide-Rich Nanoparticles for Redox-Responsive Drug Release and Combination Chemotherapy. Biomaterials 2017, 121, 41−54. (79) Tan, X.; Yang, L.; Huang, Z.; Yu, Y.; Wang, Z.; Zhang, X. Amphiphilic Diselenide-Containing Supramolecular Polymers. Polym. Chem. 2015, 6 (5), 681−685. (80) Wang, L.; Cao, W.; Yi, Y.; Xu, H. Dual Redox Responsive Coassemblies of Diselenide-Containing Block Copolymers and Polymer Lipids. Langmuir 2014, 30 (19), 5628−5636. (81) Han, P.; Li, S.; Cao, W.; Li, Y.; Sun, Z.; Wang, Z.; Xu, H. Red Light Responsive Diselenide-Containing Block Copolymer Micelles. J. Mater. Chem. B 2013, 1 (6), 740. (82) Ren, H.; Wu, Y.; Li, Y.; Cao, W.; Sun, Z.; Xu, H.; Zhang, X. Visible-Light-Induced Disruption of Diselenide-Containing Layer-byLayer Films: Toward Combination of Chemotherapy and Photodynamic Therapy. Small 2013, 9 (23), 3981−3986. (83) Sun, C.; Ji, S.; Li, F.; Xu, H. Diselenide-Containing Hyperbranched Polymer with Light-Induced Cytotoxicity. ACS Appl. Mater. Interfaces 2017, 9 (15), 12924−12929. (84) Cao, W.; Zhang, X.; Miao, X.; Yang, Z.; Xu, H. Gamma-RayResponsive Supramolecular Hydrogel Based on a DiselenideContaining Polymer and a Peptide. Angew. Chem., Int. Ed. 2013, 52 (24), 6233−6237. (85) Ma, N.; Xu, H.; An, L.; Li, J.; Sun, Z.; Zhang, X. RadiationSensitive Diselenide Block Co-Polymer Micellar Aggregates: Toward the Combination of Radiotherapy and Chemotherapy. Langmuir 2011, 27 (10), 5874−5878. (86) Cheng, G.; He, Y.; Xie, L.; Nie, Y.; He, B.; Zhang, Z.; Gu, Z. Development of a Reduction-Sensitive Diselenide-Conjugated Oligoethylenimine Nanoparticulate System as a Gene Carrier. Int. J. Nanomed. 2012, 7, 3991−4006.

(87) Gu, Z.; Yue, D.; Cheng, G.; He, Y.; Nie, Y.; Jiang, Q.; Cai, X. Influence of Reduction-Sensitive Diselenide Bonds and Disulfide Bonds on Oligoethylenimine Conjugates for Gene Delivery. J. Mater. Chem. B 2014, 2 (41), 7210−7221. (88) He, Y.; Nie, Y.; Cheng, G.; Xie, L.; Shen, Y.; Gu, Z. Viral Mimicking Ternary Polyplexes: A Reduction-Controlled Hierarchical Unpacking Vector for Gene Delivery. Adv. Mater. 2014, 26 (10), 1534− 1540. (89) Li, W.; Zhang, P.; Zheng, K.; Hu, Q.; Wang, Y. Redox-Triggered Intracellular Depegylation Based on Diselenide-Linked Polycations for DNA Delivery. J. Mater. Chem. B 2013, 1 (46), 6418−6426. (90) Deng, Q.; Li, X.; Zhu, L.; He, H.; Chen, D.; Chen, Y.; Yin, L. Serum-Resistant, Reactive Oxygen Species (Ros)-Potentiated Gene Delivery in Cancer Cells Mediated by Fluorinated, DiselenideCrosslinked Polyplexes. Biomater. Sci. 2017, 5 (6), 1174−1182. (91) Liu, J.; Pang, Y.; Chen, J.; Huang, P.; Huang, W.; Zhu, X.; Yan, D. Hyperbranched Polydiselenide as a Self Assembling Broad Spectrum Anticancer Agent. Biomaterials 2012, 33 (31), 7765−7774. (92) Li, C.; Huang, W.; Zhou, L.; Huang, P.; Pang, Y.; Zhu, X.; Yan, D. Pegylated Poly(Diselenide-Phosphate) Nanogel as Efficient SelfDelivery Nanomedicine for Cancer Therapy. Polym. Chem. 2015, 6 (36), 6498−6508. (93) Tan, X.; Yu, Y.; Liu, K.; Xu, H.; Liu, D.; Wang, Z.; Zhang, X. Single-Molecule Force Spectroscopy of Selenium-Containing Amphiphilic Block Copolymer: Toward Disassembling the Polymer Micelles. Langmuir 2012, 28 (25), 9601−9605. (94) Han, P.; Ma, N.; Ren, H.; Xu, H.; Li, Z.; Wang, Z.; Zhang, X. Oxidation-Responsive Micelles Based on a Selenium-Containing Polymeric Superamphiphile. Langmuir 2010, 26 (18), 14414−14418. (95) Ren, H.; Wu, Y.; Ma, N.; Xu, H.; Zhang, X. Side-Chain SeleniumContaining Amphiphilic Block Copolymers: Redox-Controlled SelfAssembly and Disassembly. Soft Matter 2012, 8 (5), 1460−1466. (96) Miao, X.; Cao, W.; Zheng, W.; Wang, J.; Zhang, X.; Gao, J.; Yang, C.; Kong, D.; Xu, H.; Wang, L.; Yang, Z. Switchable Catalytic Activity: Selenium-Containing Peptides with Redox-Controllable Self-Assembly Properties. Angew. Chem., Int. Ed. 2013, 52 (30), 7781−7785. (97) Liu, J.; Pang, Y.; Zhu, Z.; Wang, D.; Li, C.; Huang, W.; Zhu, X.; Yan, D. Therapeutic Nanocarriers with Hydrogen Peroxide-Triggered Drug Release for Cancer Treatment. Biomacromolecules 2013, 14 (5), 1627−1636. (98) Liu, Q.; Wang, X.; Yang, X.; Liang, X.; Guo, Z. Fast Cleavage of a Diselenide Induced by a Platinum(Ii)-Methionine Complex and Its Biological Implications. J. Inorg. Biochem. 2010, 104 (11), 1178−1184. (99) Battin, E. E.; Brumaghim, J. L. Antioxidant Activity of Sulfur and Selenium: A Review of Reactive Oxygen Species Scavenging, Glutathione Peroxidase, and Metal-Binding Antioxidant Mechanisms. Cell Biochem. Biophys. 2009, 55 (1), 1−23. (100) Cao, W.; Li, Y.; Yi, Y.; Ji, S.; Zeng, L.; Sun, Z.; Xu, H. Coordination-Responsive Selenium-Containing Polymer Micelles for Controlled Drug Release. Chem. Sci. 2012, 3 (12), 3403−3408. (101) Rosenbaum, D. M.; Rasmussen, S. G. F.; Kobilka, B. K. The Structure and Function of G-Protein-Coupled Receptors. Nature 2009, 459, 356−363. (102) Cao, W.; Gu, Y.; Meineck, M.; Li, T.; Xu, H. TelluriumContaining Polymer Micelles: Competitive-Ligand-Regulated Coordination Responsive Systems. J. Am. Chem. Soc. 2014, 136 (13), 5132− 5137. (103) Luan, J.; Shen, W.; Chen, C.; Lei, K.; Yu, L.; Ding, J. SeleniumContaining Thermogel for Controlled Drug Delivery by Coordination Competition. RSC Adv. 2015, 5 (119), 97975−97981. (104) Zeng, L.; Li, Y.; Li, T.; Cao, W.; Yi, Y.; Geng, W.; Sun, Z.; Xu, H. Selenium-Platinum Coordination Compounds as Novel Anticancer Drugs: Selectively Killing Cancer Cells Via a Reactive Oxygen Species (Ros)-Mediated Apoptosis Route. Chem. - Asian J. 2014, 9 (8), 2295− 2302. (105) Li, T.; Yi, Y.; Xu, H. Selenium-Containing Coordinating Assemblies with Selective Anti-Cancer Activity: The Control of Reactive Oxygen Species. Huaxue Xuebao 2014, 72 (10), 1079−1084. T


Perspective

Macromolecules (106) Li, T.; Smet, M.; Dehaen, W.; Xu, H. Selenium-Platinum Coordination Dendrimers with Controlled Anti-Cancer Activity. ACS Appl. Mater. Interfaces 2016, 8 (6), 3609−3614. (107) Li, T.; Xiang, W.; Li, F.; Xu, H. Self-Assembly Regulated Anticancer Activity of Platinum Coordinated Selenomethionine. Biomaterials 2018, 157, 17−25.

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