Elsevier

European Polymer Journal

Volume 159, 5 October 2021, 110752
European Polymer Journal

Amphiphilic methoxy poly(ethylene glycol)-b-poly(carbonate-selenide) with enhanced ROS responsiveness: Facile synthesis and oxidation process

https://doi.org/10.1016/j.eurpolymj.2021.110752Get rights and content

Highlights

  • Facile synthesis of selenium-containing ROS-responsive polymers was clarified.

  • The synthesized mPEG45-b-poly(MSe)m was proved to have enhanced ROS responsiveness.

  • The self-assembly and oxidation process of mPEG45-b-poly(MSe)m was monitored.

Abstract

The synthesis of ROS-responsive polymers has attracted much attentions in recent years. Herein, we report a series of amphiphilic methoxy poly(ethylene glycol)-b-poly(carbonate-selenide)s (mPEG45-b-poly(MSe)m, m = 12, 24, 36, 48, 60) by introducing selenide groups onto the backbone via one-pot lipase-catalyzed ring-opening polymerization (ROP), the synthesized amphiphilic polymers with enhanced ROS-responsiveness can self-assemble to form nanoparticles. Nuclear Magnetic Resonance (NMR), Gel Permeation Chromatography (GPC) and Fourier Transform Infrared (FTIR) are employed to confirm the structure of the polymers. Besides, the oxidation process of mPEG45-b-poly(MSe)m nanoparticles is also clarified. Ultraviolet–visible Spectrophotometer (UV–Vis), Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM) are further utilized to demonstrate the turbidity, morphology and size changes under oxidization, proving that the selenide groups endow the mPEG45-b-poly(MSe)m nanoparticles with enhanced ROS-response properties. Therefore, the above studies highlight the synthesized ROS-responsive polymers and provided a potential material for further applications.

Introduction

Stimuli-responsive polymers that are sensitive to various endogenous or exogenous stimuli have drawn a lot of attentions in chemical, physical and especially biomedical field during the past few decades [1], [2], [3], [4], [5], [6], [7]. Reactive oxygen species (ROS) are defined as a type of highly oxidative species such as singlet oxygen (1O2), hydrogen peroxide (H2O2), etc., existing universally under physiological conditions and playing significant roles in redox homeostasis [8], [9], [10], [11], [12]. It is documented that the ROS level in cellular pathological regions, such as tumor cells, could reach up to 1 × 10−4 M, much higher than in normal cells (∼2 × 10−8 M) [13]. Therefore, the abnormal level of ROS in tumor tissues which is acted as an indicator has been widely used to develop ROS-responsive polymers [14], [15], [16], [17], [18], [19], [20], [21]. However, constructing highly sensitive polymers via facile synthesis still remains a major challenge.

Generally speaking, ROS-responsive polymers are normally obtained by introducing functional groups that typically contain boron element, ferrocene, chalcogen, etc. [22], [23], [24], [25], [26], [27], [28]. A kind of phenylboronic ester-linked PEG-lipid conjugate was synthesized by Zhang and coworkers [29]. The aggregated nanoparticles exhibited typical H2O2-responsive behavior, promising for applications in ROS-responsive drug delivery. Yu and coworkers reported ROS-responsive nanoparticles composed of sulfur-containing methoxy polyethylene glycol-b-poly(diethyl sulfide) copolymers which could induce specific endosome escape in cancer cells by the hydrophobicity-hydrophilia changes of copolymers [30]. Inspired by these remarkable works, a series of oxidation-responsive aliphatic polycarbonates with sulfur in the main chain were synthesized via enzyme-catalyzed ring-opening polymerization by our group previously [31]. The amphiphilic thioether-contained polymers (mPEG-b-PS) could self-assemble into a well-defined nanostructure and response to ROS due to the thioether groups on the backbone. However, their sensitivity to ROS was less than satisfactory. Their minimum H2O2-response concentration was as high as 100 mM, and it took more than two days to complete the oxidation process, which was confined for the subsequent applications.

Correspondingly, selenium is a semimetallic element as its chemical properties resembling sulfur and is regarded as an important element in human body and biological processes [32], [33], [34]. Compared with sulfur, selenium atom has bigger radius and weaker electronegativity, making selenide-containing molecules more sensitive to oxidative stimuli [35]. Hydrophobic selenide groups are known for their ROS oxidation property to form hydrophilic selenoxide and selenone groups, which will lead to the transition of hydrophibility and hydrophobility. Hence selenide-containing polymers are attractive due to their fascinating redox-responsive properties [36], [37], [38]. Selenium chemistry has been advanced greatly in the past few years [39], [40], [41], but the introduction of selenium into polymers is still rather difficult, hindering the further progress of selenium-containing polymers.

Herein, to feasible synthesis and construct ROS-responsive polymers, we reported highly sensitive methoxy poly(ethylene glycol)-b-poly(carbonate-selenide) (mPEG45-b-poly(MSe)m) by introducing selenide groups onto the backbone via one-pot lipase-catalyzed ring-opening polymerization [42], [43] of cyclic diethylene selenide carbonate dimer (MSe). The structure of mPEG45-b-poly(MSe)m was characterized by Nuclear Magnetic Resonance (NMR), Fourier Transform Infrared (FTIR) and Gel Permeation Chromatography (GPC). The oxidation behavior of polymer was clarified by NMR, FTIR and Thermogravimetric Analysis (TGA) techniques. Furthermore, Ultraviolet–visible Spectrophotometer (UV–Vis), Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM) were also employed to demonstrate the changes of the transmittance, morphology and size of the self-assembly nanoparticles during the oxidation process. In short, the synthesized selenium-containing polymers exhibited enhanced ROS responsiveness, making them potential material for future applications.

Section snippets

Materials

The functional diol di(1-hydroxyethylene) selenide and cyclic diethylene selenide carbonate dimer (MSe) were synthesized in methods reported by our previous work [44]. Polyethylene glycol monomethyl ether (mPEG45, Mn = 2000) was purchased from Adamas and was dried via azeotropic distillation in anhydrous toluene. Lipase CA Novozym-435 was an immobilized lipase, which was dried under vacuum for 48 h before use. Diphenyl carbonate (DPC) was purchased from Adamas. Toluene was purchased from

Synthesis and characterization of mPEG45-b-poly(MSe)m polymers

The synthetic route of the amphiphilic polymers is shown in Scheme 1. Firstly, cyclic diethylene selenide carbonate dimer (MSe) was synthesized, using the macro-ring closure of the functional diol di(1-hydroxyethylene) selenide and the yield of MSe was ∼40% after silica gel column chromatography [42]. Then, mPEG45-b-poly(MSe)m was obtained via one-pot ring-opening polymerization of MSe using dried toluene as the solvent, polyethylene glycol monomethyl ether as the initiator and Novozym-435 as

Conclusion

In summary, the amphiphilic selenium-containing methoxy poly(ethylene glycol)-b-poly(carbonate-selenide) was successfully synthesized via facile lipase-catalyzed ring-opening polymerization and could form self-assembly nanoparticles. The selenide groups situated on the backbone endowed the polymers with rich ROS responsiveness under H2O2. Comparing with sulfur-containing mPEG-b-PS and low selenium content mPEG45-b-(PTMC12-co-PSe24), mPEG45-b-poly(MSe)m showed faster and more sensitive ROS

CRediT authorship contribution statement

Siqi Li: Conceptualization, Methodology, Validation, Investigation, Writing–original draft. Fangqin Song: Validation, Resources, Writing–original draft. Chuanhao Sun: Writing–review & editing. Jieni Hu: Writing–review & editing. Yan Zhang: Supervision, Project administration.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by National Natural Science Foundation of China (52073093, 51873062).

Data availability

The raw/processed data required to reproduce these findings cannot be shared at this time as the data also forms part of an ongoing study.

References (51)

  • B. Yan et al.

    Facile synthesis of ROS-responsive biodegradable main chain poly(carbonate-thioether) copolymers

    Polym. Chem.

    (2018)
  • M.P. Rayman

    Selenium and human health

    The Lancet

    (2012)
  • M.P. Rayman

    The importance of selenium to human health

    The Lancet

    (2000)
  • W. Cao et al.

    Selenium/tellurium containing polymer materials in nanobiotechnology

    Nano Today

    (2015)
  • C. Xiao et al.

    Synthesis of thermal and oxidation dual responsive polymers for reactive oxygen species (ROS)-triggered drug release

    Polym. Chem.

    (2015)
  • J. Noh et al.

    Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death

    Nat. Commun.

    (2015)
  • Y. Lu et al.

    Bioresponsive materials

    Nat. Rev. Mater.

    (2016)
  • Y. Yao et al.

    Reactive oxygen species (ROS)-responsive biomaterials mediate tissue microenvironments and tissue regeneration

    J Mater. Chem. B

    (2019)
  • L. Zhang et al.

    Enzyme and redox dual-triggered intracellular release from actively targeted polymeric micelles

    ACS Appl. Mater. Interfaces

    (2017)
  • J.F.R. Van Guyse et al.

    Acyl guanidine functional poly(2-oxazoline)s as reactive intermediates and stimuli-responsive materials

    J. Polym. Sci., Part A: Polym. Chem.

    (2019)
  • K.L. Swetha et al.

    Development of a tumor extracellular pH-responsive nanocarrier by terminal histidine conjugation in a star shaped poly(lactic-co-glycolic acid)

    Eur. Polym. J.

    (2021)
  • N.A. Bonekamp et al.

    Reactive oxygen species and peroxisomes: struggling for balance

    BioFactors

    (2009)
  • L. Xiong et al.

    Cell signaling during cold, drought, and salt stress

    Plant Cell

    (2002)
  • A. Weidinger et al.

    Biological activities of reactive oxygen and nitrogen species: oxidative stress versus signal transduction

    Biomolecules

    (2015)
  • C.C. Song et al.

    Oxidation-responsive polymers for biomedical applications

    J. Mater. Chem. B

    (2014)
  • Cited by (0)

    View full text