ChemComm Published on 08 January 2021 Downloaded by RMIT University Library on 3/28/2021 4:00:37 AM COMMUNICATION Cite this: Chem Commun., 2021, 57, 1161 Received 12th October 2020, Accepted 21st December 2020 View Article Online View Journal | View Issue Rapid synthesis of multifunctional b-cyclodextrin nanospheres as alkali-responsive nanocarriers and selective antibiotic adsorbents† Qiuju Li,ab Dandan Wang,ab Xian Fang,ab Boyang Zong,ab Ying Liu,ab Zhuo Li,ab Shun Mao *ab and Kostya Ken Ostrikov c DOI: 10.1039/d0cc06768g rsc.li/chemcomm Novel hypercross-linked b-cyclodextrin nanospheres are rapidly synthesized with 4-amino-6-hydroxy-2-mercaptopyrimidine as a cross-linker within at a low temperature of 60 8C in the open water phase, thereby radically simplifying and accelerating the conventional time-consuming and environmentally harsh synthesis of cyclodextrin-containing polymers The nanospheres demonstrate excellent and controllable performance as alkali-responsive nanocarriers and selective adsorbents for antibiotics Cyclodextrin (CD), an inexpensive, naturally produced macrocycle of oligosaccharide, is capable of capturing organic molecules with appropriate size, shape and hydrophobicity to form well-defined host–guest complexes.1 Insoluble polymer networks of cyclodextrin have been extensively studied for adsorption-based removal of various micropollutants,2–7 membrane separation8 and supporting materials.9 To date, b-CD-based polymers have been prepared by cross-linking cyclodextrin with epichlorohydrin (EPI),2 tetrafluoroterephthalonitrile (TFN),3 and TFN-derived linkers.4–6 A recent study reported a new cross-linked b-cyclodextrin polymer network (CPN) as an effective support for subnanometer metal nanoparticles.9 However, the synthesis of a CPN was conducted in DMF under a N2 atmosphere for as long as days Therefore, the obvious challenge is that all previously reported cyclodextrin-based polymers were synthesized in the organic phase (i.e., THF and DMF) with long reaction time (48 h to even days) and under strictly controlled conditions (e.g., under an N2 atmosphere) Besides, the reported CD-based polymers exhibit irregular blocks with large a Biomedical Multidisciplinary Innovation Research Institute, Shanghai East Hospital, State Key Laboratory of Pollution Control and Resource Reuse, College of Environmental Science and Engineering, Tongji University, 1239 Siping Road, Shanghai 200092, China E-mail: shunmao@tongji.edu.cn b Shanghai Institute of Pollution Control and Ecological Security, Shanghai 200092, China c School of Chemistry and Physics and QUT Centre for Materials Science, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia † Electronic supplementary information (ESI) available: Experimental details, characterization, and supplementary figures See DOI: 10.1039/d0cc06768g This journal is © The Royal Society of Chemistry 2021 dimensions, which will affect their ability to effectively disperse and further adsorb for organic molecules and their performance as catalyst supports Therefore, a simple and rapid synthesis method of well-formed cyclodextrin nanospheres is highly desired Even though CD-based supramolecular systems have been used for stimuli-responsive drug delivery primarily via host– guest interactions,10,11 the alkali-responsive cyclodextrin-based carriers in a relatively high-pH environment like that of the intestine (pH 47.4) have been rarely reported In addition, the effective adsorption of micropollutants such as antibiotics in water is also necessary to minimize their negative impacts on the ecosystem and human health after uncontrolled antibiotics discharge into the environment.12,13 Even though CD-based polymers have been explored for the removal of common micropollutants, the selective and rapid sequestration of antibiotics has not yet been reported Herein, we first propose a novel and simple route to quickly synthesize well-formed b-cyclodextrin nanospheres (CDNS) with 4-amino-6-hydroxy-2-mercaptopyrimidine (AHMP) as a cross-linker within minutes at a low temperature of 60 1C in the open water phase Antibiotic drugs can be efficiently preloaded in CDNS with high stability in a low-pH and neutral environment but can be released when moved to a slightly higher-pH (similar to the human intestine) environment (pH 47.4) with alkali-responsive disassembly of CDNS This approach exhibits a promising application potential for oral drug delivery in intestinal inflammation Besides, boronic acid-modified CDNS with porous structures are further designed to selectively remove fluoroquinolone antibiotics from water and 95% of its equilibrium uptake is completed within 10 The novel strategy for synthesizing well-formed cyclodextrin nanospheres offers new insights into the advanced application of cyclodextrin in drug-delivery systems and selective micropollutant removal Partially-oxidized b-cyclodextrin aldehyde (ACD) shown in Fig S1 (ESI†) was firstly obtained and exhibited high aqueous solubility and reactivity with functional groups such as –NH3 and –OH Different small molecular-weight cross-linkers Chem Commun., 2021, 57, 1161 1164 | 1161 View Article Online Published on 08 January 2021 Downloaded by RMIT University Library on 3/28/2021 4:00:37 AM Communication Fig (a) Synthesis of CDNS with AHMP as a cross-linker (b) SEM image of CDNS (c) TEM image and size distribution (inset) of CDNS (d) HRTEM image of CDNS with an amorphous structure (e) STEM image and elemental mapping of C, N, S, and O (scale bar: 200 nm) including 2,4,6-triaminopyrimidine (TAP), 4,6-diamino-2-mercaptopyrimidine (DAMP), and 4-amino-6-hydroxy-2-mercaptopyrimidine (AHMP) were explored to synthesize CD-based polymers With TAP as a cross-linker, an insoluble polymer of cyclodextrin was not obtained due to the steric effect on the cross-linking degree Comparatively, with DAMP as a cross-linker, the irregular complexes were obtained after 30 h as shown in Fig S2 (ESI†) Interestingly, by using AHMP as a cross-linker, well-formed cyclodextrin nanospheres were quickly synthesized just in as shown in the experimental video in the ESI.† As shown in the schematic of CDNS synthesis (Fig 1a), dimerization of AHMP firstly occurred through the oxidation of thiol to disulfide linkage in intermolecular AHMP,14,15 then CDNS were obtained by a Schiff-base reaction between the ACD molecules and disulfide-linked AHMP dimers The CDNS were quickly formed as a pale-yellow precipitate with a yield of 51% within at 60 1C SEM and TEM images in Fig 1b and c show that the well-formed CDNS exhibits good dispersity The size analysis of the CDNS in the inset of Fig 1c reveals a narrow size distribution with an average size of B270 nm The high zeta potential of À27.8 mV (Fig S3, ESI†) ensures that CDNS not agglomerate From EDS mapping in Fig 1e, rich N and S elements from AHMP are evenly distributed over the whole nanospheres This finding indicates the high cross-linking density and hence the high stability of the cyclodextrin-based network The BET surface area of CDNS was measured as 7.5 m2 gÀ1 The relatively low surface area was probably due to the high cross-linking degree of the CDNS, which is confirmed by the high content of AHMP in CDNS (in Table S1, ESI†) According to TGA results shown in Fig S4 (ESI†), CDNS 1162 | Chem Commun., 2021, 57, 1161 1164 ChemComm are thermally stable even at a high temperature of 200 1C Besides, the presence of rich N and S sites as the metal coordination sites and the dense network structure is favourable for the synthesis and stabilization of ultrafine metal nanoparticles in future studies To further characterize the structure of CDNS, XPS spectra (Fig 2a–c) were obtained The peak at 534.4 eV in O 1s XPS attributed to CQO vibration from ACD (Fig 2a) and the peak at 399.3 eV in N 1s XPS attributed to N–H vibration from AHMP (Fig 2b) disappeared in CDNS due to the formation of the CQN bond At the same time, the intensity of the peak at 398.8 eV attributed to CQN groups in the N 1s spectrum increases due to the occurrence of the Schiff-base reaction.16,17 The disappearance of the peak for the CQO bond in C 1s XPS of CDNS in Fig S5 (ESI†) also confirms the Schiff-base reaction According to the S 2p XPS spectra in Fig 2c, the binding energy of the S 2p state shifts from 162.9 eV and 161.7 eV to 165.0 eV and 163.8 eV, respectively, indicating the formation of an oxidative S–S bond The Raman spectra of AHMP and CDNS are shown in Fig 2d The disulfide stretching modes located at 480–540 cmÀ1 confirm the existence of the S–S bond in CDNS.18 This also explains why the absorption peak of –SH at 2570 cmÀ1 disappears in the FTIR spectrum of CDNS (Fig S6, ESI†) The above evidence validate the cross-linking pathway of ACD and AHMP to form CDNS as shown in Fig 1a In addition, the absorption peaks in FTIR spectra including 3478 cmÀ1 for –OH and 1157 cmÀ1 for C–O of ACD, and 1596 cmÀ1 and 1555 cmÀ1 in AHMP blue-shift to 3446 cmÀ1, 1136 cmÀ1, 1566 cmÀ1 and 1508 cmÀ1, respectively, indicating that abundant hydrogen bonds exist in CDNS This can be further confirmed by the solid 1H NMR spectra shown in Fig S7 (ESI†) The spectra reveal that the downfield shifts of proton signals in CDNS are due to the formation of hydrogen bonds.19,20 The dense hydrogen-bond networks endow CDNS with excellent chemical and thermal stability The dynamic covalent linkage offers unique advantages to construct stimuli-responsive systems.21–23 For example, the Fig (a) O 1s, (b) N 1s and (c) S 2p XP spectra of CDNS (d) Raman spectra of CDNS and AHMP This journal is © The Royal Society of Chemistry 2021 View Article Online Published on 08 January 2021 Downloaded by RMIT University Library on 3/28/2021 4:00:37 AM ChemComm Fig (a) Schematic of CDNS disassembly (b) TEM image of the resultant samples of CDNS treated with PBS solution at pH 7.8 (c) Transmittance curves of CDNS dispersion with different pH values from 4.0 to 8.8 (d) Alkali-responsive release profiles of Nor-loaded CDNS at pH values of 4.0, 7.0, 7.6, and 7.8 redox-responsive disulfide linkage and acid-labile Schiff-base bond have been used to construct redox- and pH-sensitive nanocarriers However, the CDNS based on the disulfide linkage and Schiff-base bond in our study show good chemical stability in the presence of dithiothreitol (DTT) or under acidic conditions, which may be attributed to the high cross-linking density and dense hydrogen-bond network against small molecules and H+ ions.17 Unexpectedly, the obtained CDNS show excellent alkali-responsive ability, which will disassemble at pH 47.4 as shown in Fig 3a The TEM image of the resultant samples at pH 7.8 is shown in Fig 3b, which show that CDNS disassemble to small colloidal particles The transmittance curves of CDNS suspension (1 mg mLÀ1) in Fig 3c confirm the high stability of CDNS at pH values from 4.0 to 7.2 The transmittances increase when the pH value grows from 7.2 to 8.8, which is consistent with the states of CDNS suspension with different pH values shown in the inset of Fig S9 (ESI†) Under acidic conditions, the size of CDNS increases indicating the formation of larger aggregates possibly because the zeta potential becomes smaller under acidic conditions Comparatively, the size of CDNS significantly decreases when the pH value increases to 7.4 and the size reduces to B20 nm at pH 8.8, indicating the disassembly of CDNS under alkaline conditions The gradual disassembly will take place with the prolonged time (Fig S10, ESI†) The residue samples were collected and tested with Raman and FTIR spectroscopy As shown in Fig S11 (ESI†), the disappearance of S–S peaks and appearance of the –SH peak under alkaline conditions indicate the cleavage of the disulfide bond due to the nucleophilic attack of OHÀ ions.24,25 The unique property of CDNS with stability under neutral and acidic conditions but quickly disassembling under slight alkaline conditions offers promising potential for oral drug delivery in intestine inflammation Norfloxacin (Nor), a potent antibiotic against intestine inflammation, was preloaded during the synthesis of CDNS Encapsulation was monitored by comparing the FTIR spectra of free Nor and Nor-loaded CDNS in Fig S12 (ESI†) As shown in Fig S13 (ESI†), 97% of Nor were encapsulated when Nor This journal is © The Royal Society of Chemistry 2021 Communication (10 mg) was added due to the hydrogen bonding and host– guest interaction Since the pH value of the fluid environment in the stomach is about 4.0 while in the specific small intestine it is above 7.4,26,27 we investigated the kinetic release of Nor-loaded CDNS at 37 1C in PBS at different pH (4.0, 7.0, 7.6 and 7.8) Fig 3d reveals that almost 100% release of Nor at pH 7.8 after 20 and about 90% at pH 7.6 after 30 are achieved Comparatively, only 10% of Nor is released at pH 7.0 and pH 4.0 Such release trends are promising for oral drug delivery against intestinal inflammation because the loaded drugs can remain in the nanocarriers without leakage at the stomach pH (4.0–7.0) but be quickly released once the nanocarriers meet slightly alkaline environments, e.g., in the distal small intestine The as-synthesized CDNS exhibit low surface area and weak adsorption of guest molecules As shown in Fig 4a, boronic acids can bind with diol units to form cyclic boronate esters.21,28,29 The UV/Vis (Fig S14, ESI†) and fluorescence spectra (in Fig S15, ESI†) of the ACD–APBA complex confirmed that 3-aminobenzeneboronic acid (APBA) can be anchored onto the ACD molecule As shown in Fig S16 (ESI†), with APBA modified ACD, the obtained nanospheres show a larger diameter of B450 nm The thermally heated B-modified CDNS (HB-CDNS) (at 150 1C under an N2 atmosphere) with the rich porous structure are shown in Fig S16 (c and d) (ESI†) The HBCDNS featured a larger BET specific surface area (154 m2 gÀ1) compared with CDNS (7.5 m2 gÀ1), and pore diameter peaks at 19.8 nm (Fig S17, ESI†) In addition to the porous structure, abundant boron receptor sites in HB-CDNS are available for the adsorption of fluorine-containing chemicals The FTIR spectra in Fig S18 (ESI†) and XPS survey spectrum in Fig S19 (ESI†) confirm the successful modification of boronic acid in the HB-CDNS The contents of C, O, N, S, and B elements of the B-CDNS and HB-CDNS sample are listed in Table S2 (ESI†), showing that the content of B element originating from APBA slightly decreased after the heating in an N2 atmosphere The N 1s high-resolution XPS spectra in Fig S20 (ESI†) reveal that the peak area of unbound N–H (399.3 eV), and CQN (398.8 eV) Fig (a) Schematic of HB-CDNS synthesis (b) Adsorption removal of Eno, Fle, Ofl, Cip, Nor, and BPA with HB-CDNS (c) Recyclability of HB-CDNS for adsorption removal of Eno, Ofl, Cip, and Nor (experimental conditions: 100 mg LÀ1 FQ antibiotics and BPA, 100 mg LÀ1 HB-CDNS, room temperature) Chem Commun., 2021, 57, 1161 1164 | 1163 View Article Online Published on 08 January 2021 Downloaded by RMIT University Library on 3/28/2021 4:00:37 AM Communication increase and decreased, respectively Besides, a new peak for B–N bonding was observed in HB-CDNS at 398.2 eV.30,31 The B 1s XPS peak for B–N (187.9 eV) in HB-CDNS (Fig S22, ESI†) was also observed in addition to the B–O peak (191.2 eV) and B–C peak (190.6 eV).30 It can be concluded that the loss and rearrangement of APBA during the heating process have led to the porous structures in the HB-CDNS Fluoroquinolone (FQ) antibiotics, as the third largest group of antibiotics, account for 17% of the global market The synthesized cyclodextrin nanospheres including CDNS, B-CDNS and HB-CDNS were explored as adsorbents for FQ antibiotics As shown in Fig S21 (ESI†), only B65% of enoxacin (eno) was removed in 10 minutes with CDNS as adsorbents Comparatively, 89.2% and 98.3% of Eno were removed with B-CDNS and HB-CDNS, respectively The effect can be attributed to the active boron receptor sites for F elements in FQ molecules and the porous structure of HB-CDNS The ability of HB-CDNS to remove other FQs including fleroxacin (Fle), ciprofloxacin (Cip), ofloxacin (Ofl) and norfloxacin (Nor) were also investigated As shown in Fig 4b, 90.0% of Fle, 98.3% of Cip, 95.6% of Ofl and 90.3% of Nor have been removed within 10 Furthermore, Bisphenol A (BPA) the endocrine disrupting compound was chosen as a model pollutant to demonstrate the selective adsorption for FQ antibiotics Only 9.6% of BPA was removed after 60 min, indicating the highly selective adsorption of HB-CDNS for FQ antibiotics The XPS of Eno-adsorbed HB-CDNS in Fig S22 (ESI†) shows the formation of B–F bonds, which explains the selective adsorption of HB-CDNS for FQ antibiotics.32,33 To evaluate the recyclability, the adsorption activity of HB-CDNS over five consecutive cycles was examined As shown in Fig 4c, there was no obvious decline in the removal efficiency (492% adsorption removal after cycles) These results demonstrate the easy recovery of HB-CDNS using a mild washing procedure The work reports a versatile method for the synthesis of cyclodextrin nanospheres with AHMP as a cross-linker in at 60 1C in an open water phase The nanospheres are stable under neutral and acidic conditions and feature the pH-sensitive alkali-responsive disassembly through the scission of the disulfide bond, showing great promise as oral drug delivery systems against intestinal inflammation Boronic acid-modified nanospheres with porous structures and enriched boron active sites have been obtained for rapid and selective sequestration of FQ antibiotics This study provides a novel strategy for the facile synthesis of multifunctional cyclodextrin nanospheres The new method is expected to expand CDNS applications in controlled-release oral drug delivery, antibiotic abatement in water, and potentially as supporting materials for ultrafine nanoparticles This work was supported by the National Natural Science Foundation 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3958 This journal is © The Royal Society of Chemistry 2021 ... from 4.0 to 8.8 (d) Alkali- responsive release profiles of Nor-loaded CDNS at pH values of 4.0, 7.0, 7.6, and 7.8 redox -responsive disulfide linkage and acid-labile Schiff-base bond have been used... structures and enriched boron active sites have been obtained for rapid and selective sequestration of FQ antibiotics This study provides a novel strategy for the facile synthesis of multifunctional cyclodextrin. .. and CQN (398.8 eV) Fig (a) Schematic of HB-CDNS synthesis (b) Adsorption removal of Eno, Fle, Ofl, Cip, Nor, and BPA with HB-CDNS (c) Recyclability of HB-CDNS for adsorption removal of Eno, Ofl,