“Biowheel-Axle” Assembly of β-Cyclodextrin Fitted onto Bile Acid Units

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

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“Biowheel-Axle” Assembly of β‑Cyclodextrin Fitted onto Bile Acid Units Linked by PEG Spacers through Inclusion Polymerization Yong-Guang Jia,*,†,‡,§,∥ Sa Liu,†,‡,⊥,§,∥ Jin Wang,†,‡,§,∥ Lili Cai,† Jiahong Jin,†,‡,§,∥ Lina Mo,†,‡,§,∥ Meng Gao,†,‡,§,∥ Li Ren,†,‡,§,∥ and X. X. Zhu*,⊥ †

School of Materials Science and Engineering, South China University of Technology, Guangzhou 510641, China National Engineering Research Center for Tissue Restoration and Reconstruction, §Key Laboratory of Biomedical Engineering of Guangdong Province, and ∥Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, China ⊥ Département de Chimie, Université de Montréal, C.P. 6128, Succ. Centre-ville, Montréal, QC H3C 3J7, Canada Macromolecules Downloaded from pubs.acs.org by REGIS UNIV on 10/17/18. For personal use only.

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S Supporting Information *

ABSTRACT: A “biowheel-axle” assembly of polyrotaxanes of βcyclodextrin (β-CD) threaded onto bile acid moieties linked by a poly(ethylene glycol) (PEG) spacer of tunable length was prepared through an “inclusion polymerization” approach. The bile acid-diamine derivatives were allowed to first form inclusion complexes with β-CD and then polymerized with PEG-dicarbonate, followed by end-capping with a stopper of monoamino-β-CD, resulting in “biowheels” of β-CD with PEGylated bile acids as the axle in tandem. All steps were performed without the use of catalysts. The complexation between β-CD and bile acid units of the polymer chain was confirmed by the 2D NOESY NMR technique and powder X-ray diffraction, showing 85% of bile acid units entered the cavity of β-CD. The change of PEG spacer length from 45 to 6 ethylene glycol units led to a flexible−rigid conformation transition of the polyrotaxanes, supported by the random and straight orientation of the “biowheels” shown by scanning tunneling microscopy images. The control of the conformation helps to tune the property of the polyrotaxanes. The “biowheel-axle” assembly constructed from such a natural host−guest pair may also lead to the further exploration of bio-related applications.

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INTRODUCTION Mechanically interlocked molecules (MIMs) are assemblies of molecular components or entanglements that cannot be separated without breaking a covalent bond.1,2 Research enthusiasm has been shown for the preparation of a variety of MIMs including rotaxanes,3−5 catenanes,6,7 daisy chains,8 knots,9 and Borromean rings10 over the past few decades through the combination of molecular recognition and mechanically interlocked topology.11 The dynamic nature of MIMs has also been exploited as the basis for developing molecular devices by manipulating the relative positions of their constituent components,12 such as molecular shuttles, switches, muscles, and pumps.13−15 The 2016 Nobel Prize in Chemistry was awarded jointly to Jean-Pierre Sauvage, Sir J. Fraser Stoddart, and Bernard L. Feringa “for the design and synthesis of molecular machines on the basis of rotaxanes and catenanes”.16 In rotaxanes and polyrotaxanes, host molecules with the macrocyclic structures could encapsulate guest molecules into their cavities through molecular recognitions similar to what is known for enzymes,17−19 such as enzyme−substrate complexes and antigen−antibody pairs. Research on such molecular assemblies helps to gain a better understanding of related biological systems.20,21 Cyclodextrins (CDs) are water-soluble cyclic oligomers of D-(+)-glucose with a cylindrical structure of © XXXX American Chemical Society

varying sizes depending on the number of glucose units. They can serve as hosts and recognize some substrates as guest molecules to form inclusion complexes in aqueous media.22 Unlike other synthetic macrocyclic compounds, such as crown ethers,23 calixarenes,24 cucurbiturils,25,26 and pillar[n]arenes,27,28 CDs are produced from enzymatic processing of starch, ensuring their biodegradability and biocompatibility. Moreover, the functionalization of the external hydroxyl groups of natural CDs can be selectively modified with relative ease. The ability of forming inclusion complexes and the biological origin of CDs render them very popular in the preparation of rotaxanes and polyrotaxanes, leading to interesting supramolecular materials.29−40 Bile acids are a group of physiologically important steroids and play a crucial role in lipid digestion, transportation, and absorption.41 They form stable inclusion complexes with β-CD, showing the shape of a “biowheel”.42,43 Natural bile acids are ideal guests for the preparation of polyrotaxanes due to the presence of multiple functional groups, their biological origin, and biocompatibility. To date, bile acids remain a group of unexplored guests used in preparation of polyrotaxanes. Polyrotaxanes may be conReceived: August 7, 2018 Revised: September 28, 2018

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DOI: 10.1021/acs.macromol.8b01702 Macromolecules XXXX, XXX, XXX−XXX

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Scheme 1. (A) Schematic Illustration of the Process of “Inclusion Polymerization” and (B) the Synthesis of Polyrotaxanes of βCDs with PEGylated Bile Acids Derivatives for the Preparation of “Biowheel-Axle” Supramolecular Assembly

structed by these natural compounds with β-CD as the “biowheel” and bile acids as the axle, providing a new supramolecular biomimetic assembly. In addition to providing mechanistic insights, the synthetic polyrotaxanes are useful in a number of applications such as the nanovalves of sensing, delivery, and catalysis.44 Generally, construction of polyrotaxanes using CDs can be categorized in two types: the “threading” approach and the

“inclusion polymerization” approach. The threading of CDs onto a guest in polyrotaxanes is driven by hydrophobic and van der Waals interactions between the inner surface of the CD ring and the hydrophobic sites of the guests in aqueous media.29 Previously, we synthesized polyurethanes with the alternating structures of bile acid units and PEG segments. The β-CD rings can slide onto the PEG segments and selectively recognize the bile acid units of a polyurethane chain to afford B

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Figure 1. (A) 1H NMR spectrum of CA-diamine in D2O and (B) 2D NOESY NMR spectrum of complex of CA-diamine with β-CD in D2O ([CAdiamine] = [β-CD] = 4.49 mM, mixing time of 0.50 s, 25 °C, and the peak of HDO was suppressed).

Figure 2. 1H NMR spectra of (A) the inclusion complex between CA-diamine and β-CD, (B) PEG2000-dicarbonate, (C) polypseudorotaxane with a carbonate terminal group, and (D) polyrotaxane-2000, all in D2O, and the assignments of related peaks.

polypseudorotaxanes with tunable thermosensitivity.45 However, the steric hindrance may limit the efficiency of threading. The synthesis of the guest polymer and the preparation of the final polyrotaxane are often tedious and difficult, performed in organic solvents and aqueous media separately. The conformational control of the polyrotaxanes is also a challenge. If such a

control can be achieved, it will help to tune the property of the supraomolecular assembly to use them as biomolecular device.46 In the present work, we attempt to use an “inclusion polymerization” approach in the preparation of polyrotaxanes of β-CD with a bile acid. The inclusion complexes of β-CD and a bile acid derivative are first prepared and then polymerized C

DOI: 10.1021/acs.macromol.8b01702 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules with PEG-dicarbonate in situ, to be followed by end-capping with a stopper, resulting in a “biowheel” of β-CD fitted onto a bile acid axle linked through a PEG spacer (Scheme 1A). All steps can be performed in a one-pot reaction in a tandem way. The control of the conformation of the resulting polyrotaxanes may be adjusted by changing the length of PEG spacer.

unchanged in the polymers and become broader in comparison to their corresponding monomers. The complexation ratio of β-CD with the CA units in PR2000 is estimated to be ca. 85% based on the integration ratio of the proton NMR signals of H1 (ca. 5.0 ppm) from β-CDs and of methyl groups from CA units in Figure 2D, indicating that less than 15% of β-CDs may have slipped off during polymerization and/or capping. The number of CA units on each polyrotaxane chain is estimated to be ca. 26 through the integration ratio of peaks from methyl groups to end groups in Figure 2C. This result agrees well with the value obtained from size exclusion chromatograph (Figure S5). NOE correlation of protons from the methyl groups of CA with the interior H3/ H5 of β-CD (0.6−1.2 ppm, red rectangles in Figure S1) is similar to what is shown for the simple “biowheel-axle” of in Figure 1 and confirms the successful preparation of the polyrotaxanes. Powder X-ray diffraction (XRD) measurements (Figure 3) were employed to investigate the solid-state structures of PR-

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RESULTS AND DISCUSSION Preparation of CA-Diamine and Its Inclusion Complex with β-CD. Bile acids possess multiple functional groups to modify and may be easily incorporated into the main chain of polymers. Two amino groups are introduced into the “head” and “tail” of the bile acid skeleton (C3- and C26-position, respectively), resulting in a water-soluble cholic acid (CA, the most abundant bile acid in humans) derivative (CA-diamine). CA-diamine was synthesized via a reaction of methyl 3aminocholate with excess ethylenediamine in a yield of 78% (Scheme S1). The 1H NMR spectrum of CA-diamine in D2O (Figure 1A) shows well-resolved signals of the three methyl protons on CA moieties. The “biowheels”, i.e., the inclusion complexes between CA-diamine and β-CD, were then prepared by mixing equal molar amounts of the guest and host in water. The peaks of three methyl groups (18−18′, 19− 19′, and 21−21′) and proton of position 12 all shift downfield in the inclusion complex. This shift is different from our previous observation, where peak 18 split into two peaks, corresponding to complexed and free CA species.45 The presence of single peaks for these groups is an indication of stronger and more stable complexation of β-CD with CAdiamine than that of β-CD with guest polymers derived from bile acids.45 The 1H NMR spectral changes were further investigated by a nuclear Overhauser enhancement spectroscopy (NOESY) experiment. NOE correlation of protons from peaks 18′, 19′, and 21′ with the interior H3/H5 of β-CD has been observed (red rectangles in Figure 1B), indicating the proximity of the groups and therefore confirming the formation of the inclusion complex, i.e., the insertion of the CA moiety inside the cavity of β-CD.47 Synthesis of Polyrotaxane via “Inclusion Polymerization”. To monitor the polymerization in situ by the use of 1 H NMR technique, the condensation of the inclusion complexes with PEG-dicarbonate was performed in D2O (experimental details shown in the Supporting Information). The feed ratio of PEG2000-dicarbonate and inclusion complex was set to 1.1:1, ensuring that the resulting polypseudorotaxanes would bear terminal carbonate groups. There remained 7% of unreacted carbonate groups before capping, based on results obtained from the 1H NMR spectrum of polypseudorotaxane without purification (Figure 2C). The carbonate groups were replaced with capping groups of monoamino-βCD, followed by dialysis against water through a dialysis bag (MWCO 3500), resulting in polyrotaxane-2000 (PR-2000). The 1H NMR spectrum of PR-2000 (Figure 2D) shows the disappearance of the peaks “a” and “b” of p-nitrophenyl on PEG-dicarbonate (Figure 2B). Peaks “3” and “26” of amino groups on CA-diamine (Figure 2A) show downfield shifts at ca. 3.4 and 3.0 ppm, respectively, after polymerization. The peak at 4.4 ppm from the protons of PEG-dicarbonate on position “c” exhibits an upfield shift (c−c′) in Figures 2C and 2D. These changes in chemical shifts are all caused by the newly formed carbamate bond. The other peaks remain almost

Figure 3. Powder XRD spectra of (A) β-CD, (B) PR-2000, and (C) the model guest polymer PU-amide without complexation with β-CD.

2000. The characteristic diffraction peaks (2θ) of β-CD19 at 10.7° and 12.6° (Figure 3A) completely disappear in PR-2000 (Figure 3B), indicating the β-CDs have adopted more symmetric and possibly dynamic conformations after complexation.48 The only two peaks (2θ) at 19.1° and 23.3° may be assigned to the characteristic diffraction peaks of the PEG segments49 in the polyrotaxanes. The corresponding guest polymer (PU-amide) without β-CD was synthesized (structure shown in Figure S2) and used to confirm the peaks (2θ) from PEG. The characteristic diffraction peaks of PU-amide appear at the same position (Figure 3C) as PR-2000. Therefore, the complexation of the β-CDs with CA units does not change the crystal structure of PEG in PR-2000. This is consistent with our previous observation that β-CD would selectively recognize the CA units rather than the PEG segments in polypseudorotaxanes.45 Polyrotaxane-300 (PR-300) with a shorter spacer of PEG300 was also prepared through the condensation of PEG300dicarbonate with the inclusion complexes of CA-diamine and β-CD (characterization shown in Figures S3 and S4). The shorter PEG spacer was used to evaluate the effect of spacer D

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polymers are complexed with β-CD, which is more efficient than the “threading approach”. The change of the PEG spacer length from 45 to 6 ethylene glycol units leads to a conformational change from a random coil to a rigid rod of the polyrotaxane as visualized by STM. This provides a convenient way to control the conformation of such polyrotaxanes and may be applicable to other biomacromolecular assemblies. This work here represents the first model of polyrotaxane construction with a natural host−guest pair. Their applications as biomaterials are being explored in our laboratories.

length on the conformation and the self-assembly of the polyrotaxanes. Conformation and Assembly of Polyrotaxanes. Scanning tunneling microscopy (STM) was used to visualize the conformation of these polyrotaxanes. The STM image of PR-2000 exhibits a necklace structure of the aligned bright spots (oriented along the dashed curve in Figure 4A). These

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.8b01702. Experimental procedures and characterization of monomer (CA-diamine, PEG300-dicarbonate) and polyrotaxanes as well as PU-amide; 1H NMR spectra of PU-amide and PR-300; 2D NOESY NMR spectra, SEC and DLS results of PR-2000 and PR-300 (PDF)

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Figure 4. Representative STM images of (A) PR-2000 on Au (111) interface and (B) PR-300 on graphite interface prepared from their DMF solutions (2.0 g/L) and representative TEM images of the aggregates formed by (C) PR-2000 and (D) PR-300 in water (0.2 g/ L).

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (X.X.Z.). *E-mail: [email protected] (Y.-G.J.). ORCID

“biowheels” randomly adsorbed on the surface of the substrate, which is similar to the STM image of polypseudorotaxane of βCD on bile acid-derived polymers.45 The diameter of ca. 2.7 nm shown by these bright features agrees well with that of βCD (ca. 2.6 nm) on the STM images. When the PEG spacer is shortened from 2000 to 300 Da, the “biowheel-axle” assembly appears almost as a straight line on the substrate surface (Figure 4B). This clearly shows a conformational change of the polyrotaxane due to the more limited mobility of the “biowheel-axle” when a shorter spacer is used. The selfassembly of PR-2000 and PR-300 in water is clearly visualized by TEM (Figures 4C and 4D). PR-2000 shows the major population of uniformed micelles with a diameter of ca. 70 nm on TEM images (Figure 4C), which also agrees well with its narrower size distribution shown by the DLS measurements (Figure S6). The relatively thick hydrophilic shell of PEG-2000 may stabilize the hydrophobic core of cholic acid units, resulting in the flower-like micelles. Under the same conditions, the rod-like assembly of PR-300 is observed in Figure 4D. For the assembly of PR-300, the PEG-300 segments may not be long/hydrophilic enough to form stable micelles, leading to the formation of rigid aggregations with a broad distribution, consistent with the results of STM. Therefore, the choice of the spacer may help to tune the rigidity and the conformation of the polyrotaxanes.

Yong-Guang Jia: 0000-0001-8924-2820 Meng Gao: 0000-0001-8071-8079 Li Ren: 0000-0003-0604-9166 X. X. Zhu: 0000-0003-0828-299X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by National Natural Science Foundation of China (21704026) and Foundation for Xinghua Scholar of South China University of Technology. Financial support from NSERC of Canada and FRQNT of Quebec is also gratefully acknowledged.

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CONCLUSION A natural host−guest complex of β-CD and a bile acid derivative was polymerized by condensation with PEGdicarbonate, followed by end-capping with monoamino-β-CD to afford a “biowheel-axle” assembly of polyrotaxanes. This “inclusion polymerization” approach was achieved through a one-pot reaction in water, without the use of any catalysts. We have demonstrated that 85% of the bile acid units of the E

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DOI: 10.1021/acs.macromol.8b01702 Macromolecules XXXX, XXX, XXX−XXX