Supramolecular redox-responsive substrate carrier activity of a ferrocenyl Janus device

doi:10.1016/j.jinorgbio.2018.12.018

Journal of Inorganic Biochemistry

Volume 193, April 2019, Pages 31-41

https://doi.org/10.1016/j.jinorgbio.2018.12.018 Get rights and content

Highlights

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A ferrocene-containing amphiphilic Janus dendrimer was synthesized.
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A supramolecular Janus molecule was fabricated by host-guest interaction.
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Supramolecular Janus molecule can self-assemble into nanoscale micelles.
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Redox-stimuli can regulate the self-assembly behavior.
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Supramolecular micelles can load substrate molecules for oxidation-triggered release.

Abstract

Supramolecular Janus compounds have recently attracted increasing attention owing to their dynamic reversible properties, distinct topological structures, and remarkable physicochemical characteristics, e.g., amphiphilicity, heterofunctionality, and high-density of terminal groups. Herein, a new redox-responsive supramolecular Janus device was designed and synthesized involving β-cyclodextrin and 2-fold ferrocene host-guest interactions. The complex formation was analyzed via one-dimensional ¹H NMR and two-dimensional Nuclear Overhauser Enhancement Spectroscopy. FeCl₃ and ascorbic acid were used as oxidation and reduction triggers, respectively, to modulate the self-assembly behavior in water through complexation/dissociation of β-cyclodextrin inclusion compounds resulting from redox-conversion of the ferrocenyl guest moieties. The redox-responsiveness of the obtained supramolecular micelles was studied via scanning electron microscopy and dynamic light scattering. Substrate-loading ability of the supramolecular micelles was confirmed with Rhodamine B, and the oxidation of ferrocenyl groups led to the release of the loaded cargos. The present work illustrates a valuable design example of supramolecular Janus systems using the host-guest complexation between β-cyclodextrin and ferrocenyl structures. The present supramolecular micelle may be used as a promising molecular vehicle for application in the field of stimuli-responsive drug delivery.

Graphical abstract

A new redox-responsive supramolecular Janus device was designed involving β-cyclodextrin and ferrocene in host-guest interaction. FeCl₃ and ascorbic acid were used as oxidation and reduction triggers to modulate the self-assembly behavior in water. Substrate-loading ability was confirmed with Rhodamine B.

Introduction

Janus molecules or devices are asymmetric molecules or macromolecules containing two distinct hemispheres, i.e. with distinct sizes and functionalities. They have recently attracted the specific attention of scientists in various research fields including macromolecular chemistry [1], molecular materials [2,3] and biomedicine [4]. The reported Janus derivatives were innovatively applied in various fields such as thermal actuators [5], ionic liquids [6], catalysis [7], light capture [8], bioimaging [9], optoelectronics [10,11] and drug delivery [[12], [13], [14], [15], [16]]. Unlike conventional symmetric molecules [17], Janus molecules are normally constructed using two distinct hemispheres with different sizes and functionalities, featuring asymmetric structures [[1], [2], [3], [4]].

Owing to their dynamic nature, various supramolecular interactions including hydrogen bonding [18], host-guest complexes [[19], [20], [21]], or metal complexation [[22], [23], [24]] have been widely investigated in macromolecular chemistry and materials in order to enable stimuli-responsive properties. The redox-sensitive host-guest complexation between β-cyclodextrin (β-CD) and ferrocene (Fc) derivative has been first reported in the mid 1980's [[25], [26], [27]], reviewed [28,29] and applied to smart redox devices such as molecular machines [29] and self-healing materials [29,30]. Recently Schmidt et al. have described a redox- and thermo-responsive gated supramolecular star polymers by using the host–guest complexation of a 6-fold β-CD functionalized core molecule and RAFT-derived Fc end modified by poly(N,N-dimethylacrylamide) (PDMA) and poly(N,N-diethylacrylamide) (PDEA) linear polymers [31]. Furthermore, β-CD-modified G5 poly(amidoamine) (PAMAM) and adamantane (Ad)-functionalized G3 PAMAM dendrimers with amine termini were synthesized by Shen and Shi et al. [32] and used to fabricate core–shell tecto dendrimers based on the supramolecular host-guest complexation between β-CD and Ad units. These supramolecular devices were effective vehicles used for gene transfection [32]. Along this line, of exceptional interest are supramolecular Janus macromolecules that possess the key asymmetry property of Janus derivatives and dynamic supramolecular host–guest interactions for the purpose of tailoring their properties via external stimuli, e.g. self-assembly behavior.

Among various host–guest inclusion complexes, a typical β-CD/Fc-based molecular recognition system has been used to fabricate a plethora of supramolecular devices [[33], [34], [35], [36], [37], [38], [39]]. β-CD is a cyclic oligosaccharide composed of seven d-glucose repeating units coupled through α-1,4-glucosidic linkages [[40], [41], [42]], and it resembles a truncated-cone construction with hydrophilic outside surface and hydrophobic internal cavity on the truncated cone [[40], [41], [42]]. Especially, β-CD is capable of complexing the sandwich-like hydrophobic Fc moiety at an equivalent molar ratio [[43], [44], [45]]. The formed inclusion complex is dissociated after the neutral hydrophobic Fc is transferred into cationic hydrophilic ferricinium (Fc⁺) using chemical oxidants or electrochemical oxidation and recovered upon reduction of Fc⁺ back to its original neutral Fc structure [44]. This unique transition has been utilized to construct various redox-responsive supramolecular systems [[46], [47], [48], [49], [50], [51], [52], [53]]. For example, Zhang and Li et al. synthesized Fc modified camptothecin (Fc-CPT) via a dithioether bond and methoxy polyethylene glycol containing β-CD end (mPEG-β-CD). These authors further fabricated Fc-CPT and mPEG-β-CD-based supramolecular micelles possessing dual redox-responsiveness of reactive oxygen species (ROS) and glutathione (GSH) [54]. These spherical supramolecular micelles in water exhibit hydrophobic inner core and mPEG as a hydrophilic outer shell and show remarkable hyper-fast CPT release under tumor cell redox microenvironment [54]. In human cancer cells, there is a higher amount of ROS (such as H₂O₂) than normal cells, which may oxidize Fc into Fc⁺ and thus lead to the release of the loaded drugs [54].

Critically, however, no redox-responsive supramolecular Janus dendrimer system has been fabricated using the oxidation and reduction properties of Fc/β-CD complexes. Herein, as shown in Scheme 1, a Janus metallodendrimer 11 was first synthesized by a typical chemo selective coupling route [4] in which two dendrons containing three triethylene glycol (TEG) branches and two Fc termini, respectively, were connected by an ester bond. Fc-terminated dendrons have already been designed and shown to introduce remarkable switching properties in macromolecular devices and ensembles [[55], [56], [57], [58], [59], [60]]. The supramolecular Janus molecule β-CD@11 (Fig. 1) was then fabricated by simply mixing the Fc-containing Janus molecule 11 with β-CD host molecules by host–guest complexation between β-CD and Fc. The formation of inclusion complex is verified via one-dimensional ¹H NMR and two-dimensional nuclear Overhauser enhancement spectroscopy (NOESY). Chemical redox triggers, namely the use of FeCl₃ as oxidant and ascorbic acid as reductant, were utilized to control the self-assembly behavior of the Fc-containing supramolecular Janus assembly β-CD@11 in water via the association/dissociation transition resulting from the redox-conversion of Fc moieties, and the changes of micelles were carefully detected by scanning electron microscopy (SEM) and dynamic light scattering (DLS). Finally, the β-CD@11 micelles were used as supramolecular carriers to encapsulate Rhodamine B (RhB), and the loaded RhB were released using a chemical oxidation trigger.

Section snippets

Synthesis of 11

9 (1.58 g, 2.60 mmol, 1 equiv) was dissolved in 25 ml of dry CH₂Cl₂, and oxalyl dichloride (3.30 g, 26.0 mmol, 10 equiv) was then injected dropwise into the solution at 0 °C under N₂ atmosphere. After the addition, the obtained mixture was agitated at r. t. for 12 h under N₂ atmosphere, and the solvent was then removed in vacuo to yield crude 10. The product was directly used in the future step, and no further purification was conducted. 5 (0.95 g, 2.6 mmol, 1 equiv) and triethylamine (2.63 mg,

Synthesis, structure and electrochemical properties of the Janus substrate 11

The targeted amphiphilic Janus molecule 11 is prepared by a typical chemo selective coupling method [4,69]. As shown in Scheme 1, two dendrons 5 and 9 containing three TEG branches and two Fc termini, respectively, are first synthesized and linked together in the last esterification reaction to yield the new Janus macromolecule 11. Specially, methyl 3,5-dihydroxybenzoate is used as the starting compound to prepare the hydrophobic dendron 5. Its reaction with 3-bromo-1-propyne provides the

Conclusion

The design and facile synthesis of a new supramolecular Janus system with a redox response based on the inclusion complexation of Fc groups into β-CD is reported here. A typical chemo selective coupling method is successfully used for the efficient synthesis of a new bis-Fc-terminated Janus molecule containing three hydrophilic triethylene glycol branches. The new bimetallic Janus molecule is then employed as a building block to fabricate a supramolecular Janus device through the strong

Abbreviations

β-CD

β-cyclodextrin

ferrocene

PDMA

poly(N,N-dimethylacrylamide)

PDEA

poly(N,N-diethylacrylamide)

PAMAM

poly(amidoamine)

adamantane

Fc⁺

ferricinium

ROS

reactive oxygen species

GSH

glutathione

TEG

triethylene glycol

NOSEY

Nuclear Overhauser Enhancement Spectroscopy

SEM

scanning electron microscopy

DLS

dynamic light scattering

RhB

Rhodamine B

MWCO

molecular weight cutoff

loading content

encapsulation efficiency

CuAAC

copper(I)-catalyzed azide alkyne cycloaddition

cyclopentadienyl

DMSO

dimethyl sulfoxide

CMC

critical

Acknowledgements

We thank Ms. Wang Zhonghui (College of Light Industry, Textile and Food Engineering, Sichuan University) for her great help in AFM and DLS measurements and the ceshigo (www.ceshigo.com) for help in SEM. The financial support from the Science and Technology Department of Sichuan Province (No. 2018HH0038), the University of Bordeaux and the Centre National de la Recherche Scientifique (CNRS) are gratefully acknowledged.

Notes

The authors declare no competing financial interest.

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Supramolecular redox-responsive substrate carrier activity of a ferrocenyl Janus device

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Synthesis of 11

Synthesis, structure and electrochemical properties of the Janus substrate 11

Conclusion

Abbreviations

Acknowledgements

Notes

Eur. J. Pharm. Sci.

Tetrahedron

Eur. Polym. J.

J. Colloid Interface Sci.

Colloids Surf. B Biointerfaces

Prog. Polym. Sci.

Coord. Chem. Rev.

Polymer

C.R. Acad. Sci., Ser. IIc

Tetrahedron

Coord. Chem. Rev.

React. Funct. Polym.

Polym. Chem.

Chem. Soc. Rev.

Acc. Chem. Res.

New J. Chem.

J. Am. Chem. Soc.

Soft Matter

New J. Chem.

Nanoscale

J. Org. Chem.

Chem. Sci.

J. Am. Chem. Soc.

Proc. Natl. Acad. Sci. U. S. A.

Nanoscale

Appl. Organomet. Chem.

Angew. Chem. Int. Ed.

Chem. Mater.

J. Am. Chem. Soc.

Acc. Chem. Res.

Acc. Chem. Res.

Chem. Commun.

Angew. Chem. Int. Ed.

Chem. Commun.

J. Chem. Soc. Chem. Commun.

Makromol. Chem. Rapid Commun.

J. Am. Chem. Soc.

Acc. Chem. Res.

Acc. Chem. Res.

Nat. Commun.