Near-infrared photoswitching of cyclodextrin–guest complexes using lanthanide-doped LiYF₄ upconversion nanoparticles

Abstract

This communication reports a new type of supramolecular cyclodextrin–guest complexes using cyclodextrin coated upconversion nanoparticles as hosts and monovalent and divalent azobenzenes and arylazopyrazoles as guests. A potentially biocompatible photocontrol of the interaction by isomerization of the azobenzene or arylazopyrazole was achieved by laser irradiation at 980 nm and a very low light intensity of 0.22 W cm⁻².

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The use of light responsive molecules in supramolecular chemistry is of particular interest, as their integration enables the photochemical, reversible or irreversible control over self-assembly processes. One leading representative is the class of azobenzenes, which show a reversible, photo-induced E/Z-isomerization.¹ By light irradiation at 350 nm azobenzene can be isomerized from its thermodynamically stable trans- into its metastable cis-state. The reverse isomerization into its trans-state can be either obtained by irradiation at 440 nm or by thermal treatment. The photoresponse of azobenzene can additionally be exploited in host–guest interactions. Azobenzenes form inclusion complexes with α- and β-cyclodextrins (CDs). Whereas the trans-state of the azobenzenes is included in the cavity of CD, the interaction is inhibited in the cis-state due to the change in polarity and the sterical hindrance. This characteristic provides a photoswitchable control over host–guest-complexations and a broad range of applications for example light responsive hydrogels,² molecular shuttles,³ micelles and vesicles,⁴ surfaces⁵ and drug delivery vehicles.⁶

However, in most cases the use of UV light is inevitable for the photoswitch, which becomes problematic in biological applications since UV light causes damage to those tissues. Therefore the use of low energy irradiation – such as near-infrared light (NIR) – would be desirable. Irradiation with NIR light can be – compared to UV – biocompatible and has the additional advantage of a deeper penetration depth into biological specimens.⁷ In principle, NIR excitation can be achieved by using upconversion nanoparticles (UCNPs). The advantage of using UCNPs is their property to show the anti-Stokes effect, i.e. UCNPs absorb several low energy photons and in return emit a high energy photon.⁸ Depending on the nanocrystal lattice and doping of the UCNPs even the emission of UV light can be achieved. Of special interest are lanthanide doped UCNPs, which exhibit, in contrast to conventional two-photon absorbing dyes or fluorophores, several long-lived excited states, enabling the irradiation at low light intensities, which significantly increases the biocompatibility of this approach.⁹ NIR laser intensities higher than several W cm⁻² are categorized dangerous. The maximum permissible exposure of skin for a continuous irradiation at 980 nm is 0.726 W cm⁻².¹⁰ Wu et al. recently showed a strategy to reduce the NIR light intensity in photochemical processes to an ultralow-intensity of 0.35 W cm⁻².¹¹

Various examples of photochemical processes in supramolecular systems involving UCNPs can be found in the literature ranging from photoisomerization of dithienylethenes,¹² spiropyranes¹³ and azobenzenes¹⁴ to photolysis¹⁵ and photopolymerization.¹⁶ Furthermore CDs were occasionally applied as ligands for UCNPs to render them water-soluble or combine UCNPs with supramolecular chemistry.¹⁷

Herein, we describe NIR switchable supramolecular materials using LiYF₄:Yb³⁺,Tm³⁺,Gd³⁺-UCNPs coated with α- and β-cyclodextrin acid (CDA@UCNPs) as host and azobenzene as guest (Scheme 1). We have previously shown that β-cyclodextrin persubstituted with carboxylic acid (per-6-deoxy(carboxylpropyl)thio-β-cyclodextrin, β-CDA) is an excellent ligand for magnetite nanoparticles.¹⁸ We now show that CDA@UCNPs can isomerize azobenzene by NIR irradiation at 980 nm and a very low light intensity of 0.22 W cm⁻². Due to the host–guest interaction with the CD on the particle a close proximity between UCNPs and light-responsive guests was expected, leading to higher efficiencies for photoswitching. Furthermore we developed a reversible aggregation of the UCNPs by supramolecular cross-linking with a divalent azobenzene and redispersion of the resulting aggregates by NIR irradiation (Scheme 1). Finally, we show that also arylazopyrazole (AAP), which shows a strong binding to β-CD¹⁹ can be isomerized by NIR excitation of UCNPs.

Scheme 1 (A) Host–guest complexation of monovalent Azo-TEG or AAP-TEG in the cavity of CDA@UCNPs and release after NIR irradiation; (B) aggregation experiment using a divalent Azo-linker or AAP-linker and CDA@UCNPs; (C) schematic illustration of the CDA@UCNPs and structures of monovalent Azo-TEG and AAP-TEG and divalent Azo-linker and AAP-linker.

Water-soluble UCNPs were synthesized in a modified ligand exchange reaction by adding per-6-deoxy(carboxylpropyl)thio-α- or β-cyclodextrin (α- or β-CDA) to a dispersion of methyl oleate (MO) coated LiYF₄:Yb³⁺,Tm³⁺,Gd³⁺-UCNPs in ultra-pure water (MO@UCNPs) and sonication for 20 min.²⁰ The CDA ligand, containing six or seven carboxylic acid functionalities, binds to the UCNPs in multivalent mode and easily replaces the weaker, monovalent MO ligand.

In order to verify that the ligands are on the surface of the UCNPs, Fourier transform infrared (FTIR) measurements were performed, comparing the spectrum of the free ligands α- and β-CDA with the spectrum of CDA@UCNPs (Fig. 1). In both cases, the free ligand spectra are in good agreement to the CDA@UCNPs spectra. Additionally the absence of the characteristic peaks of MO indicate that the ligand exchange was quantitative.

Fig. 1 FTIR spectra of (A) free α-CDA and α-CDA@UCNPs and (B) free β-CDA and β-CDA@UCNPs.

The water-soluble UCNPs were further characterized by transmission electron microscopy (TEM, Fig. 2). It can be seen from the TEM images that all particles have a diameter around 40 nm and did not significantly change in size or shape compared to the MO@UCNPs. For the α-CDA@UCNPs an average size of 39.6 ± 7.0 nm was obtained while the β-CDA@UCNPs have a size of 41.0 ± 7.5 nm. The TEM images further show some aggregation of the particles, which is most likely a consequence of the drying during sample preparation.

Fig. 2 TEM images and size histograms of (A) α-CDA@UCNPs and (B) β-CDA@UCNPs.

In addition the emission measurements of CDA@UCNPs upon irradiation with a NIR laser at 980 nm show identical spectra for both types of particles (Fig. 3A). The images of the corresponding samples are shown in Fig. 3B. We note that the emission around 350 nm should be suitable to photoisomerize azobenzene as well as AAP.

Fig. 3 (A) Emission spectra of α- and β-CDA@UCNPs irradiated with a NIR laser at 980 nm (intensity ca. 5.1 kW cm⁻²). (B) Images of the corresponding excited α-CDA@UCNPs (top) and β-CDA@UCNPs (down) in ultra-pure water.

With the CDA functionalized UCNPs in hand we investigated if they are capable to isomerize azobenzene in an upconversion process by irradiation at 980 nm (see Scheme 1A). Indeed, a successful isomerization could be obtained for both α- and β-CDA@UCNPs. For α-CDA@UCNPs we prepared a water soluble, tetraethyleneglycol functionalized azobenzene derivative (Azo-TEG). For β-CDA@UCNPs we prepared tetraethyleneglycol functionalized arylazopyrazole (AAP-TEG). For the switching experiment a dispersion of CDA@UCNPs in ultra-pure water (2 mg mL⁻¹) was mixed with a solution of either Azo-TEG or AAP-TEG and irradiated with a defocused laser beam at 980 nm and a light intensity of 0.22 W cm⁻², which is under the maximum permissible exposure of skin, for a defined period. The reduced intensity is achieved by defocusing the laser beam. Control experiments showed that the UCNPs are still able to emit UV light at these intensities (see Fig. S12–S15, ESI†). The progress of the isomerization was monitored by consecutive UV/Vis measurements to determine the decreasing absorption maxima of the trans-isomers of azobenzene and AAP around 350 nm (Fig. 4). Although the upconversion-mediated NIR isomerization is slow (i.e. several hours) compared to a UV isomerization at 350 nm (i.e. several min), the switching is remarkably efficient considering the very low quantum yield of upconversion.⁸ These experiments confirm our hypothesis that host–guest interaction will bring the UCNPs and the azobenzene or AAP in close proximity and hence increase the efficiency of photoisomerization. The photostationary state of both systems after irradiation was determined by NMR to be 53% trans-isomer and 47% cis-isomer, which is less than for UV light induced photoisomerization (see Fig. S16–S20, ESI†).

Fig. 4 UV/Vis measurements for the photoisomerization of (A) 0.91 mM Azo-TEG by 2 mg mL⁻¹ α-CDA@UCNPs and (B) 0.91 mM AAP-TEG by 2 mg mL⁻¹ β-CDA@UCNPs. The dispersion was irradiated with a defocused 980 nm laser beam and a light intensity of 0.22 W cm⁻².

Furthermore, photoreversible aggregation experiments were performed using divalent cross-linkers (Azo-linker or AAP-linker, see Scheme 1B). The aggregation of the UCNPs upon addition of the trans-Azo-linker was monitored by optical density measurements at 600 nm (OD₆₀₀). In all aggregation experiments the CDA@UCNPs concentration was constant at 0.085 μg mL⁻¹.

During the initial equilibration time a constant OD₆₀₀ value around 0.02 was measured derived from the scattering of the UCNPs dispersion. However, upon addition of the trans-Azo-linker a significant increase of the OD₆₀₀ up to approximately 0.22 in 20 min was observed, indicating the formation of aggregates of UCNPs (Fig. 5A). Upon addition of the AAP-linker an even higher increase up to 0.51 in 20 min could be achieved (Fig. 5A). If no linker was added, OD₆₀₀ remained constant for 20 min. In a control experiment using only the Azo-linker or AAP-linker without the α- or β-CDA@UCNPs no agglomeration was observed (see Fig. S10, ESI†). These observations indicate that aggregation of UCNPs is due to the host–guest-interaction of the CD-functionalized nanoparticles with the divalent cross-linker. The aggregation of UCNPs was verified by TEM measurements (see Fig. S5 and S6, ESI†) and showed large aggregates between 0.4 and 1.2 μm in diameter.

Fig. 5 (A) Aggregation experiment of α- and β-CDA@UCNPs (0.085 mg mL⁻¹) with the Azo-linker or the AAP-linker (80 μM) monitored via OD₆₀₀ measurements. Aggregation and redispersion of the α-CDA@UCNPs (B) or β-CDA@UCNPs (C) by consecutive irradiation with 980 nm (red area) or 450 nm (green area).

Finally, a successful, reversible aggregation and disaggregation cycle was obtained by alternating NIR irradiation at 980 nm (trans- to cis-isomer) and VIS irradiation at 450 nm (cis- to trans-isomer) (see Fig. 5B and C). However, it was found that the disaggregation of cross-linked UCNPs is slower compared to the switching experiments using the monovalent guest. Nevertheless, complete redispersion of the aggregates was achieved after 7 h, which enhances their potential application for host–guest interactions under biologically relevant conditions.

In this study we developed a versatile protocol for an efficient and broadly applicable combination of cyclodextrin coated upconversion nanoparticles and photoresponsive host–guest interactions. A near-infrared light stimulus was used to induce the photoisomerization of azobenzene and arylazopyrazole to control the formation of host–guest complex. Both the surface functionalization and aggregation of upconversion nanoparticles can be controlled by near-infrared irradiation. This attractive combination could become especially useful for the near-infrared induced local release of payload from cyclodextrin complexes under physiological conditions.^4,6

We thank Christian Schwickert (MEET) for XRD measurements and Wilke de Vries and Andreas Rühling for helpful discussions. Martin Peterlechner is acknowledged for advice on TEM measurements.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Methods, synthesis, analytical data, additional experiments. See DOI: 10.1039/c6cc08321h

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