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. 2020 Feb 28;11(4):451–456. doi: 10.1021/acsmedchemlett.9b00559

Supramolecular Hyaluronic Assembly with Aggregation-Induced Emission Mediated in Two Stages for Targeting Cell Imaging

Yang Yang †, Ya-Jun Jin †, Xin Jia †, Shi-Kuo Lu †, Ze-Rui Fu †, Yu-Xi Liu †, Yu Liu ‡,*
PMCID: PMC7153013  PMID: 32292549

Abstract

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Supramolecular aggregation-induced emission (AIE) has become a research hotspot in cell imaging. Herein, supramolecular assembly with AIE effect was constructed in two stages, where adamantane modified tetraphenylethene self-assembly emitted weak fluorescence, and then after adding β-cyclodextrin modified hyaluronic acid, the formed nanoparticles enhanced AIE fluorescence for targeted cancer cell imaging.

Keywords: Supramolecular assembly, aggregation-induced emission, tetraphenylethene, hyaluronic acid, cell imaging

Nowadays, supramolecular aggregation-induced emission (AIE) and its application in cell imaging have become the research focus in the field of supramolecular chemistry.1,2 The phenomenon of AIE fluorescence, which exhibits negligible emission in dilute solution but emits intense fluorescence in aggregation or solid state, was first discovered by Ben Zhong Tang et al. in 2001.3 The mechanism of AIE effect is the restriction of intramolecular rotations and inhibition of nonradiative decay.4,5 In recent decades, AIE materials have gained more and more interest due to the superior features compared to conventional fluorescent reagents, such as high solid quantum yield and photostability, excellent biocompatibility, free of random blinking, and strong photobleaching resistance, which jointly facilitated applications of AIE materials on fluorescence imaging.6,7 Among the variety of AIE materials, tetraphenylethene (TPE) with aggregation and fluorescence behaviors was considered as a candidate material used in fluorescent imaging at the subcellular, cellular, or tissue levels in noninvasive and high contrast manners due to its facile synthesis and easy modification.8−11

On the other hand, supramolecular aggregates with remarkable fluorescence and drug loading capability were frequently studied in recent years due to the easy fabrication using building blocks via supramolecular and amphiphilic interactions.12−15 The traditional host–guest interaction between adamantane and β-cyclodextrin (β-CD) cavity had been employed for construction of numerous supramolecular architectures.16−19 Moreover, hyaluronic acid (HA), a water-soluble acidic polysaccharide, is frequently used as the aggregation-inducing scaffold, AIE turn-on agent,20,21 and targeting unit22−24 due to its biocompatibility, biodegradability, easy modification, low toxicity, and specific targeting toward CD44 and RHAMM (receptor for HA-mediated motility) receptors overexpressed on the surface of cancer cells.25−27 Therefore, HA-based supramolecular AIE assemblies possess great potential in fluorescence imaging applications. For instance, Qian Zhao et al.28 fabricated tetraphenylethylene-bridged β-CD (TPECD) and adamantyl-grafted hyaluronic acids (HAAD), and formed spherical nanoparticles by mixing the two building blocks together. However, the rigid structure of TPECD grafted four bulk β-CDs is adverse to π stacking and molecular restriction of tetraphenylethene core; then the further enhancement of AIE fluorescence was not prominent for nanoparticles. Therefore, fluorescent doxorubicin was employed to be loaded into the nanoparticles for cancer cell imaging. For another, Bang-Ping Jiang et al.29 reported a novel multifunctional AIE nanoaggregate fabricated through electrostatic interactions between positive charged quaternary ammonium-modified TPE derivative and negative charged crude HA. The obtained nanoaggregate presented AIE turn-on fluorescence for targeted imaging of cancer cells. Nevertheless, the investigation of the aggregation strategy of TPE derivatives before and after adding host molecules (such as β-CD-modified hyaluronic acid (HACD)) at different stages and acquiring enhanced AIE effect is still rarely reported.

In this work, adamantane-modified tetraphenylethene (TPE-ADA) with two small adamantane groups and low solubility could self-assemble and emit low fluorescence in aqueous solution at the first stage. When HACD was added, supramolecular nanoparticles (TPE-ADA/HACD) were formed via the strong host–guest interaction. Then the hydrophobic TPE core in the nanoparticles would stack and emit strong AIE fluorescence at the second stage (Scheme 1). Then the hydrophilic HA shell of TPE-ADA/HACD nanoparticle could specially target HA-receptor positive cancer cells and realize the targeted fluorescent imaging toward cancer cells at the cellular level as well as presenting no cytotoxicity to both of cancer cells and normal cells. This work is considered as the great improvement of Qian Zhao et al.’s study,28 where the synthetic step of TPE derivative was shorten from 4 (TPECD) to 2 (TPE-ADA), and TPE-ADA/HACD nanoparticle has greater fluorescence enhancement and quantum yield promotion than the TPECD-HAAD assembly. Therefore, cancer cell imaging could be realized by AIE effect of TPE-ADA/HACD without introducing other fluorescent agents. Compared with Bang-Ping Jiang et al.’s work,29 the interaction between HA and TPE derivative was stronger by host–guest interaction in TPE-ADA/HACD than electrostatic interaction in QA-TPE/HA, and the cellular cytotoxicity could be greatly reduced without introducing positively charged tetraquaternary ammonium.

Scheme 1. Construction Process of TPE-ADA/HACD Nanoparticle.

Scheme 1

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HACD was synthesized by hyaluronic acid (Mw = 190 000) and mono-6-deoxyl-6-ethylenediamino-β-CD in PBS according to the reported methods.30,31 On the other hand, TPE-ADA was prepared from a facile two-step synthetic method containing nucleophilic substitution reaction and McMurry coupling reaction,32 which were relatively simple and illustrated in Figure S1. The characterization of reaction intermediates and final TPE-ADA product by 1H/13C NMR spectroscopy and mass spectra were presented in Figures S2–S7. Moreover, it is obvious to find that cis–trans isomerism would exist in TPE-ADA fabrication. In this study, two fluorescent white solids with similar polarity and 1H NMR spectra were separated from column chromatography. The less polar one had higher yield (45.2%), which was believed to be trans-isomer of TPE-ADA due to less steric hindrance than the cis-isomer. The higher polar one with 1.7% yield was assigned to the cis-isomer. Similar results could be also found in previous studies.33,34 On the other hand, through theoretical simulation by Materials Studio 6.0, the cis-isomer indeed had a larger dipole (5.15 D, Figure S8a) than the trans-isomer (3.69 D, Figure S8b), and the trans-isomer had a higher melting point (341–342 °C) than the cis-isomer (310–311 °C) because the cis-isomers destroyed the molecular accumulation and were facile to be disorganized when the temperature increased. Therefore, trans-isomer and cis-isomer of TPE-ADA could be assigned, and the trans-isomer of TPE-ADA was employed as guest molecule in the following experiments.

Because of the hydrophobic nature of TPE-ADA, it tended to self-assemble in aqueous solution. Figure S9a exhibited amorphous structures in a high resolution transmission electron microscope (HR-TEM) image, indicating that TPE-ADA assembled in an incompact way. Dynamic light scattering (DLS, Figure S9b) revealed that the hydrodynamic diameter of TPE-ADA assembly was around 262 nm, which also presented ζ potential as +0.72 mV on the assembly’s surface (Figure S9c). Therefore, TPE-ADA could form amorphous assembly with slightly positive charged surface in aqueous solution as stage I.

By utilizing the strong supramolecular interaction between adamantane groups and β-CD cavities, HACD was added into TPE-ADA to form supramolecular nanoparticle TPE-ADA/HACD in aqueous solution as stage II, where TPE-ADA was employed as typical molecule with AIE properties, and HACD was employed as targeting units for cancer cell recognition. As shown in Figure S10, in a typical Job’s plot, a maximum value was observed at fraction ratio of 0.33, revealing the binding stoichiometry between TPE-ADA and β-CD was 1:2. Two adamantane groups in TPE-ADA could be included into cavities of two individual β-CD due to the supramolecular interaction. Next, the morphology and nanostructure of TPE-ADA/HACD were systematically investigated by atomic force microscope (AFM), HR-TEM, DLS, and ζ potential experiments. As shown in Figure 1a, a series of discrete spherical nanoparticles was observed in a typical AFM image. The average height of collapsed nanoparticle was measured as 5.8 nm, which was basically equal to the sum of two HA backbones (ca. 1.5 nm), two β-CD units, which included adamantane groups (ca. 2.0 nm), and anchored tetraphenylethene cores (ca. 2.0 nm). The HR-TEM image in Figure 1b also exhibited well-dispersed TPE-ADA/HACD nanoparticles, whose diameters were about 30–50 nm. Furthermore, the DLS experiment (Figure 1c) was performed to measure the hydrodynamic diameter of TPE-ADA/HACD as ∼84 nm, which was in accordance with the results of the HR-TEM image indicating good dispersity of nanoparticles in aqueous solution. To acquire more structural information about TPE-ADA/HACD nanoparticles, ζ potential experiment was employed to detect the charge distribution on nanoparticles’ surface. As shown in Figure S11, the ζ potential of TPE-ADA/HACD was measured as −18.4 mV, indicating that the TPE-ADA/HACD nanoparticles were covered by negative charged HA shell owing to the ionization of carboxyl groups on the HA skeleton.

Figure 1.

Figure 1

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Typical (a) AFM, (b) HR-TEM, and (c) DLS results of TPE-ADA/HACD nanoparticles.

Besides, the elemental composition of TPE-ADA assembly in stage I and TPE-ADA/HACD nanoparticles in stage II was also measured by X-ray photoelectron spectroscopy (XPS, Figure S12). Only C (87.95 at%) and O (12.05 at%) elements could be found in TPE-ADA assembly. After the addition of HACD, due to abundant hydroxyl and carboxyl groups on the nanoparticle’s surface, the content of O increased to 30.69 at%, the content of C decreased to 65.60 at%, and the element N appeared as 3.71 at% deriving from acetyl amino group on HACD. Therefore, HA skeleton was considered as the cover shell of TPE-ADA/HACD nanoparticles. Together with morphology comparison of TPE-ADA assembly and TPE-ADA/HACD nanoparticles, the addition of HACD could greatly change the assembly strategy of TPE-ADA, and the second stage nanoparticle TPE-ADA/HACD possessed good stability, dispersibility, and biocompatibility in the biological environment. Also, the negative charged HA shell could also promote the targeting of TPE-ADA/HACD nanoparticles toward cancer cells.

After successful construction of TPE-ADA assembly and TPE-ADA/HACD nanoparticle, we performed UV/vis and fluorescent spectra to investigate their photophysical properties. As shown in Figure S13, HACD showed almost no UV/vis absorption in the range from 250 to 800 nm, and TPE-ADA assembly exhibited maximum absorption peak at λ = 263 nm, which was assigned to π–π* electronic transitions of the TPE-ADA skeleton.16 Besides, the shoulder peak at λ = 330 nm was observed. After adding HACD into TPE-ADA, the obtained TPE-ADA/HACD supramolecular nanoparticle gave similar UV/vis spectra, where a maximum absorption peak appeared at λ = 262 nm. This phenomenon revealed that the incorporation of HACD did not extremely change the energy level state of TPE-ADA in aqueous solution.

For further study of supramolecular AIE effect of TPE-ADA, fluorescent spectra were employed to investigate the aggregation behavior of TPE-ADA assembly and TPE-ADA/HACD nanoparticle. Figure S14 presented the fluorescence excitation spectrum of TPE-ADA, and 330 nm was selected as the excitation wavelength for fluorescence experiments. As shown in Figure S15a, when the concentration of TPE-ADA increased from 1 × 10–6 M to 5 × 10–5 M by 50-fold in pure DMSO, almost no fluorescence was observed from 350 to 650 nm, indicating that no AIE occurred for TPE-ADA in DMSO. However, at the same TPE-ADA concentration as 3 × 10–5 M, the fluorescence intensity of TPE-ADA at λem = 460 nm in aqueous solution containing 4% DMSO was 110-fold higher than that in pure DMSO solution (Figure S15b). In pure DMSO solution as good solvent, TPE-ADA existed as monomeric form to display feeble emission due to the intramolecular rotation of aromatic rings.35 When water was added at fraction of 96 vol % as the nonsolvent, the TPE-ADA molecules aggregated, and the rotation of aromatic rings of TPE-ADA was restricted in aggregation, and then the fluorescence intensity was enhanced, which was typically called AIE phenomenon.33,34

As shown in Figure 2, under excitation wavelength of λex = 330 nm, HACD showed no fluorescence, and TPE-ADA exhibited a weak aggregation-induced fluorescent peak at λem = 460 nm. The relatively weak AIE phenomenon of TPE-ADA could be attributed to the poor solubility nature and self-aggregation impediment of the tetraphenylethene group of TPE-ADA in aqueous solution. Because the hydrophobic adamantane group in TPE-ADA would have the same trend to self-assemble and compete with π stacking of the tetraphenylethene group, then incompact TPE-ADA assembly formed with low AIE effect at the first stage. After addition of HACD, the hydrophobic adamantane group was included by β-CD of HACD and turned hydrophilic, and then the π–π stacking in TPE core and restriction of adamantane group by HACD together restrained the intramolecular motions (including rotation and vibration) of phenyl groups and increased the rigidity of tetraphenylethene,36,37 which reduced the nonradiative decay with turn-on AIE emission. Therefore, the fluorescent intensity of TPE-ADA/HACD nanoparticle increased by 4.5-times at the second stage (λem = 465 nm) compared with TPE-ADA assembly.

Figure 2.

Figure 2

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Fluorescent spectra of HACD, TPE-ADA, and TPE-ADA/HACD nanoparticle (λex = 330 nm, [TPE-ADA] = 3 × 10–5 M, [HACD] = 8.8 × 10–7 M, containing 6 × 10–5 M β-CD, solvent was aqueous solution containing 4% DMSO at 25 °C).

On the other hand, the turn-on AIE emission was accompanied by variation in fluorescence lifetime and fluorescence quantum yield. As shown in Figure S16, after addition of HACD, the lifetime of TPE-ADA/HACD (4.60 ns, χ2 = 1.10) was slightly increased compared with TPE-ADA assembly (3.96 ns, χ2 = 1.09), but the quantum yield was greatly enhanced (from Φ = 17.88% of TPE-ADA to Φ = 66.07% of TPE-ADA/HACD).

Combined with the results in ζ potential experiment (Figure S11), which indicated negative charge existence on TPE-ADA/HACD nanoparticle surface, we could affirm that TPE-ADA/HACD nanoparticle was composed of hydrophilic HA shell and hydrophobic tetraphenylethene core, which could give enhanced AIE effect compared with TPE-ADA self-aggregation. Furthermore, the two-stage enhancement of AIE effect by TPE-ADA and TPE-ADA/HACD formation can be distinguished by naked eyes. As shown in Figure S17, the prepared TPE-ADA powder exhibited obvious solid fluorescence under UV light (365 nm) due to the AIE effect of TPE-ADA in solid state. However, as shown in Figure 3a, compared with weak fluorescent intensity of TPE-ADA assembly at the first stage in aqueous solution, the second-stage enhancement of AIE effect was realized for TPE-ADA/HACD nanoparticles, which was in accordance with Figure 2. On the other, the promoted Tyndall phenomenon could be also observed after addition of TPE-ADA into HACD aqueous solution (Figure 3b), further proving the formation of TPE-ADA/HACD nanoparticle with nanosize.

Figure 3.

Figure 3

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(a) Fluorescent image of TPE-ADA (left) and TPE-ADA/HACD (right); (b) Tyndall effects of HACD (left) and TPE-ADA/HACD (right).

Taking advantage of AIE effect and targeted HA shell of TPE-ADA/HACD nanoparticle, fluorescent confocal experiments by TPE-ADA/HACD nanoparticles using HA-receptor positive PC-3 human prostate cancer cells and HA-receptor negative NIH3T3 mouse embryonic fibroblasts were performed. As shown in Figure 4, after incubation with TPE-ADA/HACD nanoparticle for 4 h, PC-3 cells exhibited bright blue fluorescence assigned to AIE effect, revealing that TPE-ADA/HACD nanoparticles were relative stable in vitro and successfully delivered into cancer cells by HA-receptor mediated endocytosis. In contrast, lacking HA-receptor on the cell membrane, no fluorescence was observed in NIH3T3 cells under the same experimental condition. All the experimental phenomena testified that TPE-ADA/HACD nanoparticles could be applied for cancer cell imaging with high efficiency, which was ascribed to the specific TPE-ADA/HACD nanoparticle’s structure of hydrophilic HA shell with cancer cell targeting function, and hydrophobic tetraphenylethene core with AIE effect.

Figure 4.

Figure 4

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Fluorescent confocal images of PC-3 cells in (a) bright field, (b) dark field, (c) merged field; NIH3T3 cells in (d) bright field, (e) dark field, (f) merged field after incubation with TPE-ADA/HACD nanoparticles for 4 h (containing 5 × 10–5 M TPE-ADA and 1 × 10–4 M β-CD).

For the purpose of studying the safety of TPE-ADA/HACD nanoparticle in application of cancer cell imaging, cytotoxicity experiments were performed through incubation of PC-3 cancer cells and NIH3T3 cells with TPE-ADA/HACD nanoparticles for 24 and 48 h by CCK8 assay. As shown in Figure 5, after incubation with TPE-ADA/HACD nanoparticles with different concentrations ([TPE-ADA] = 0, 2.06, 6.17, 18.5, 55.5, 167, 500, 1500 μM) for 24 and 48 h, respectively, no cytotoxicity could be observed on both normal NIH3T3 cells and PC-3 cancer cells, whose cellular viability completely exceeded 95%. These experimental results proved that even high concentration of TPE-ADA/HACD nanoparticles would not damage the cytomembrane and organelle of normal cells or cancer cells and was safe and biocompatible enough for cancer cell imaging application.

Figure 5.

Figure 5

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Cytotoxicity experiments of NIH3T3 cells (a) in 24 h, (b) in 48 h, and PC-3 cells (c) in 24 h, (d) in 48 h after incubation with TPE-ADA/HACD nanoparticles with different concentrations ([TPE-ADA] = 0, 2.06, 6.17, 18.5, 55.5, 167, 500, 1500 μM).

In conclusion, a novel supramolecular nanoparticle bearing TPE-ADA and HACD was successfully constructed via host–guest interactions, which exhibited enhanced AIE effect mediated in two stages. The obtained TPE-ADA/HACD nanoparticle could specifically target cancer cells through HA–HA receptor interactions and emit blue fluorescence in vitro to distinguish cancer cells from normal cells without introducing obvious side effects. The supramolecular construction strategy in this study would be applied for multiple cancer cell imaging and recognition.

Acknowledgments

We thank the NNSFC (21871154, 21772099, and 21402038) and the Hebei Provincial Natural Science Foundation of China (B2015202291 and B2019202003) for financial support.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00559.

  • Experimental details, compounds characterization, theoretical simulation, TPE-ADA assembly characterization, Job’s plot, ζ potential, XPS spectra, fluorescence characterization results (PDF)

The authors declare no competing financial interest.

Supplementary Material

ml9b00559_si_001.pdf (1.1MB, pdf)

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