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. 2019 Jul 10;4(7):11981–11987. doi: 10.1021/acsomega.9b01436

Fluorescent Supramolecular Assembly with Coronene Centers for Controlled DNA Condensation and Drug Delivery

Yu-Hui Zhang †, Jie Yu ‡, Jie Wang †, Li-Juan Wang §, Wen-Han Yao †, Siqintana Xin †, Xianliang Sheng †,*, Zeyu Guo §,*
PMCID: PMC6682016  PMID: 31460309

Abstract

graphic file with name ao-2019-014368_0006.jpg

A multifunctional supramolecular assembly was successfully constructed by the host–guest complexation of doubly positively charged adamantane (ADA) with β-CD-modified hexabenzocoronene and the π-stacking of coronene with mitoxantrone, which was characterized by transmission electron microscopy, scanning electron microscopy, dynamic light-scattering, and zeta potential experiments. Possessing a small size and rigid backbone coronene center, the water-soluble biocompatible supramolecular assembly has intracellular imaging abilities. Moreover, after the ester group of ADA was hydrolyzed into a carboxyl group, the positively charged quaternary amine strand converted into a zwitterion structure, which realized the controlled plasmid DNA binding and release. Besides, the cytotoxicity experiments showed that the supramolecular assembly possesses slightly lower toxicity and a slightly higher anticancer activity than free drug. We believe that this work might present a convenient method for synergetic cancer treatment.

1. Introduction

The construction of multifunctional nanocarriers incorporating two or more different therapeutic strategies with synergistic effects has recently emerged as a promising approach for improving cancer therapy.1−3 To this end, a number of multifunctional carriers based on inorganic nanoparticles,4 carbon nanomaterials,5 liposomes,6 and vesicles7 were constructed and exhibited effective therapeutic activities to cancer cells. Nevertheless, the synthetic procedure is complicated and time-consuming to construct multifunctional integrated diagnosis, imaging, and drug delivery systems with multifarious therapeutic approaches, which hinder the further advance. In this regard, supramolecular host–guest complexation provides a facile and rapid procedure to construct complicated molecular assemblies through noncovalent interactions, because the representative macrocycles, such as cyclodextrin (CD), is water-soluble, nontoxic, and possessing a hydrophobic cavity, which can construct biocompatible supramolecular assemblies with various substrates in biomedical science.8−17 For instance, Liu and co-workers developed a new type of magnetism and photo dual-controlled supramolecular nanofiber that integrates targeting peptide-coated magnetic nanoparticles with β-CD-bearing polysaccharides for suppression of tumor invasion and metastasis, demonstrating that the nanofibers provide a convenient tool for tumor therapy.18 Besides, the effective macrocycle-based delivery systems with suitable size, good water solubility, and stability in physiological environments still deserve our careful attention.19−23

It is significant to note that multifunctional nanocarriers simultaneously loading imaging and therapeutic agents have appeared as a potential candidate in imaging-guided therapy to realize early detection and prompt treatment of cancer.24,25 Among various imaging agents, nanographenes (coronene derivatives) have attracted considerable attention because of their intrinsic properties including superior fluorescence emission, anti-photobleaching ability, and intermolecular π–π stacking behaviors.26−28 In this work, a conjugated supramolecular assembly was constructed by the noncovalent multiple interactions with β-CD-modified hexabenzocoronene (HBCCD) as scaffold centers, which could simultaneous intracellular imaging and plasmid DNA (pDNA) binding and anticancer drug loading. The chemical structure and construction route for the preparation of HBCCD–ADA fluorescent supramolecular assembly are shown in Scheme 1. There are some unique characteristics of such a system: (1) a small size coronene derivative was chosen as scaffold because of its inherent fluorescence properties, which could act as a fluorescence probe to real-time monitor the drug release, distribution, and accumulation of the supramolecular assembly; (2) the controlled binding and release of pDNA was easily achieved via ester hydrolyze into “zwitterionic” structure;29−31 and (3) anticancer drugs, such as mitoxantrone (MTZ), could be readily integrated into the water-soluble supramolecular assembly of HBCCD–adamantane (ADA) by the π–π stacking interaction between the coronene surface and the aromatic ring of drug molecule MTZ. Therefore, this water-soluble and biocompatibility multifunctional nanostructure is taken into account as a novel strategy for improving cancer treatment.

Scheme 1. Construction of HBCCD–ADA Supramolecular Assembly.

Scheme 1

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2. Results and Discussion

Benefiting from the strong host–guest inclusion complexation between ADA and β-CD,32 the fluorescent supramolecular assembly was prepared by simply mixing the aqueous solutions of ADA and HBCCD together. The structural and morphological features of the HBCCD–ADA supramolecular assembly were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), dynamic light-scattering (DLS), and zeta potential measurements. The TEM image in Figure 1a showed that HBCCD–ADA supramolecular assembly have a spherical morphology with a diameter of ca. 300 nm. The SEM image (Figure 1b) also showed the 280–310 nm homogeneous spherical nanoparticles. Moreover, DLS measurement indicated that the hydrodynamic diameter of HBCCD–ADA assembly was ca. 465 nm with a narrow distribution (Figure 1c), which was in accordance with the results in microscopic images. The zeta potential of HBCCD–ADA was measured as ca. +14.8 mV (Figure 1d), suggesting that the surface charge of assembly was positive charged, which is beneficial to promote the electrostatic interaction between HBCCD–ADA supramolecular assembly and pDNA.

Figure 1.

Figure 1

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Typical (a) TEM and (b) SEM images of HBCCD–ADA supramolecular assembly. (c) DLS and (d) zeta potential experiment results of HBCCD–ADA supramolecular assembly in deionized aqueous solution.

Considering that the quaternary amine strands of ADA were positively charged in aqueous solution, the HBCCD–ADA supramolecular assembly could be used to bind nucleic acid via electrostatic interaction. The pDNA binding behavior was examined by evaluating the electrophoretic mobility at different N/P ratios in agarose gel. As shown in Figure 2a,b, pDNA was completely retarded by HBCCD–ADA supramolecular assembly at an N/P ratio of 10, which was much lower than that for ADA alone (N/P = 50). This phenomenon might be that the assembly enriches the quaternary ammonium chains of ADA together and facilitates the pDNA binding, thus leading to the enhanced DNA condensation capability. Meanwhile, other information about the pDNA condensation by the HBCCD–ADA supramolecular assembly comes from TEM and DLS experiments. The TEM image (Figure S1a) revealed that pDNA was condensed into even tighter spherical particles with an average diameter of 270 nm at the N/P ratio of 20. The DLS result further indicated that the HBCCD–ADA supramolecular assembly could effectively bind pDNA into uniform nanoparticles with a hydrodynamic diameter centered at 414 nm (Figure S1b).

Figure 2.

Figure 2

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Agarose gel electrophoresis experiments of (a) ADA, (b) HBCCD–ADA supramolecular assembly with pDNA at N/P ratios of 5, 10, 20, 30, 40, 50, and 60 from lane 1 to lane 7, respectively, (c) ADA with pDNA before (lane1) and after (lane 2) esterolysis at the N/P ratio of 50, (d) HBCCD–ADA supramolecular assembly with pDNA before (lane 3) and after (lane 4) esterolysis at the N/P ratio of 20.

Subsequently, the controlled pDNA release behavior was investigated by analyzing electrophoretic mobility of supramolecular assembly before and after hydrolysis of ester group in ADA under aqueous NaOH solution. As shown in Figure 2c,d, pDNA could be released from ADA and HBCCD–ADA supramolecular assembly (lane 2 and lane 4) after hydrolysis. This indicated that ADA and HBCCD–ADA supramolecular assembly could bind pDNA through electrostatic interaction before esterolysis (lane 1 and lane 3). Nevertheless, when the neutral ester group in ADA was hydrolyzed to a negatively charged carboxyl group, the quaternary amine strand in ADA changed to a zwitterion structure, which realize pDNA-controlled binding and release (Scheme S1).

As a consequence of the satisfactory π-stacking interaction, MTZ was chosen as a model anticancer drug and loaded onto the surface of coronene (Scheme S2).33 As expected, a new shoulder band at 609 and 660 nm was observed in the UV/vis spectrum of MTZ@HBCCD–ADA (Figure 3), which was assigned to the characteristic absorption of MTZ.34 Meanwhile, the MTZ-loaded solution (MTZ@HBCCD–ADA) turns to light blue compared with the pale yellow MTZ-unloaded solution (Figure 3, inset). By monitoring the UV/vis spectrum of MTZ at 609 nm, the photometric standard curve of MTZ was measured (Figure S2). Therefore, the encapsulation and loading efficiency of MTZ by HBCCD–ADA supramolecular assembly was calculated to be 32.74 and 4.76%, respectively. In addition, with the gradual addition of MTZ, the fluorescence intensity of HBCCD–ADA assembly gradually decreased (Figure S3). The efficiency of fluorescence quenching was calculated to be 36.3%, which may originate from π-stacking between MTZ and HBCCD, and then result in the photo-induced electron transfer process. Moreover, the TEM image in Figure S4a indicated that the MTZ@HBCCD–ADA assembly still exists in the spherical morphology with a diameter of 260 nm, and the DLS results revealed a narrow size distribution of ca. 380 nm accordingly (Figure S4b). These results demonstrated that the anticancer drug MTZ was loaded on the HBCCD–ADA supramolecular assembly efficiently. Subsequently, the releasing behavior of MTZ from HBCCD–ADA supramolecular assembly was investigated in physiological environments (0.01 M PBS, 37 °C) at pH 5.7 (the endosomal pH of a cancer cell) and pH 7.2 (physiological pH). As shown in Figure S5, the MTZ@HBCCD–ADA displayed a controlled and sustained release of MTZ, and the release efficiency of MTZ from MTZ@HBCCD–ADA was much faster at pH 5.7. The low cumulative release of MTZ probably because the release process is a dynamic equilibrium process, which results in the drug not being released completely. This pH responsive releasing behavior could definitely improve the cytotoxic efficiency to cancer cells and reduce the toxicity to normal tissues. It is reported that MTZ hydrochloride is hydrophilic because of the two positively charged nitrogen atoms, the acidity of protonated MTZ is reduced in the hydrophobic environment of assembly and pack more closely, which would prolong the circulation time and favor its stability and biocompatibility of the drug under the cellular environment.35 In addition, free MTZ is too hydrophilic to penetrate into the lipid bilayer of the cell membrane, while the assembly can carry drug into cells through endocytosis. These advantages jointly demonstrate that the assembly could be used as a safe and promising candidate for drug delivery systems.

Figure 3.

Figure 3

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UV/vis absorption of HBCCD–ADA and MTZ@HBCCD–ADA, respectively. Inset: Color change of unloaded HBCCD–ADA assembly (left) compared with MTZ-loaded HBCCD–ADA assembly (right).

Next, cytotoxicity experiments were performed to evaluate the anticancer activity of MTZ@HBCCD–ADA supramolecular assembly in vitro. As shown in Figure S6, the half-maximal inhibitory concentrations (IC50) of MTZ and MTZ@HBCCD–ADA toward HCT-116 human colon cancer cells were measured as 2.2236 and 2.04 μM by the MTT assay, which indicated the enhanced anticancer activity of MTZ@HBCCD–ADA assembly. In addition, after a 24 h incubation, the MTZ@HBCCD–ADA assembly exhibited satisfactory malignant cell inhibition effect toward the HCT-116 cell line with a relative cellular viability of 43.7% (Figure S7a), which was slightly lower than that of commercial anticancer drug MTZ (49.1%); this might be attributed to the assembly that was preferably internalized in HCT-116 cells through the endocytosis. The side effects of MTZ@HBCCD–ADA assembly were also tested by using NIH3T3 mouse embryonic fibroblast cells. As shown in Figure S7b, MTZ@HBCCD–ADA assembly gave a relative cellular viability as 56.5%, which was slightly higher than that with free MTZ. Moreover, it is also noteworthy that HBCCD–ADA assembly was nontoxic to all the examined cell lines because of its good biocompatibility. These results indicated that the supramolecular assembly could facilitate the selective and accumulation of MTZ in cancer cells, which holds great promise to present a safe and effective tool for cancer therapy. Similar results were also observed at 48 h of incubation (Figure S8). Afterward, we investigated the intracellular fluorescence imaging ability of the conjugated supramolecular assembly. As shown in Figure 4, HCT-116 cells gave a green fluorescence in cytoplasm after a 24 h incubation with HBCCD–ADA fluorescence supramolecular assembly. Besides, late endosomes and lysosomes were stained with Lysotracker Red for colocalizing assembly.37 As shown in Figure S9, high colocalization was observed for HBCCD–ADA assembly, suggesting that the assembly was successfully internalized into cells, which might have a potential application value in cancer diagnosis.

Figure 4.

Figure 4

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Confocal fluorescence images of HCT-116 cells incubated with HBCCD–ADA for 24 h. The nucleus was stained by 4′,6-diamidino-2-phenylindole dihydrochloride hydrate (DAPI).

Moreover, the real-time cellular uptake of assembly was evaluated by confocal laser scanning microscopy during the incubation from 2 to 6 h. As shown in Figure S10, green fluorescence can be observed at 2 h, and the green fluorescent intensities increased with time, indicating that the assembly has entered the cells. This phenomenon validated that the assembly could act as a fluorescence probe to monitor the distribution, accumulation, and real-time drug release. After verifying the internalization of HBCCD–ADA assembly, we continued to investigate the pathway of cellular internalization with confocal laser scanning microscopy. First, we examined the cellular uptake of assembly at 4 and 37 °C (Figure S11). At the lower temperature, the cellular uptake ability weakened, indicating an energy-dependent process in the cellular internalization. In order to further understand which of the energy-dependent processes involved in the internalization of assembly, we performed the cellular uptake treated with two types of biochemical inhibitors, that is, NaN3/2-deoxyglucose (NaN3/DOG) was utilized to inhibit the energy-dependent pathway and sucrose was used to perturb clathrin-mediated endocytosis.37,38 As shown in Figure S11, compared with control, the cells treated with inhibitors exhibited dramatic decrease in the cellular uptake of assembly. Thus, we deduced that the internalization of assembly might be via multiple endocytic pathways.

3. Conclusions

In conclusion, we successfully constructed a fluorescent supramolecular assembly composed of doubly positively charged ADA with β-CD modified HBCCD as a multifunctional supramolecular platform for controlled DNA condensation, cell imaging, and drug delivery via host–guest inclusion complexation of ADA with β-CD and further π-stacking of coronene with anticancer drug MTZ. After the ester group in ADA was hydrolyzed to a negative carboxyl, the positively charged quaternary ammine strand converted into a zwitterion structure, which realized the controlled binding and release of pDNA. Moreover, cytotoxicity experiments indicated that the assembly displayed a slightly higher inhibition effect and a lower toxicity than free drug. Besides, because of the coronene intrinsic fluorescence properties, it has potential application as cell imaging agent. Considering the facile synergetic interaction in the design of macrocycle-based assembly, we envision that the constructed multifunctional assembly can be further functionalized easily by chemical modification of other guest molecules, thus providing us a facile modular approach for supramolecular cancer therapy.

4. Experimental Section

4.1. General Methods

All chemicals were of reagent grade unless noted. HBCCD was synthesized according to our reported method,25 and ADA was synthesized according to the reported method.30 NIH3T3 mouse embryonic fibroblast cell line and HCT-116 human colon cancer cell line were obtained from China Infrastructure of Cell Line Resource. The absorbance spectra were recorded in a conventional quartz cell (light path 10 mm) by using a UV/vis spectrophotometer (U-2900, Hitachi). Steady-state fluorescence emission spectra were recorded in a conventional quartz cell (10 × 10 × 45 mm) on a fluorescence spectrometer (Fluorolog-MAX 4, Horiba). TEM images were acquired by an FEI Tecnai G2 F20 transmission electron microscope. The samples were prepared by placing a drop of solution onto a carbon-coated copper grid and air-dried. The SEM images were recorded on a JSM-6700F scanning electronic microscope. The DLS and zeta potentials were recorded on Malvern Zetasizer Nano ZS90 (Malvern Instruments Ltd., Worcestershire, UK). Gel electrophoresis experiments were measured on a 1% (w/v) agarose gel at 60 V for 45 min and photographed using a UV transilluminator and a WD-9415B gel documentation system (Beijing Liuyi Instrument Factory, P. R. China). Confocal laser scanning microscopy was performed on a fluorescence inverted microscope (Zeiss LSM 800).

4.2. Preparation of HBCCD–ADA Supramolecular Assemblies

ADA was dissolved in 10 mL of deionized water to prepare a stock solution with the concentration of 2 mM, and HBCCD was dissolved in 5 mL of dimethyl sulfoxide to obtain a stock solution with the [CD] concentration of 4 mM. The stock solution ADA was diluted 20 folds to 0.1 mM. Upon sonication, the HBCCD solution (0.5 mL) was slowly added into the diluted ADA solution (19.5 mL) over 5 min. The resulting HBCCD–ADA solution was stored at 4 °C.

4.3. Agarose Gel Electrophoresis Experiments

The controlled condensation ability of assembly to pDNA was measured by evaluating the electrophoretic mobility on the agarose gel at different N/P ratios. The gel electrophoresis experiments were performed in TAE (0.04 M Tris, 0.02 M acetic acid, and 2.0 mM EDTA) buffer at 25 °C. After samples loading and electrophoresis process, pDNA bands were stained in Gen Green solution and were photographed using UV light at 302 nm.

4.4. MTZ Loading on the HBCCD–ADA Supramolecular Assembly

The solution of MTZ (0.65 mg) in 0.5 mL of deionized water was dropwise added to 10 mL of above prepared aqueous solution of HBCCD–ADA assembly, and the obtained mixture was stirred overnight at room temperature in dark for 12 h. The resulting solution was dialyzed against deionized water for 2 h, and the deionized water was replaced every 0.5 h. Then, the mixture was freeze-dried. The drug loading efficiency and encapsulation of MTZ onto HBCCD–ADA were estimated by the following equations

4.4.
4.4.

4.5. MTZ Releasing in Vitro

The release of MTZ from HBCCD–ADA in vitro was investigated using the dialysis method in PBS buffer (pH 5.7 and 7.2, I = 0.01 M) at 37 °C. The solution of 2 mL MTZ@HBCCD–ADA was placed into a dialysis membrane with a molecular weight cut off 500 and dialyzed against 30 mL PBS buffer with stirring. At certain intervals, 2 mL of dialysate was taken out and an equal volume of PBS buffer was added. The amount of released MTZ was analyzed by the absorbance of MTZ at 609 nm. This experiment was performed in three groups, and the data were presented as the mean ± standard deviation.

4.6. Cytotoxicity Experiments

The NIH3T3 mouse embryonic fibroblast cell line was cultured in Dulbecco’s modified Eagle’s medium, the HCT-116 human colon cancer cell line was cultured in the McCoy’s 5A medium, and both of the medium were supplemented with 10% fetal bovine serum. NIH3T3 cells and HCT-116 cells were seeded in 96-well plates (5 × 104 cells/mL, 100 μL per well) for 24 h; then, the cells were incubated with MTZ, MTZ@HBCCD–ADA, HBCCD–ADA, HBCCD, and ADA for 24 and 48 h, respectively. The relative cellular viability of the cells was determined by the MTT assay.

Furthermore, the IC50 values of MTZ and MTZ@HBCCD–ADA toward HCT-116 cell line were evaluated by MTT assay. HCT-116 cells were seeded in 96-well plates (5 × 104 cells/mL, 100 μL per well) for 24 h, and then the cells were incubated with MTZ and MTZ@HBCCD–ADA at different concentrations for 48 h. The anticancer activities were determined with MTT assay. All the data were presented as the mean ± standard deviation.

4.7. Fluorescent Confocal Imaging

HCT-116 cells were cultured in confocal dish (5 × 104 cells/mL, 1.5 mL per well) for 24 h. The cells incubated with HBCCD–ADA for 24 h and washed with PBS buffer for three times. Then, the cells were fixed with 4% paraformaldehyde for 15 min. After that, the cell nuclei were stained with DAPI (1 μg/mL) for 5 min and observed by a confocal laser scanning microscope. In order to evaluate the location of assembly in cells, late endosomes and lysosomes were stained with Lysotracker Red at 200 nM for 30 min after incubation with cells.

4.8. Cellular Uptake of the HBCCD–ADA Supramolecular Assembly

HCT-116 cells were cultured in confocal dish (5 × 104 cells/mL, 1.5 mL per well) for 24 h. The cells incubated with HBCCD–ADA for 2, 4, and 6 h. Then, the cells were washed with PBS buffer for three times and fixed with 4% paraformaldehyde for 15 min. After that, the cell nuclei were stained with DAPI (1 μg/mL) for 5 min and observed by a confocal laser scanning microscope.

4.9. Inhibition Studies of Endocytosis

HCT-116 cells were cultured in confocal dish (5 × 104 cells/mL, 1.5 mL per well) for 24 h. The cells were separately incubated with 0.1% NaN3/50 mM 2-deoxy-glucose for 1 h and 225 mM sucrose for 30 min or 4 °C for 1 h. Then, they are washed with PBS buffer for three times and further incubated with HBCCD–ADA assembly for 2 h at 37 °C. The cells were washed with PBS buffer for three times and fixed with 4% paraformaldehyde for 15 min. After that, the cell nuclei were stained with DAPI (1 μg/mL) for 5 min and observed by a confocal laser scanning microscope.

Acknowledgments

We thank the Inner Mongolia Autonomous Region Natural Science Fund Project (2017BS0206), the Program for Young Talents of Science and Technology in Universities of Inner Mongolia Autonomous Region (NJYT-19-B26), the Programs of Higher-level Talents of Inner Mongolia Agricultural University (NDGCC2016-21), and NNSFC (51602162) for financial support.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.9b01436.

  • Process of pDNA binding and release; construction route of MTZ@HBCCD–ADA assembly; TEM and DLS results of pDNA@HBCCD–ADA assembly at N/P ratio of 20; UV/vis absorption of MTZ; fluorescence spectral changes of HBCCD–ADA assembly; TEM and DLS results of MTZ@HBCCD–ADA assembly; release profiles of MTZ from MTZ@HBCCD–ADA assembly in PBS at pH 5.7 and 7.2; curves of HCT-116 cell inhibitory rate at different concentrations of MTZ and MTZ@HBCCD–ADA assembly; relative cellular viability in 24 and 48 h; confocal fluorescence images of cellular internalization; real-time cellular uptake; and inhibition studies of endocytosis (PDF)

Author Contributions

∥ Y.-H.Z. and J.Y. are equal contributors.

The authors declare no competing financial interest.

Supplementary Material

ao9b01436_si_001.pdf (1.3MB, pdf)

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