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Article Cite This: Langmuir 2019, 35, 8045−8051

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Ultrasound and Redox-Triggered Morphology Transitions of Supramolecular Self-assemblies with pH Responsiveness for TripleControlled Release Hao Yao,†,∥ Tianfeng Yang,‡,∥ Jia He,†,∥ Guowen Du,† Xin Song,† Yanmin Zhang,*,‡ and Wei Tian*,†,§

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†

MOE Key Laboratory of Material Physics and Chemistry under Extraordinary Conditions, Shanxi Key Laboratory of Macromolecular Science and Technology, School of Science, Northwestern Polytechnical University, Xi’an 710072, P. R. China ‡ School of Pharmacy, Health Science Center, Xi’an Jiaotong University, No. 76, Yanta West Street, #54, Xi’an, Shaanxi Province 710061, P. R. China § Xi’an Institute for Biomedical Materials & Engineering, Northwestern Polytechnical University, Xi’an 710072, P. R. China S Supporting Information *

ABSTRACT: The realization of multistage-controlled drug delivery at the cell level through the morphology transitions of supramolecular self-assemblies (SSA) is still a challenge. Herein, successive morphology transitions of SSA with pH responsiveness were successfully achieved through the subsequent action of ultrasound and redox stimuli. Specifically, we first prepared noncovalently PEGylated spherical self-assemblies formed by host−guestconjugated amphiphilic β-CD dimers. The functionalized PEG could be associated/disassociated onto the spherical self-assemblies by adjusting pH values of solutions. They could reassemble into branched self-assemblies induced by ultrasonication. Such branched self-assemblies could be further dissociated into second spherical self-assemblies under a redox stimulus. This morphology transition process was used to conduct triple-controlled targeted drug delivery and release in cancer cells. This work will be beneficial for the design of smart SSA for controlled release in vivo.

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first formed initial spherical self-assemblies (ISSA), and doxorubicin (DOX) was synchronously encapsulated into these self-assemblies (Scheme 1a,b). Benzimidazole and lactobionic acid bifunctional polyethylene glycol (BM− PEG−LA) were then postgrafted onto the surfaces of ISSA via the β-CD/BM host−guest interaction, resulting in the formation of larger spherical self-assemblies (LSSAs) (Scheme 1b,c). When DOX-loaded LSSAs enter into blood circulation (Scheme 1c,d), the BM−PEG−LA segments could promote the protection of DOX-loaded LSSAs, target delivery to the tumors (Scheme 1d,e), and dissociate from the LSSA surfaces in an acidic environment; meanwhile, the LSSA size showed a corresponding decrease (Scheme 1e,f). With the subsequent ultrasonication, the LSSA morphology was transformed into branched aggregates (BA) (Scheme 1f,g). BA could be further dissociated under H2O2 and finally formed the second spherical self-assemblies (SSSA) (Scheme 1g,h). During the above morphology transitions, a triple-controlled release of DOX from different DOX-loaded SSA in cancer cells was successfully conducted.

INTRODUCTION Supramolecular self-assemblies (SSA), formed through noncovalent interactions, have gained growing interest recently owing to their unique advantages in chemistry, biomedicine, and so on.1−10 In particular, the dynamic and reversible noncovalent interactions such as host−guest interaction provide opportunities for creating stimuli-responsive SSA that can fine-tune the morphology of the assemblies by external stimuli (pH, photo, temperature, and ultrasound).11−16 The ability to transform the morphology of the self-assemblies may lead to new biomedical opportunities,17−24 such as drug release, and is important for realizing the functions of the self-assemblies in vivo.25−32 In our previous work,33 a switchable drug release system was constructed on the basis of light-induced morphology transitions of SSA. Nevertheless, the realization of triple-controlled drug delivery at the cell level through morphology transitions of SSA is still a challenge that represents an essential step for the achievement of controlled release in vivo by SSA. In this study, by utilizing ultrasound/redox-triggered morphology transitions of SSA with pH responsiveness, a triple-controlled drug release system in cancer cells was achieved. Such SSA were obtained on the basis of a host− guest-conjugated amphiphilic β-cyclodextrin dimer containing a single ferrocene moiety (Fc-CD2) (Scheme 1). These dimers © 2019 American Chemical Society

Received: April 18, 2019 Revised: May 23, 2019 Published: May 29, 2019 8045

DOI: 10.1021/acs.langmuir.9b01153 Langmuir 2019, 35, 8045−8051

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Scheme 1. Possible Mechanism of the Triple-Controlled Drug Release in Cancer Cells by Utilizing Ultrasound/RedoxTriggered Morphology Transitions of SSA with pH Responsivenessa

a

(a) Fc-CD2 dimer; (b) DOX-loaded initial spherical self-assemblies (ISSAs); (c) DOX-loaded larger spherical self-assemblies (LSSAs) formed through the host−guest interaction; (d−f) BM−PEG−LA-protected self-assemblies were delivered in blood circulation and targeted to the tumors, then partially dissociated in an acidic environment; (g, h) DOX molecules were released from DOX-loaded self-assemblies to tumor cells utilizing ultrasound/redox-triggered morphology transitions.

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solution (10 mg/mL) was added into a dialysis bag (MWCO 3500) and dialyzed against the PBS solution for drug releasing at different conditions. Four milliliters of PBS medium was taken out and replaced by 4 mL of fresh PBS each time. The amount of DOX in the solution was determined by UV−vis spectrometry at 485 nm. Cell Culture. HepG2 and A549 cell were, respectively, cultured in DMEM and RPMI 1640 medium; both were grown in a humidified atmosphere with 5% CO2 at 37 °C. Cell Proliferation Assay. MTT assay was performed to test the biological compatibility of AB2 and nanoparticle targeting, ultrasonic responsiveness, and oxidative responsiveness of LA-AB2/DOX on cell viability. Cells (2 × 104) were plated to each well of the 96-well plate. The cells were treated with different nanoparticle complexes with increased concentrations for 72 h. The inhibition ratio (I %) was calculated by recording the absorbance at 490 nm. Cell Uptake Assay. The cells mentioned above were then incubated with AB2/DOX or LA-AB2/DOX (DOX concentration, 5 μg/mL) for 12 h, followed by washing with PBS and fixing with 4% (w/v) paraformaldehyde aqueous solution for 10 min at predetermined intervals. Afterward, the plates were stained with propidium iodide (DAPI) for 10 min at 37 °C. The fixed cell monolayer was finally observed by fluorescence microscopy. Image-Pro plus 6.0 software (Media Cybernetics, Inc., Rockville, MD) was used to analyze the fluorescence colocalization.

MATERIALS AND METHODS

Chemicals and Materials. NH2-PEG1000-N3, 12-O-tetradecanoylphorbol 13-acetate (PMA), 2-(4-amidinophenyl)-6-indolecarbamidine dihydrochloride (DAPI), and Dulbecco’s minimal essential medium (DMEM) were purchased from Sigma-Aldrich. HepG2 (TCHu72) and A549 (TCHu150) cancer cell lines were purchased from the Shanghai Institute of Cell Biology (Shanghai, China). The other reagents were purchased from Adamas-β Chemical Reagent Co., Ltd. (China). Methods. Fourier Transform Infrared (FTIR) spectra were recorded on a Thermo-Scientific Nicolet iS10 IR spectrometer. 1H NMR, 13C NMR, and two-dimensional (2D) nuclear overhauser enhancement spectroscopy (NOESY) spectra were recorded on a Bruker Avance 300 or Avance III 400 spectrometer operating in CDCl3, DMSO-d6, or D2O. Transmission electron microscopy (TEM) was operated by using a Hitachi H-7650 electron microscope at 70 kV. With dynamic light scattering (DLS), the sizes and polydispersity of the aggregates at different temperatures were determined by using the Malvern Zetasizer Nano ZS instrument. Preparation of drug-loaded supramolecular assemblies: For preparing DOX-loaded self-assemblies, 20 mg of Fc-CD2 was dissolved in 1.5 mL of DMF/H2O (1:2); upon stirring, 0.5 mL of DMF containing 2 mg of DOX was dropwise added within 3 min. The resulting solution was stirred for another 3 h, followed by adding 18 mL of deionized (DI) water via a syringe within 2 h. Free DOX was then removed via dialysis (MWCO 3500) against DI water for 48 h. The DOX loading content in SSA is 6.12%. The encapsulation efficiency is 48.7%. drug loading content (%) =

Wdrug in nanocapsules

encapsulation efficiency (%) =

Wnanocapsules

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RESULTS AND DISCUSSION The Fc-(CD)2 dimer was synthesized through click chemistry between Fc molecule modified with two azide groups (Fc(N3)2) and mono-6-deoxy-6-alkyne β-CD (β-CD-CCH) (Scheme S1). BM−PEG−LA was synthesized through the click chemistry of N3−PEG−NH2 with alkyne-terminal BM and subsequent amidation with LA-bearing carboxyl groups (Schemes S2 and S3). The detailed characterization data, including FTIR, 1H NMR, 13C NMR, ESI-MS, and MALDITOF-MS results, are shown in the Supporting Information

× 100

Wdrug in nanocapsules Wdrug used in encapsulation

× 100

The drug release of the self-assemblies was conducted as follows: Two milliliters of DOX-loaded self-assembled phosphate buffer (PBS) 8046

DOI: 10.1021/acs.langmuir.9b01153 Langmuir 2019, 35, 8045−8051

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Figure 1. TEM and DLS results for the morphology transitions of SSA: (A) ISSA at pH 7.4; (B) LSSA at pH 7.4; (C) LSSA at pH 6.0; (D) LSSA at pH 6.0 with ultrasonication for 10 min; (E) LSSA at pH 6.0 with ultrasonication for 10 min followed by the H2O2 treatment; (F) corresponding DLS results.

(Figures S1−S10), jointly confirming the well-defined structure of Fc-(CD)2 and BM−PEG−LA. The self-assembly morphologies of Fc-(CD)2 dimer under different conditions were then confirmed through TEM, DLS, 2D NOESY, and 1H NMR. The as-prepared Fc-(CD)2 dimers were first dissolved in a pH 7.4 buffer solution to form ISSA. TEM revealed that these ISSAs have the average diameter (Dav) of 40 nm (Figure 1A), which was close to the obtained hydrodynamic diameter (Dh) of 60 nm determined by DLS (Figure 1F). Then, LSSAs were prepared by adding BM− PEG−LA (the molar ratio of BM and β-CD is 1:1) into these ISSA solutions. Both TEM and DLS results suggested the formation of LSSAs with the Dav of 50 nm and Dh of 100 nm, which were larger than the corresponding ISSA values (Figure 1B). Furthermore, the 2D NOESY spectra of LSSA displayed that the proton signals belonging to BM (H protons of benzene) were correlated with that of inner 3-H and 5-H protons of β-CD (Figure S11A), indicating the formation of the β-CD/BM host−guest complex.34,35 These results confirmed the successful preparation of LSSAs. Then, the pH-responsive reversible association/disassociation of BM− PEG−LA segments from the surfaces of LSSAs was studied. TEM indicated that the Dav of LSSAs decreased to 38 nm at pH 6.0 (Figure 1C) and then increased to 50 nm at pH 7.4 (Figure S12A). Similarly, DLS showed that the average diameter of LSSAs decreased to 43 nm at pH 6.0 (Figure 1F) and returned to 105 nm at pH 7.4 (Figure S12B). The results of 1H NMR measurements in D2O (Figure 2) of LSSAs showed that the BM signals shifted to a lower field when pH changed from 7.4 to 6.0 but shifted back to the initial state when pH changed back to 7.4. In addition, the 2D NOESY spectra of LSSAs showed no correlation peak between the signals of BM and the inner 3-H and 5-H protons of β-CD for pH 6.0 (Figure S11B), whereas this peak reappeared when pH changed to 7.4 (Figure S11C). These results further indicated that the pH-responsive BM/β-CD host−guest complex induced the reversible association/disassociation between BM−PEG−LA and LSSA. The ultrasound and redox-triggered morphology transitions of LSSAs without BM−PEG−LA segments in a pH 6.0 buffer

Figure 2. pH-responsive reversible association/disassociation of LSSA confirmed by 1H NMR (A) at pH 7.4; (B) when pH was changed to 6.0; and (C) when pH was changed back to 7.4.

solution were further investigated. After ultrasonic treatment for 10 min in pH 6.0 buffer solutions, the LSSAs transformed into BAs, as shown in Figure 1D. DLS revealed that the corresponding Dz value increased to 334 nm (Figure 1F). Furthermore, upon the addition of H2O2, these BAs were dissociated into SSSAs with Dav of 25 nm (Figure 1E), accompanied by a decrease in the Dz value of 60 nm. Moreover, 2D NOESY spectra showed no correlation peak between the signals of Fc and the inner 3-H and 5-H protons of β-CD in the initial state (Figure 3A), whereas a clear correlation peak appeared after ultrasonication (Figure 3B) and then disappeared after the H2O2 treatment (Figure 3C) and reappeared again after the glutathione (GSH) treatment 8047

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Figure 3. Ultrasound and redox-responsive reversible association and disassociation of LSSA confirmed by 2D NOESY NMR spectra: (A) initial state; (B) after ultrasound treatment; (C) then by H2O2 treatment; and (D) finally by GSH treatment.

(Figure 3D), which confirmed the reversibility of β-CD/Fc host−guest interaction. These results further confirmed that the morphology transitions from LSSAs without BM−PEG−LA segments to BAs and finally to SSSAs in aqueous solutions were indeed carried out by sequentially applying ultrasonication and H2O2. The ultrasound stimulus enhanced the host−guest interaction between Fc and β-CD, leading to the formation of BA. Meanwhile, the oxidation of Fc by H2O2 reduced the host− guest interaction, resulting in the disassociation of BAs, and then SSSAs were formed due to the hydrophobic interactions.36 In addition, the pure Fc-CD2 dimer without BM− PEG−LA could also realize the ultrasound and redox dualtriggered sequential morphology transitions, as confirmed through TEM and DLS (Figure S13). This result indicated that the reversible association and disassociation process of BM−PEG−LA segments from the surfaces of LSSAs has no evident effect on their ultrasound and redox-triggered morphology transition behaviors. The ultrasound and redox-triggered morphology transitions of SSA with pH responsiveness described above were considered for the loading and release of drugs. DOX was loaded into LSSAs for the release experiment. The morphology-controlled three-stage release process was confirmed by the DOX release curves. Figure 4 represented the cumulative release curves of DOX from LSSAs under different stimuli, including pH 7.4 without stimulus (curve a), pH 6.0 without stimulus (curve b), pH 6.0 with the ultrasonication stimulus (curve c), and pH 6.0 with the ultrasonication and H2O2 stimuli (curve d). By comparison, when pH is at 7.4, the drug release rate was relatively slow and only about 30% of DOX was released after 20 h (curve a). At pH 6.0, the release rate of DOX evidently increased (curves b, c, and d, stage I) and the cumulative release amount correspondingly reached 40% after 12 h without other stimuli (curve b). This may be

Figure 4. Cumulative release curves of DOX-loaded SSA. (a) pH at 7.4, (b) pH at 6.0, (c) pH at 6.0 with ultrasonication for 10 min, and (d) pH at 6.0 with ultrasonication for 10 min followed by treatment with H2O2.

attributed to the disassociation of BM−PEG−LA segments from the surfaces of LSSAs in an acidic environment. The curves c and d show an enhanced release after ultrasonic stimulation. Upon ultrasonic stimulation, LSSAs were dissociated and BAs were formed, thereby releasing DOX more rapidly (stage II). Furthermore, curve d shows increased DOX release after the H2O2 treatment compared with that of curve c. BA was dissociated into SSSA after H2O2 oxidation, enhancing the release of DOX (stage III). These results indicated that pH, ultrasonication, and redox triple-controlled three-stage drug release were successfully conducted on the basis of the sequential morphology transitions of SSA from large spherical self-assemblies to small spherical self-assemblies, followed by branched aggregates, and finally second spherical self-assemblies. Herein, MTT assay was first utilized to evaluate the biocompatibility of drug-free self-assembled LSSAs toward 8048

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caused a significant loss of cell viability. The cell viability gradually decreased with increased sample concentrations, attesting to their dose-dependent action. By comparing the viability of HepG2 (Figure 6A,B) and A549 (Figure 6C,D) cells after treatment with DOX-loaded ISSAs and DOX-loaded LSSAs for 72 h, it was concluded that there was no evident viability difference between the HepG2 and A549 cell lines processed by DOX-loaded ISSAs. By contrast, clear differences were observed in the samples with DOX-loaded LSSA. Specifically, the viability of the HepG2 cells after the treatment with DOX-loaded LSSA was much lower than that with DOXloaded ISSA treatment. Therefore, DOX-loaded LSSA could exert a specific therapeutic effect to liver cells via receptormediated targeting, playing a critical role in cancer cells targeting drug delivery with overexpressed ASGPR. The ultrasound and redox-controlled drug release behavior of DOX from DOX-loaded ISSA and LSSA at the cell level was further evaluated. For this purpose, the HepG2 (Figure 6A) and A549 (Figure 6C) cell lines were treated with DOX-loaded ISSA and LSSA with and without ultrasound for 5 min. In another experiment, the cell lines were treated with and without phorbol-12-myristate-13-acetate (PMA, a kind of phorbol ester as a tumor promoter, could accelerate the metabolism and caused the enrichment of H2O2 in cancer cells.38) for 12 h (Figure 6B,D). Specifically, the cell viabilities decreased clearly when ultrasonic treatment was applied to DOX-loaded ISSA and DOX-loaded LSSA both in the HepG2 (Figure 6A) and A549 (Figure 6C) cell lines. It could be explained that the ultrasound-triggered morphology transitions from large spherical self-assemblies to branched assemblies could facilitate the release of DOX. Similarly, DOX-loaded ISSA and DOX-loaded LSSA preprocessed with PMA resulted in the decrease of cell viabilities against the HepG2 (Figure 6B) and A549 (Figure 6D) cell lines, which was known to give rise to a greater cell killing ability than that obtained without the pretreatment. This phenomenon may be due to the redoxtriggered morphology transitions from branched self-assemblies to second spherical self-assemblies. On the other hand, in the case of either ultrasound or redox treatment, the viability of HepG2 cells after treatment with DOX-loaded LSSA was much lower than that with DOX-loaded ISSA treatment, indicating that the introduction of BM−PEG−LA played a critical role in cancer cells targeting drug delivery. Fluorescence microscope imaging was further utilized to confirm the intracellular uptake of DOX-loaded ISSA and DOX-loaded LSSA (Figure 7A,B). The cells treated with DOX-loaded ISSA indicated DAPI blue fluorescence in their nuclei and DOX red fluorescence in their cytosol after incubation for 12 h, and the overlapping area between red and blue fluorescence was negligible. By contrast, the overlapping area was very bright, and much more red dots emerged when the HepG2 cell was treated with DOX-loaded LSSA, confirming that DOX-loaded LSSA had more cellular uptake in the HepG2 cells. For comparison, A549 cells with low ASGPR expression showed weaker red fluorescence signals treated with DOX-loaded ISSA and LSSA. Moreover, after the ultrasound and PMA treatments, the overlapping area became much brighter, implying that the ultrasound and redox dual stimuli enhanced the cellular uptake. The data for the fluorescence colocalization ratios between the red and blue fluorescence were obtained by Image-Pro plus software in Figure 7C. The colocalization ratios of the A549 cells and HepG2 cells treated with DOX-loaded ISSA were 25.3 and

A549 and HepG2 cells. The MTT assay was performed after incubation in A549 and HepG2 cells for 72 h with different concentrations of LSSAs (Figure 5). The results of LSSAs

Figure 5. In vitro cytotoxicity of plain LSSA against A549 or HepG2 cell lines.

show less cytotoxicity against the above cell lines. Cell viability reached 80% even when LSSA concentration was 450 μg/mL, confirming the good biocompatibility of the LSSAs used for drug carriers. Furthermore, the targeting and ultrasound/redox-responsiveness of the DOX-loaded LSSAs was then conducted by MTT assay. LA as a targeted molecule could effectively target ASGPR.37 Herein, HepG2 cells with overexpressed asialoglycoprotein receptor (ASGPR) and A549 cells as the negative control were used as the model cell lines. As observed from Figure 6A,C, the DOX-loaded ISSA and DOX-loaded LSSA

Figure 6. MTT studies of DOX-loaded self-assemblies against A549 or HepG2 cancer cell lines: (A) DOX-loaded ISSA with and without ultrasonication stimulus, DOX-loaded LSSA with and without ultrasonication stimulus against the HepG2 cancer cell line; (B) DOX-loaded ISSA with and without redox stimulus, DOX-loaded LSSA with and without redox stimulus against the HepG2 cancer cell line; (C) DOX-loaded ISSA with and without ultrasonication stimulus, DOX-loaded LSSA with and without ultrasonication stimulus against the A549 cancer cell line; (D) DOX-loaded ISSA with and without redox stimulus, DOX-loaded LSSA with and without redox stimulus against the A549 cancer cell line. 8049

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Figure 7. (A) Fluorescence microscopy studies of cellular uptake of DOX-loaded ISSA and DOX-loaded LSSA with and without ultrasonication/ redox dual stimulus against the HepG2 cancer cell line at a concentration of 5 μg/mL; (B) fluorescence microscopy studies of cellular uptake of DOX-loaded ISSA and DOX-loaded LSSA with and without ultrasonication/redox dual stimulus against the A549 cancer cell line with a concentration of 5 μg/mL; (C) quantification of fluorescence microscopy colocalization ratios of DOX-loaded ISSA and DOX-loaded LSSA with and without ultrasonic/redox dual stimulus against the A549 and HepG2 cancer cell lines.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21674086 and 81773772), Natural Science Basic Research Plan in Shaanxi Province of China (2018JZ2003), and the Fundamental Research Funds for the Central Universities (3102019PY003).

28.4%, respectively. However, in the case of DOX-loaded LSSA, the colocalization ratios of A549 cells and HepG2 cells showed a remarkable increase, with obtained values of 41.3 and 86.1%, respectively. Moreover, the application of ultrasound and redox stimuli led to a further increase in the colocalization ratio of the HepG2 cells from 86.1 to 94.8%. These results confirmed that the cooperative action of the targeted molecule LA, ultrasonication, and redox-triggered morphology transitions enhanced the intracellular uptake of the DOX-loaded supramolecular assemblies. In summary, we have successfully prepared noncovalently PEGylated spherical self-assemblies formed by AB2-type host− guest-conjugated amphiphilic β-CD dimers for the first time. The size of spherical self-assemblies decreased under acidic conditions. They could reassemble into branched selfassemblies induced by ultrasonication. Such branched selfassemblies could be further dissociated into second spherical self-assemblies under a redox stimulus. The above successive self-assembly morphology transitions could be utilized to conduct a three-stage DOX release in cancer cells. This work will be beneficial for the design of smart SSA for controlled release in vivo.

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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.langmuir.9b01153. Materials and methods synthesis; characterization results of Fc-CD2 and BM−PEG−LA; partial characterization about self-assembly of Fc-CD2 dimers under different conditions and cell biology experiments of SSA solutions (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (Y.Z.). *E-mail: [email protected] (W.T.). ORCID

Wei Tian: 0000-0002-2159-4181 Author Contributions ∥

H.Y., T.Y., and J.H. contributed equally.

Notes

The authors declare no competing financial interest. 8050

DOI: 10.1021/acs.langmuir.9b01153 Langmuir 2019, 35, 8045−8051

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DOI: 10.1021/acs.langmuir.9b01153 Langmuir 2019, 35, 8045−8051