Biological Macrocycle: Supramolecular Hydrophobic Guest Transport

Article Cite This: Langmuir 2019, 35, 7824−7829

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Biological Macrocycle: Supramolecular Hydrophobic Guest Transport System Based on Nanodiscs with Photodynamic Activity Yan Ge,† Xin Shen,† Hongqian Cao,‡,∥ Lin Jin,† Jie Shang,† Yangxin Wang,† Tiezheng Pan,*,† Yang Yang,*,‡ and Zhenhui Qi*,†,§

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†

Sino-German Joint Research Lab for Space Biomaterials and Translational Technology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, Shaanxi 710072, China ‡ CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China § Institute of Biomedical Materials & Engineering (IBME), Northwestern Polytechnical University, Xi’an, Shaanxi 710072, China ∥ Department of Public Health, Shandong University, Jinan, Shandong 250012, China S Supporting Information *

ABSTRACT: A biogenic macrocycle-based guest loading system has been developed by the self-assembly of membrane scaffold protein and phospholipids. The resulting 10 nm level transport system can increase the solubility of hydrophobic photodynamic agent hypocrellin B in aqueous medium and exhibited a cellular internalization capacity with substantial photodynamic activity.

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INTRODUCTION The development of biocompatible and efficient guest-loading complexes is not only of fundamental scientific interest but also exerts significant value for pharmaceutical applications.1 Supramolecular structures involving macrocycles have been an intense area of research because they serve as models for understanding natural molecular recognition motifs2 and the relationship between structures and functions.3 More importantly, they provide precursors for designing functionoriented materials for biomedical applications.4 Many host molecules such as cyclodextrins,5 cucurbit[n]urils,6 pillar[n]arenes,7 calixarenes,8 and their derivatives have been explored in the water phase, which can act as a solubilizing macrocycle and may improve not only the solubility but also the stability of the guest drugs9 because the drugs are encapsulated into the cavity of the host; however, such method is not universally applicable for all drugs, and it is limited by the selective property of host−guest interactions. Therefore, it is of essential practical significance to seek new potential complexing moieties as effective solubilizing agents for poorly watersoluble drugs. In contrast with the vast number of fully organic synthetic macrocyclic carrier systems, the design of proteinbased macrocyclic transport systems is largely lagging, but it is regarded as a promising strategy for biomedical applications.10 Nanodiscs (NDs) are biogenic macrocycles that are composed of phospholipids and encircling amphipathic helical © 2019 American Chemical Society

belt proteins, termed membrane scaffold proteins (MSPs; Scheme 1a).11 The self-assembly of NDs originates from the robust tendency of phospholipids to form bilayers and the enhanced stability of the amphipathic helix structure of the MSP due to the strong interaction with lipid acyl chains. Therefore, unlike most of the self-assembled systems (e.g., liposomes), the particle size of NDs (∼10 nm) is constrained by the coating of MSPs, and they are relatively monodisperse and stable.12 Owing to the biogenicity of MSPs that derive from the human ApoA-I protein component of high-density lipoprotein (HDL) particles, NDs are found to effectively avoid systemic toxicity and autoimmunity.13 Initially, NDs were found to be particularly useful in structural studies of membrane proteins because different insoluble membrane proteins can be simultaneously monomerized, solubilized, and incorporated into the well-defined membrane environment provided by NDs.14 Recently, by specific modifications of functional lipids on the surface, NDs have emerged as new protein-based building blocks in supramolecular polymerization,15 magnetic resonance imaging,16 and light-harvesting devices.17 With all of these seminal studies that have solidly proven that NDs have immeasurable potential in biotechnoReceived: January 13, 2019 Revised: April 24, 2019 Published: May 29, 2019 7824

DOI: 10.1021/acs.langmuir.9b00126 Langmuir 2019, 35, 7824−7829

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first, 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) was dispersed by 20 mM pH 7.4 PBS buffer. Then, HB DMSO solution was added to the DMPC solution. The solution was ultrasonically mixed with 5 mg/mL MSP in a volume ratio of 3:2 until the solution became clear. Finally, the protein, DMPC, and HB mixture was dialyzed against PBS buffer overnight and centrifuged. The supernatant was taken for dynamic light scattering (DLS), transmission electron microscopy (TEM), atomic force microscopy (AFM), and size exclusion chromatography (SEC) characterizations. The results showed that the HB−ND complexes were successfully constructed with a diameter of 11 nm and a height of 3 nm (Figure 1).

Scheme 1. (a) Structural Composition of Biogenic Macrocycle Nanodisc and (b) Schematic Representation of the Loading Process of Hydrophobic Photodynamic Agent Hypocrellin B (HB) into Nanodiscs

logical areas, we wonder whether the lipid bilayer ND macrocycles could be used as drug-transport systems to complex poorly water-soluble drugs to enhance their water solubility and bioactivity. Indeed, as a 10 nm level large biogenic macrocycle that contains bilayer lipids, its guest complexation behavior remains elusive in comparison with those of organic synthetic macrocycles. Among the present anticancer treatments, photodynamic therapy (PDT) possesses obviously outstanding advantages, such as few side effects, low toxicity, and remote controllability, especially avoiding chemoresistance.18 The light-activated photosensitizer can generate reactive oxygen species (ROS), such as singlet oxygen (1O2) or free radicals, which can irreversibly damage the treated tissues; however, most photosensitizer molecules are hydrophobic and can easily aggregate in aqueous media, which poses a great challenge to the development of an optimal formulation and results in a dramatic decrease in quantum yield. In this study, hypocrellin B (HB), a typical hydrophobic photodynamic therapeutic agent, was formulated into NDs without any chemical modification of the loaded guest or the ND itself (Scheme 1b). On account of its advantages in the biological source and topological structures, ND also exhibited good biocompatibility and cell-internalization properties. The resulting stable monodisperse HB−ND complex nanostructure maintained the PDT activity of HB.

Figure 1. (a) Dynamic light scattering, (b) transmission electron microscopy, and (c) atomic force microscopy images of HB−ND.

A UV−vis absorbance spectrum of HB gave rise to a single major peak centered at 470 nm. In comparison, the spectrum of HB−ND was of similar intensity to that of free HB in DMSO, and the HB−ND sample became crystal clear after the assembly process, indicating the solubilization of HB in the aqueous solution (Figure 2a). In addition, excitation (at 470 nm) of free HB in DMSO induced an emission peak centered at 640 nm. HB−ND gave rise to an emission spectrum whose intensity was identical to that of HB in DMSO (Figure 2b). Moreover, the size exclusion chromatography (SEC) characterization of HB−ND monitored at 280 and 370 nm received the same retention time, showing that HB had been integrated into the NDs (Figure 2c,d).

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RESULTS AND DISCUSSION The MSP, recombinant apolipoprotein A-I (apoA-I), was expressed in E. coli and purified according to Sligar’s and our own methods.11,19 SDS-PAGE showed the presence of only one protein band at ∼26 kDa, indicating that apoA-I was successfully purified (Figure S1). In the assembly of the ND, 7825

DOI: 10.1021/acs.langmuir.9b00126 Langmuir 2019, 35, 7824−7829

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Figure 2. (a) UV−vis absorbance spectra of HB−ND. One mg/mL free HB in DMSO (black), HB−ND in PBS (pH 7.4) buffer (red), and empty NDs (blue) in 20 mM PBS (pH 7.4) buffer were scanned from 400 to 750 nm. (b) Fluorescence spectra of free HB in DMSO (black), HB−ND in PBS (pH 7.4) buffer (red), and empty NDs (blue) in 20 mM PBS (pH 7.4) buffer. (c) Size exclusion chromatography (SEC) characterization of HB−ND monitored at λ = 280 nm. (d) SEC characterization of HB−ND monitored at λ = 470 nm.

storage in the refrigerator of the HB-containing NDs, further evaluation of their thermal stability was achieved by differential scanning calorimetry (DSC). Heating curves of the empty ND (blank ND) and the HB−ND complex were recorded at a scan rate of 10 °C/min (Figure 3b). The phase-transition temperature (Tm) of HB−ND appeared at a similar position as that of the empty ND (Tm ≈ 53 °C), demonstrating that the HB loading did not interface the stability of the ND to a large extent. The ROS generation of free HB and HB−ND in vitro were characterized by a liposome-based assay.21 A solution of soybean lecithin/cholesterol liposome in phosphate buffer (pH 7.4) was prepared by the thin-film hydration method. HB and HB−ND under light and dark conditions were added to the liposome solution to initiate the peroxidation of the lecithin, respectively. Methanol was added in the free HB group to dissolve the same concentration of HB as that of the HB−ND group (25 μM). In this process, unsaturated fatty acids were involved as components to produce malonaldehyde (MDA). After incubation at 37 °C for 3 h, the concentration of MDA was determined with thiobarbituric-acid-reactive substances (MDA-2-TBA) by UV at 532 nm to quantify the ROS generation (Figure 4a). This showed that HB and HB−ND under the dark conditions showed limited ROS generation. By contrast, HB and HB−ND with light irradiation exhibited an obvious and similar ROS generation as the incubation time went on. This indicated that HB inside the ND still retained the ability to absorb light and generate ROS (Figure 4b). In addition, cellular ROS generation (Figure S3) and apoptosis (Figure S4) experiments were also conducted, showing that

Upon the formation of HB−ND, the solubility of HB increased to 50.1 μg/mL or 94.8 μM, which was 11.7 times higher than that of the native HB (4.3 μg/mL).20 The reason was that the phospholipid in the center of the NDs offered a hydrophobic environment for HB. In consideration of the fact that the initial HB concentration was 125 μg/mL, the loading efficiency of the ND was 40.1%. According to the consumption of MSP, the overall yield of HB−ND was 65.3%. Compared with liposomes, the smaller size and monodisperse characteristic of HB−ND are beneficial for cell internalization. More importantly, HB−ND was proven to be very stable and to maintain its structural integrity for as long as 3 weeks at 4 °C (Figure 3a and Figure S2). Given the remarkable stability upon

Figure 3. (a) Stability characterization of HB−ND at 4 °C by size exclusion chromatography (SEC). (b) Differential scanning calorimeter (DSC) characterization of blank ND (black), HB−ND (red), and free HB (blue). 7826

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Figure 4. ROS generation of 25 μM free HB and HB−ND under dark and light conditions, respectively. (a) Lipid peroxidation product MDA reacted with thiobarbituric acid to generate the pink product MDA-2-TBA, which can be detected by UV at 532 nm. (b) UV absorption at 532 nm to quantity the MDA production of each group versus the incubation time.

fluorescence signal arising from HB was observed in the cytoplasm after culturing the MCF-7 cells with 1 μM HB− NDs for 2 h. The fluorescence and luminescence signals in Figure 5b appear to be strongly localized at the area of treated cells, thus suggesting a substantial degree of interactions between cells and these particles. The red dots scattered in the cytoplasm and on the membrane indicated that the HB−NDs were effectively internalized; however, free HB under the same conditions showed only poor internalization ability (Figure S6). Also, the 3Dimage (Figure S7) provides additional evidence of the endocytosis of HB−ND according to the distribution of the green and red channels.

HB−ND can generate ROS and practically lead to apoptosis in cells. Compared with other delivery systems, ND had no adverse impact on the pesticide effectiveness of HB. The cell viability assay (CCK-8) was used to assess the antineoplastic efficacy of the HB−NDs (Figure 5a). MCF-7

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SUMMARY AND CONCLUSIONS We have developed a biogenic macrocycle-based system for photodynamic cancer therapy in vitro. Without any chemical modification to the PDT antineoplastic drug HB, the ND acted as the host to significantly improve the solubility of HB in comparison with individual HB. On account of its advantages in biological sources and topological structures, the ND transport system also exhibited good biocompatibility and cellinternalization properties. The resulting HB−ND showed a stable monodisperse structure and maintained the PDT activity of HB, which is promising for cancer theragnostic applications.

Figure 5. (a) MCF-7 cell viability in vitro measured by CCK-8 assay (n = 3) with dependence on HB concentration. (b) CLSM images of MCF-7 cells’ cellular uptake of 1 μM HB−ND after 2 h coculture. The scale bar is 10 μm.

cells were treated with the solutions of HB−NDs containing 0 to 10 μM HB, and the incubation time was 24 h. As minimal changes of cell viability and cell proliferation occurred in the empty ND group, NDs showed great biocompatibility to the cell lines. On the contrary, the viability of cells incubated with HB−NDs decreased with the increasing concentration. However, HB−NDs under the dark condition showed limited antineoplastic efficacy. By contrast, HB−NDs with light irradiation exhibited obvious antineoplastic efficacy with an IC50 value of 5 μM. The antineoplastic efficacy of HB−ND under light is comparable to that of free HB (Figure S5). These results demonstrated that HB−ND not only enhanced the water solubility of HB but also maintained the PDT activity of the antineoplastic drug. Furthermore, confocal laser scanning microscopy (CLSM) was used to assess the internalization ability of the HB−NDs. Free particles outside the plasma membrane were removed, and the live cells were imaged at multitrack mode. The red

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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.9b00126. Figure S1. SDS-PAGE of the expression and purification of MSP. Figure S2. Stability characterization of HB−ND by size exclusion chromatography during 3 weeks. Figure S3. Cellular ROS generation detected by the probe DCFH-DA. Figure S4. Cellular apoptosis upon irradiation detected by the probes Calcein-AM and PI. Figure S5. Cell viability of free HB under the laser irradiation as control. Figure S6. CLSM images of MCF-7 cells’ 7827

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cellular uptake of 1 μM free HB after 2 h of coculture. Figure S7. x−y top view at a given z and two other images of the respective x−z and y−z side views (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Lin Jin: 0000-0002-7951-6602 Yang Yang: 0000-0002-1535-718X Zhenhui Qi: 0000-0002-4718-1430 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge financial support from the Thousand Talents Program of China, Postdoctoral Innovative Talents Supporting Project (BX20180255) of China, China Postdoctoral Science Foundation (2017M623231), Key R&D Program of Shaanxi Province (2019KW-031, 2019KW-038), Fundamental Research Funds for the Central Universities (3102018zy051, 3102018jcc007, 3102017OQD044, 3102017OQD045, 3102017OQD040, 3102017OQD115, 3102019ghxm005), Natural Science Basic Research Plan in Shaanxi Province of China (2018JQ2017), National Nature Science Foundation of China (21673056), State Key Laboratory of Solidification Processing in NPU (SKLSP201817), and the open project of the CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety (No. NSKF201801). We thank the Analytical & Testing Center of NPU for the characterization of materials.

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ABBREVIATIONS HB, hypocrellin B; ND, nanodisc; PDT, photodynamic therapy; ROS, reactive oxygen species REFERENCES

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