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Supramolecular assembly of protein-based nanoparticles based on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) for cancer therapy
Colloids and Surfaces A 590 (2020) 124486
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Colloids and Surfaces A journal homepage: www.elsevier.com/locate/colsurfa
Supramolecular assembly of protein-based nanoparticles based on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) for cancer therapy
T
Hong Lia,1, Jie Zhaob,1, Anhe Wangc, Qi Lic, Wei Cuib,* a
College of Chemistry and Chemical Engineering, Xi'an Shiyou University, Xi'an 710065, China Beijing National Laboratory for Molecule Sciences, CAS Key Lab of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China c State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China b
G R A P H I C A L A B S T R A C T
A R T I C LE I N FO
A B S T R A C T
Keywords: TRAIL Diphenylalanine Self-assembly Cancer therapy
Molecular self-assembly of functional proteins has garnered intense interest for the development of nanomaterials. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as one of the most promising agents for cancer therapy, could selectively induce the apoptotic cell death in tumor cells while not on normal cells. In this study, protein-based nanoparticles were constructed with TRAIL and a dipeptide, diphenylalanine (FF), through molecular self-assembly. TRAIL-FF nanoparticles with sizes ranging from 60 nm to 500 nm could be prepared by controlling the concentration and the ratio of the two components. These nanoparticles could locate around the cytomembrane of MCF-7 cells due to the specific interaction between TRAIL and death receptors, thus transduce apoptotic signal. Therefore, the TRAIL-FF nanoparticles showed distinct killing effect on the cancer cells, such as MCF-7 and H460 cells, and the IC50 of the nanoparticles on H460 cells was about 260 ng/mL. The approach presented herein may be applicable to the fabrication of an extended range of protein-based functional biomaterials.
1. Introduction Molecular self-assembly of complex nanostructures with size
dimensions ranging from ∼10 nm to submicron is by far one of the most versatile way to prepare functional nanomaterials, which is also known as ‘bottom-up’ approach. The self-assembly strategy provides a
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Corresponding author. E-mail address: [email protected] (W. Cui). 1 They contributed equally to this work. https://doi.org/10.1016/j.colsurfa.2020.124486 Received 4 January 2020; Received in revised form 16 January 2020; Accepted 18 January 2020 Available online 21 January 2020 0927-7757/ © 2020 Elsevier B.V. All rights reserved.
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(﹥97.0 %) was determined by SDS-PAGE experiment and size-exclusion HPLC. Diphenylalanine (FF) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) were purchased from Sigma-Aldrich Company. Penicillin, streptomycin, Dulbecco's modified eagle medium (DMEM), and fetal bovine serum (FBS) were obtained from Invitrogen. Phosphate buffered saline (PBS) was purchased from AMRESCO. Ultrapure water used in all experiments was prepared in a Milli-Q apparatus (Millipore) and had a resistivity higher than 18.2 MΩ cm.
feasible access to well-defined nanostructures through the construction of multiple non-covalent molecular interactions, such as electrostatic attractions [1,2], π-π stackings [3], hydrogen bonds [4], van der Waals forces [5], guest-host interactions [6], etc. Compared with the conventional ‘top-down’ approach, self-assembly is more widely used for the fabrication of organized nanomaterials due to its unique advantages including controlled construction, low-cost production, and faster preparation of highly ordered nanostructures. Therefore, the self-assembly method has aroused much research interest for the biomedical applications of nanomaterials both in vitro and in vivo [7–11]. In nature, biomacromolecules including DNA, RNA, protein, and polysaccharide have their own characteristic conformation to form nanostructure through the self-assembly [12]. Inspired by the special structure of these biomacromolecules, natural and synthetic molecules were employed to construct novel nanomaterials by using the self-assembly strategy [13,14]. Protein, as an attractive biomolecule in the human body, possesses versatile function and distinguished self-assembly feature [15]. The proteins could self-assemble into highly designed hierarchical nanostructures ranging from tetrahedrons, hexahedrons to icosahedrons [16]. Moreover, nanocomposites based on the component of protein has become an important type of nanomedicine, which are very suitable for drug delivery due to their better biocompatibility than the synthetic polymer [17]. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a soluble type II transmembrane protein involved in the cell apoptosis by the extrinsic apoptotic pathway. It binds to the death receptors and transduces apoptotic signal into the cells. Recently, TRAIL has been proven to be a promising anticancer agent owing to its capability to induce apoptotic cell death in a wide range of cancer cells. It was reported that TRAIL could selectively recognize and eliminate cancer cells both in vivo and in vitro, while normal cells were relatively resistant [18,19]. Furthermore, several chemotherapies have synergized TRAIL with chemotherapeutic drugs including paclitaxel, carboplatin, and doxorubicin to enhance cancer cells’ killing efficacy [20]. However, it is worthy to note that the blood circulatory half-life of TRAIL is too short, thereby restricting its antitumor effects in clinical therapy [21]. To overcome this drawback, TRAIL has been designed to be encapsulated into nanoscale drug delivery systems to improve its stability. For this regard, different kinds of drug carriers were prepared, such as colloidal nanoparticles, liposomes, and single-walled carbon nanotubes [22]. These TRAIL-based nanoparticles could not only extend the short plasma half-life of therapeutic protein, but also improve the pro-apoptotic potential of TRAIL. In our previous studies, TRAIL/alginate (ALG) multilayer films were coated on the CaCO3 particles and bovine serum albumin (BSA) nanoparticles through layer-by-layer assembly techniques, respectively [23,24]. It was demonstrated that TRAIL loaded on these carriers could not only retain its anticancer activity, but also exhibit a remarkable enhancement in cell uptake efficiency. Herein, a new TRAIL-based complex nanoparticle was fabricated using supramolecular assembly method. Diphenylalanine (FF), as a versatile small molecular building block for preparation of various nanostructures, was employed to assemble with TRAIL to form well-defined TRAIL-FF nanoparticle in the aqueous medium. In vitro cell culture experiment was conducted to evaluate the anticancer effect of the TRAIL-FF nanoparticles. This work might be envisaged helpful for the preparation of other protein-based nanoparticle for biomedical applications.
2.2. Preparation of TRAIL-FF nanoparticles The TRAIL-FF nanoparticles were prepared by supramolecular assembly method. Briefly, TRAIL protein was dissolved in PBS solution pH = 7.4 with the concentration from 1 to 5 mg/mL. A fresh FF/HFIP solution was prepared by dissolving 1 mg FF in 8 μL HFIP. Then, the FF/ HFIP solution was added into the TRAIL solution as soon as possible. It was found that the opalescent, cloudy suspension appeared in solution instantaneously, indicating that the nanoparticles were formed. The TRAIL-FF nanoparticles were gathered by centrifugation at 10,000 rpm for 15 min. And the collected nanoparticles were re-dispersed in 1 mL deionized water, and re-collected by centrifugation 10,000 rpm, 15 min for 3 cycles. 2.3. Cell culture experiments Standard cell culture techniques were used. MCF-7 and H460 cells were cultured in DMEM supplemented with 10 % FBS, 1 % penicillin and streptomycin at 37 °C in a humidified 5 % CO2 incubator, and passaged every 2–3 days. The cells were seeded (5 × 104 cells/mL), grown to reach about 90 % confluency, and then they were split into a 35 mm glass-bottom Petri dish. For in vitro cellular uptake of the nanoparticles, the TRAIL protein was labelled by 5-(4,6-dichlorotriazinyl) aminofluoresce (5-DTAF) based on the reaction between the dichlorotriazines part of 5-DTAF and the primary amino group of TRAIL. Then, the MCF-7 cells were incubated with TRAIL-FF nanoparticles for 60 min. The cells were washed three times with PBS, and 1 mL of DMEM medium was added. The cell nucleus and cytomembrane were labelled with Hoechst 33258 and Alex-488, respectively. And then the cells were rinsed with PBS for three times. The cells with TRAIL-FF nanoparticles were examined by confocal laser scanning microscopy (CLSM). To determine the anticancer activity of as-prepared TRAIL-FF nanoparticles, MCF-7 and H460 cells (5 × 104 cells per well) were allowed to adhere to 96-well plates for 48 h in 500 mL of 10 % FBS/ DMEM. Then, they were co-cultured with the free TRAIL and different concentrations of TRAIL-FF nanoparticles, respectively. After co-incubation for 24 h, the cell viability was measured by using MTT assays. 2.4. Characterizations
2. Materials and methods
The images of the TRAIL-FF nanoparticles were acquired using scanning electron microscope (SEM, HITACHI S-4800, 15 kV) and transmission electron microscope (TEM, JEOL, JEM-2100). UV–vis (UV–vis) spectra were recorded with a HITACHI U-3010 UV–vis spectrophotometer. Average particle size and size distribution were measured by dynamic light scattering (Malvern Instrument Ltd. ZEN3600). Confocal laser scanning microscopy (CLSM) images were obtained on a confocal microscope (Olympus FV1000) equipped with a UPLSAPO 60× objective (1.35 numerical aperture).
2.1. Materials
3. Results and discussion
The recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that was kindly supplied by Beijing Sunbio Biotech. Co., Ltd. was expressed in E. coli from a DNA sequence encoding extracellular domain of human TRAIL (amino acids 114–281), and its purity
3.1. Fabrication and characterization of TRAIL-FF nanoparticles Advances in nanotechnology and rapid development of nanomaterial provide a solid foundation upon building up functional 2
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(Fig. 2D), a great deal of well-organized nanoparticles with a size around 180 nm could be formed, and the size distribution is relatively narrow. Magnified TEM image (Fig. 2E) shows a single TRAIL-FF nanoparticle, which confirms the solid core and intact structure of asprepared nanoparticles. For the drug delivery application of nanomedicine, the particle size is a key factor that influences their property and function. Thus, the dynamic light scattering (DLS) measurement was employed to characterize the size distribution of as-prepared TRAIL-FF nanoparticles (Fig. 3). The sample with a ratio of 1:1 presents two different sizes, one is below 100 nm and the other one is several hundreds of nanometers. The 2:1 TRAIL-FF nanoparticle exhibits narrower size distribution and smaller size with an average size at around 60 nm. In all of the samples, the 5:1 sample shows the largest size. For 5:2 sample, the mean hydrodynamic diameter of TRAIL-FF nanoparticles is a little larger than that obtained from electron microscope images. To further study the composition of as-prepared TRAIL-FF nanoparticles, UV–vis measurement was carried out. Fig. 4 shows the UV–vis adsorption curves of a series of TRAIL-FF nanoparticles. For TRAIL, as a protein, it has absorption at around 280 nm due to the threonine (Tyr) and tryptophan (Trp) residues [24]. The main peak of the TRAIL-FF nanoparticles prepared with a ratio of 2:1 appears at 257 nm, indicating the strong interactions between the TRAIL and FF, which might be π-π interactions [36]. As increasing the concentration and the ratio of TRAIL, for the sample 5:1 and 10:1, the main peaks show obvious red shift towards the peak of TRAIL. It could be attributed to the augment of threonine and tryptophan residues in the TRAIL-FF nanoparticles with increasing the concentration of TRAIL.
Fig. 1. Schematic illustration of the assembly of TRAIL-FF nanoparticles.
nanoparticles for modern medicine. In some cases, nanomedicine is the representative of modern medicine. It works at the molecular level, which is beneficial for understanding of human body and pathologies of diverse diseases. In the past few years, traditional tumor therapies, including surgery, radiotherapy, and chemotherapy, have turned to the nanomaterials to seek for safer and more effective nanomedicines [25]. For example, to improve the stability of TRAIL protein in blood circulation system, some nanocarriers, such as liposomes [26], polymer nanoparticles [27], inorganic nanoparticles [28], and nanovesicles [29], have been employed. These nanoparticles loaded with TRAIL have demonstrated encouraging results in reducing the cytotoxicity and improving the blood circulatory half-life [30]. However, it has to be noted that most of these nanoparticles were prepared based on the chemical reaction via terminal thiol, carboxylic, and amino groups of TRAIL that often needed harsh reaction conditions. Recently, the selfassembly method offers an alternative way to deliver TRAIL through rationally manipulating the bioactive nanostructures. To this end, TRAIL-FF nanoparticles were prepared by self-assembly strategy with the building blocks of diphenylalanine (FF) and TRAIL. The scheme of Fig. 1 displays the molecular structures of the capable self-assembly building block of diphenylalanine, which is the core recognition motif of β-amyloid peptide associated with the neurodegenerative disorder of Alzheimer's disease [31,32]. Therefore, a series of analogies of FF, such as LVFF, KLVFF, and LPFFD, have been designed and used for targeting the hydrophobic region of β-amyloid peptide [33,34]. It is noteworthy that the sequence of TRAIL274-275 is also the FF fragment [35], which might act as the interaction site that combines with the free FF via multiple intermolecular forces, such as π-π stackings and hydrogen bonds. Herein, through adjusting the concentrations of the two building blocks, different ratios of TRAIL to FF from 1:1, 2:1, 5:1 to 5:2 were employed to investigate their self-assembly behavior. For each sample, it could be seen that the TRAIL aqueous solution was clear and transparent. After adding the FF solution, the mixed solution turned turbid gradually, suggesting the formation of TRAIL-FF nanoparticles by self-assembly of the TRAIL protein and the FF peptide. Moreover, the solution became more turbid as increasing the concentrations of the two components, which indicates the increment of the production amount of nanoparticles. Furthermore, SEM was conducted to display the morphology of TRAIL-FF nanoparticles prepared with different ratios of TRAIL to FF (Fig. 2A–D). A great amount of small nanoparticles and some capsule-like product could be clearly seen in the samples with low concentrations, such as 1:1 (Fig. 2A) and 2:1 (Fig. 2B). As the concentration of TRAIL was increased to 5 mg/mL, the nanoparticles grew bigger. There are some big particles that could be observed for the sample 5:1 (Fig. 2C). For the sample with a ratio of 5:2
3.2. Anticancer application of TRAIL-FF nanoparticles Immobilization of biologically active proteins into nanoparticles is of great importance for the preparation of multi-functional nanostructures for biomedical applications. In the previous studies, FF has been widely used as unexceptionable building block for co-assemby with other small molecules. However, there has been few researches focusing on the interaction between the biomacromolecules and FF. In this study, TRAIL, as a model of biologically active protein, was employed to co-assemble with FF to construct novel biofunctionalized nanoparticles. To study the the cytotoxic effect of TRAIL-FF nanoparticles, MCF-7 and H460 cells were employed. Three different groups, TRAIL-FF nanoparticles, free TRAIL, and control group without drug, were incubated with MCF-7 cancer cells for 24 h, respectively. The cell viability of MCF-7 treated with a series of dosages of TRAIL-FF nanoparticles and free TRAIL is shown in Fig. 5A. The initial concentration of TRAIL-FF nanoparticles was about 1 mg/mL calculated based on TRAIL-equivalent. Then, it was diluted to 10, 100, and 1000 folds to obtain the 10x, 100x, and 1000x samples, respectively. In detail, MCF-7 cell viability decreases gradually from 75.1 ± 0.98%–61.8 ± 0.55 % with increasing the TRAIL-FF nanoparticle concentration. It should be concerned that the cell viability of MCF-7 cells treated with TRAIL-FF nanoparticles is almost the same as that treated with free TRAIL, which suggests that TRAIL could effectively retain its original bioactivity after being encapsulated into the nanoparticles. Moreover, H460 cell line was also used to further confirm the cytotoxicity of TRAIL-FF nanoparticles. As shown in Fig. 5B, the half maximal inhibitory concentration (IC50) of TRAIL-FF nanoparticles is about 260 ng/mL for H460 cells. Overall, these results indicate that TRAIL-FF nanoparticles could act as a drug delivery carrier while keeping the satisfying anticancer activity. In order to directly visualize the endocytosis and distribution of TRAIL-FF nanoparticles, confocal laser scanning microscopy was employed. TRAIL-FF nanoparticles and MCF-7 cells were co-cultured for 60 min at 37 °C, followed by washing step to remove the uncombined nanoparticles and the dead cells. As shown in Fig. 6A, TRAIL-FF nanoparticles labeled with fluorochrome DTAF are represented by the red 3
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Fig. 2. SEM and TEM images of TRAIL-FF nanoparticles prepared with different ratios of TRAIL to FF: A) 1:1, B) 2:1, C) 5:1, and D, E) 5:2. The concentrations of FF were fixed at A–C) 1 mg/mL and D, E) 2 mg/mL, respectively.
fluorescent domains. From the merged image (Fig. 6B), it could be seen that a large number of TRAIL-FF nanoparticles are localized around the cytomembranes of MCF-7 cells after 60 min’s co-culture. In our previous studies, death receptors expressed in cancer cells were confirmed to be distributed on the cytomembranes of MCF-7 cells [35]. Therefore, it might be reasonable to conclude that TRAIL-FF nanoparticles located on the cytomembranes bound with the death receptors, and thus transduce apoptotic signal into MCF-7 cells.
4. Conclusions In summary, the novel protein-based nanoparticles were fabricated by supramolecular assembly method. Two biomolecules, tumor necrosis factor-related apoptosis-inducing ligand and diphenylalanine, were employed as the building blocks for the formation of functionalized TRAIL-FF nanoparticles with potential anticancer activity. The size of as-prepared TRAIL-FF nanoparticles could be simply modulated by varying the concentration and the ratio of the two components. Moreover, the nanoparticles located around the cytomembrane after 60 min’s co-culture, facilitating the apoptotic signal transduction into MCF-7 cells though binding with the death receptors. Thus, these TRAIL-FF nanoparticles showed distinct killing effect on the cancer cells, and the IC50 of the nanoparticles on H460 cells was about 260 ng/ mL. For the future work, the TRAIL-FF nanoparticles may be combined with other chemotherapeutics like doxorubicin, carboplatin, and fluorouracil to realize the synergistic anticancer effect.
Fig. 3. Size distributions of TRAIL-FF nanoparticles prepared with different ratios of TRAIL to FF from 1:1 (curve 1, red), 2:1 (curve 2, green), 5:1 (curve 3, blue) to 5:2 (curve 4, pink). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
CRediT authorship contribution statement Hong Li: Investigation, Formal analysis, Writing - original draft. Jie Zhao: Investigation, Validation, Writing - review & editing. Anhe Wang: Validation, Visualization. Qi Li: Data curation, Investigation. Wei Cui: Conceptualization, Methodology, Funding acquisition, Supervision.
Declaration of Competing Interest
Fig. 4. UV–vis spectra of TRAIL-FF nanoparticles prepared with different ratios of TRAIL to FF.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 4
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Fig. 5. A) Cell viability of MCF-7 cells cultured in different conditions for 24 h: Group 1, the cells cultured in normal state (red); Group 2, the cells cultured with TRAIL-FF nanoparticles (green); Group 3, the cells cultured with free TRAIL (blue). B) Cell viability of H460 cells treated with TRAIL-FF nanoparticles of different concentrations from 8 × 10−6 to 2 × 10-3 mg/mL for 24 h. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 6. CLSM images of A) TRAIL-FF nanoparticles (labeled with DTAF in red), B) the overlapped image of TRAIL-FF nanoparticles and MCF-7 cells, in which the nuclei and the membrane were stained by DAPI (blue) and Alexa 488 (green), respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Acknowledgments
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Contents lists available at ScienceDirect
Colloids and Surfaces A journal homepage: www.elsevier.com/locate/colsurfa
Supramolecular assembly of protein-based nanoparticles based on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) for cancer therapy
T
Hong Lia,1, Jie Zhaob,1, Anhe Wangc, Qi Lic, Wei Cuib,* a
College of Chemistry and Chemical Engineering, Xi'an Shiyou University, Xi'an 710065, China Beijing National Laboratory for Molecule Sciences, CAS Key Lab of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China c State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China b
G R A P H I C A L A B S T R A C T
A R T I C LE I N FO
A B S T R A C T
Keywords: TRAIL Diphenylalanine Self-assembly Cancer therapy
Molecular self-assembly of functional proteins has garnered intense interest for the development of nanomaterials. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as one of the most promising agents for cancer therapy, could selectively induce the apoptotic cell death in tumor cells while not on normal cells. In this study, protein-based nanoparticles were constructed with TRAIL and a dipeptide, diphenylalanine (FF), through molecular self-assembly. TRAIL-FF nanoparticles with sizes ranging from 60 nm to 500 nm could be prepared by controlling the concentration and the ratio of the two components. These nanoparticles could locate around the cytomembrane of MCF-7 cells due to the specific interaction between TRAIL and death receptors, thus transduce apoptotic signal. Therefore, the TRAIL-FF nanoparticles showed distinct killing effect on the cancer cells, such as MCF-7 and H460 cells, and the IC50 of the nanoparticles on H460 cells was about 260 ng/mL. The approach presented herein may be applicable to the fabrication of an extended range of protein-based functional biomaterials.
1. Introduction Molecular self-assembly of complex nanostructures with size
dimensions ranging from ∼10 nm to submicron is by far one of the most versatile way to prepare functional nanomaterials, which is also known as ‘bottom-up’ approach. The self-assembly strategy provides a
⁎
Corresponding author. E-mail address: [email protected] (W. Cui). 1 They contributed equally to this work. https://doi.org/10.1016/j.colsurfa.2020.124486 Received 4 January 2020; Received in revised form 16 January 2020; Accepted 18 January 2020 Available online 21 January 2020 0927-7757/ © 2020 Elsevier B.V. All rights reserved.
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(﹥97.0 %) was determined by SDS-PAGE experiment and size-exclusion HPLC. Diphenylalanine (FF) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) were purchased from Sigma-Aldrich Company. Penicillin, streptomycin, Dulbecco's modified eagle medium (DMEM), and fetal bovine serum (FBS) were obtained from Invitrogen. Phosphate buffered saline (PBS) was purchased from AMRESCO. Ultrapure water used in all experiments was prepared in a Milli-Q apparatus (Millipore) and had a resistivity higher than 18.2 MΩ cm.
feasible access to well-defined nanostructures through the construction of multiple non-covalent molecular interactions, such as electrostatic attractions [1,2], π-π stackings [3], hydrogen bonds [4], van der Waals forces [5], guest-host interactions [6], etc. Compared with the conventional ‘top-down’ approach, self-assembly is more widely used for the fabrication of organized nanomaterials due to its unique advantages including controlled construction, low-cost production, and faster preparation of highly ordered nanostructures. Therefore, the self-assembly method has aroused much research interest for the biomedical applications of nanomaterials both in vitro and in vivo [7–11]. In nature, biomacromolecules including DNA, RNA, protein, and polysaccharide have their own characteristic conformation to form nanostructure through the self-assembly [12]. Inspired by the special structure of these biomacromolecules, natural and synthetic molecules were employed to construct novel nanomaterials by using the self-assembly strategy [13,14]. Protein, as an attractive biomolecule in the human body, possesses versatile function and distinguished self-assembly feature [15]. The proteins could self-assemble into highly designed hierarchical nanostructures ranging from tetrahedrons, hexahedrons to icosahedrons [16]. Moreover, nanocomposites based on the component of protein has become an important type of nanomedicine, which are very suitable for drug delivery due to their better biocompatibility than the synthetic polymer [17]. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a soluble type II transmembrane protein involved in the cell apoptosis by the extrinsic apoptotic pathway. It binds to the death receptors and transduces apoptotic signal into the cells. Recently, TRAIL has been proven to be a promising anticancer agent owing to its capability to induce apoptotic cell death in a wide range of cancer cells. It was reported that TRAIL could selectively recognize and eliminate cancer cells both in vivo and in vitro, while normal cells were relatively resistant [18,19]. Furthermore, several chemotherapies have synergized TRAIL with chemotherapeutic drugs including paclitaxel, carboplatin, and doxorubicin to enhance cancer cells’ killing efficacy [20]. However, it is worthy to note that the blood circulatory half-life of TRAIL is too short, thereby restricting its antitumor effects in clinical therapy [21]. To overcome this drawback, TRAIL has been designed to be encapsulated into nanoscale drug delivery systems to improve its stability. For this regard, different kinds of drug carriers were prepared, such as colloidal nanoparticles, liposomes, and single-walled carbon nanotubes [22]. These TRAIL-based nanoparticles could not only extend the short plasma half-life of therapeutic protein, but also improve the pro-apoptotic potential of TRAIL. In our previous studies, TRAIL/alginate (ALG) multilayer films were coated on the CaCO3 particles and bovine serum albumin (BSA) nanoparticles through layer-by-layer assembly techniques, respectively [23,24]. It was demonstrated that TRAIL loaded on these carriers could not only retain its anticancer activity, but also exhibit a remarkable enhancement in cell uptake efficiency. Herein, a new TRAIL-based complex nanoparticle was fabricated using supramolecular assembly method. Diphenylalanine (FF), as a versatile small molecular building block for preparation of various nanostructures, was employed to assemble with TRAIL to form well-defined TRAIL-FF nanoparticle in the aqueous medium. In vitro cell culture experiment was conducted to evaluate the anticancer effect of the TRAIL-FF nanoparticles. This work might be envisaged helpful for the preparation of other protein-based nanoparticle for biomedical applications.
2.2. Preparation of TRAIL-FF nanoparticles The TRAIL-FF nanoparticles were prepared by supramolecular assembly method. Briefly, TRAIL protein was dissolved in PBS solution pH = 7.4 with the concentration from 1 to 5 mg/mL. A fresh FF/HFIP solution was prepared by dissolving 1 mg FF in 8 μL HFIP. Then, the FF/ HFIP solution was added into the TRAIL solution as soon as possible. It was found that the opalescent, cloudy suspension appeared in solution instantaneously, indicating that the nanoparticles were formed. The TRAIL-FF nanoparticles were gathered by centrifugation at 10,000 rpm for 15 min. And the collected nanoparticles were re-dispersed in 1 mL deionized water, and re-collected by centrifugation 10,000 rpm, 15 min for 3 cycles. 2.3. Cell culture experiments Standard cell culture techniques were used. MCF-7 and H460 cells were cultured in DMEM supplemented with 10 % FBS, 1 % penicillin and streptomycin at 37 °C in a humidified 5 % CO2 incubator, and passaged every 2–3 days. The cells were seeded (5 × 104 cells/mL), grown to reach about 90 % confluency, and then they were split into a 35 mm glass-bottom Petri dish. For in vitro cellular uptake of the nanoparticles, the TRAIL protein was labelled by 5-(4,6-dichlorotriazinyl) aminofluoresce (5-DTAF) based on the reaction between the dichlorotriazines part of 5-DTAF and the primary amino group of TRAIL. Then, the MCF-7 cells were incubated with TRAIL-FF nanoparticles for 60 min. The cells were washed three times with PBS, and 1 mL of DMEM medium was added. The cell nucleus and cytomembrane were labelled with Hoechst 33258 and Alex-488, respectively. And then the cells were rinsed with PBS for three times. The cells with TRAIL-FF nanoparticles were examined by confocal laser scanning microscopy (CLSM). To determine the anticancer activity of as-prepared TRAIL-FF nanoparticles, MCF-7 and H460 cells (5 × 104 cells per well) were allowed to adhere to 96-well plates for 48 h in 500 mL of 10 % FBS/ DMEM. Then, they were co-cultured with the free TRAIL and different concentrations of TRAIL-FF nanoparticles, respectively. After co-incubation for 24 h, the cell viability was measured by using MTT assays. 2.4. Characterizations
2. Materials and methods
The images of the TRAIL-FF nanoparticles were acquired using scanning electron microscope (SEM, HITACHI S-4800, 15 kV) and transmission electron microscope (TEM, JEOL, JEM-2100). UV–vis (UV–vis) spectra were recorded with a HITACHI U-3010 UV–vis spectrophotometer. Average particle size and size distribution were measured by dynamic light scattering (Malvern Instrument Ltd. ZEN3600). Confocal laser scanning microscopy (CLSM) images were obtained on a confocal microscope (Olympus FV1000) equipped with a UPLSAPO 60× objective (1.35 numerical aperture).
2.1. Materials
3. Results and discussion
The recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that was kindly supplied by Beijing Sunbio Biotech. Co., Ltd. was expressed in E. coli from a DNA sequence encoding extracellular domain of human TRAIL (amino acids 114–281), and its purity
3.1. Fabrication and characterization of TRAIL-FF nanoparticles Advances in nanotechnology and rapid development of nanomaterial provide a solid foundation upon building up functional 2
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(Fig. 2D), a great deal of well-organized nanoparticles with a size around 180 nm could be formed, and the size distribution is relatively narrow. Magnified TEM image (Fig. 2E) shows a single TRAIL-FF nanoparticle, which confirms the solid core and intact structure of asprepared nanoparticles. For the drug delivery application of nanomedicine, the particle size is a key factor that influences their property and function. Thus, the dynamic light scattering (DLS) measurement was employed to characterize the size distribution of as-prepared TRAIL-FF nanoparticles (Fig. 3). The sample with a ratio of 1:1 presents two different sizes, one is below 100 nm and the other one is several hundreds of nanometers. The 2:1 TRAIL-FF nanoparticle exhibits narrower size distribution and smaller size with an average size at around 60 nm. In all of the samples, the 5:1 sample shows the largest size. For 5:2 sample, the mean hydrodynamic diameter of TRAIL-FF nanoparticles is a little larger than that obtained from electron microscope images. To further study the composition of as-prepared TRAIL-FF nanoparticles, UV–vis measurement was carried out. Fig. 4 shows the UV–vis adsorption curves of a series of TRAIL-FF nanoparticles. For TRAIL, as a protein, it has absorption at around 280 nm due to the threonine (Tyr) and tryptophan (Trp) residues [24]. The main peak of the TRAIL-FF nanoparticles prepared with a ratio of 2:1 appears at 257 nm, indicating the strong interactions between the TRAIL and FF, which might be π-π interactions [36]. As increasing the concentration and the ratio of TRAIL, for the sample 5:1 and 10:1, the main peaks show obvious red shift towards the peak of TRAIL. It could be attributed to the augment of threonine and tryptophan residues in the TRAIL-FF nanoparticles with increasing the concentration of TRAIL.
Fig. 1. Schematic illustration of the assembly of TRAIL-FF nanoparticles.
nanoparticles for modern medicine. In some cases, nanomedicine is the representative of modern medicine. It works at the molecular level, which is beneficial for understanding of human body and pathologies of diverse diseases. In the past few years, traditional tumor therapies, including surgery, radiotherapy, and chemotherapy, have turned to the nanomaterials to seek for safer and more effective nanomedicines [25]. For example, to improve the stability of TRAIL protein in blood circulation system, some nanocarriers, such as liposomes [26], polymer nanoparticles [27], inorganic nanoparticles [28], and nanovesicles [29], have been employed. These nanoparticles loaded with TRAIL have demonstrated encouraging results in reducing the cytotoxicity and improving the blood circulatory half-life [30]. However, it has to be noted that most of these nanoparticles were prepared based on the chemical reaction via terminal thiol, carboxylic, and amino groups of TRAIL that often needed harsh reaction conditions. Recently, the selfassembly method offers an alternative way to deliver TRAIL through rationally manipulating the bioactive nanostructures. To this end, TRAIL-FF nanoparticles were prepared by self-assembly strategy with the building blocks of diphenylalanine (FF) and TRAIL. The scheme of Fig. 1 displays the molecular structures of the capable self-assembly building block of diphenylalanine, which is the core recognition motif of β-amyloid peptide associated with the neurodegenerative disorder of Alzheimer's disease [31,32]. Therefore, a series of analogies of FF, such as LVFF, KLVFF, and LPFFD, have been designed and used for targeting the hydrophobic region of β-amyloid peptide [33,34]. It is noteworthy that the sequence of TRAIL274-275 is also the FF fragment [35], which might act as the interaction site that combines with the free FF via multiple intermolecular forces, such as π-π stackings and hydrogen bonds. Herein, through adjusting the concentrations of the two building blocks, different ratios of TRAIL to FF from 1:1, 2:1, 5:1 to 5:2 were employed to investigate their self-assembly behavior. For each sample, it could be seen that the TRAIL aqueous solution was clear and transparent. After adding the FF solution, the mixed solution turned turbid gradually, suggesting the formation of TRAIL-FF nanoparticles by self-assembly of the TRAIL protein and the FF peptide. Moreover, the solution became more turbid as increasing the concentrations of the two components, which indicates the increment of the production amount of nanoparticles. Furthermore, SEM was conducted to display the morphology of TRAIL-FF nanoparticles prepared with different ratios of TRAIL to FF (Fig. 2A–D). A great amount of small nanoparticles and some capsule-like product could be clearly seen in the samples with low concentrations, such as 1:1 (Fig. 2A) and 2:1 (Fig. 2B). As the concentration of TRAIL was increased to 5 mg/mL, the nanoparticles grew bigger. There are some big particles that could be observed for the sample 5:1 (Fig. 2C). For the sample with a ratio of 5:2
3.2. Anticancer application of TRAIL-FF nanoparticles Immobilization of biologically active proteins into nanoparticles is of great importance for the preparation of multi-functional nanostructures for biomedical applications. In the previous studies, FF has been widely used as unexceptionable building block for co-assemby with other small molecules. However, there has been few researches focusing on the interaction between the biomacromolecules and FF. In this study, TRAIL, as a model of biologically active protein, was employed to co-assemble with FF to construct novel biofunctionalized nanoparticles. To study the the cytotoxic effect of TRAIL-FF nanoparticles, MCF-7 and H460 cells were employed. Three different groups, TRAIL-FF nanoparticles, free TRAIL, and control group without drug, were incubated with MCF-7 cancer cells for 24 h, respectively. The cell viability of MCF-7 treated with a series of dosages of TRAIL-FF nanoparticles and free TRAIL is shown in Fig. 5A. The initial concentration of TRAIL-FF nanoparticles was about 1 mg/mL calculated based on TRAIL-equivalent. Then, it was diluted to 10, 100, and 1000 folds to obtain the 10x, 100x, and 1000x samples, respectively. In detail, MCF-7 cell viability decreases gradually from 75.1 ± 0.98%–61.8 ± 0.55 % with increasing the TRAIL-FF nanoparticle concentration. It should be concerned that the cell viability of MCF-7 cells treated with TRAIL-FF nanoparticles is almost the same as that treated with free TRAIL, which suggests that TRAIL could effectively retain its original bioactivity after being encapsulated into the nanoparticles. Moreover, H460 cell line was also used to further confirm the cytotoxicity of TRAIL-FF nanoparticles. As shown in Fig. 5B, the half maximal inhibitory concentration (IC50) of TRAIL-FF nanoparticles is about 260 ng/mL for H460 cells. Overall, these results indicate that TRAIL-FF nanoparticles could act as a drug delivery carrier while keeping the satisfying anticancer activity. In order to directly visualize the endocytosis and distribution of TRAIL-FF nanoparticles, confocal laser scanning microscopy was employed. TRAIL-FF nanoparticles and MCF-7 cells were co-cultured for 60 min at 37 °C, followed by washing step to remove the uncombined nanoparticles and the dead cells. As shown in Fig. 6A, TRAIL-FF nanoparticles labeled with fluorochrome DTAF are represented by the red 3
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Fig. 2. SEM and TEM images of TRAIL-FF nanoparticles prepared with different ratios of TRAIL to FF: A) 1:1, B) 2:1, C) 5:1, and D, E) 5:2. The concentrations of FF were fixed at A–C) 1 mg/mL and D, E) 2 mg/mL, respectively.
fluorescent domains. From the merged image (Fig. 6B), it could be seen that a large number of TRAIL-FF nanoparticles are localized around the cytomembranes of MCF-7 cells after 60 min’s co-culture. In our previous studies, death receptors expressed in cancer cells were confirmed to be distributed on the cytomembranes of MCF-7 cells [35]. Therefore, it might be reasonable to conclude that TRAIL-FF nanoparticles located on the cytomembranes bound with the death receptors, and thus transduce apoptotic signal into MCF-7 cells.
4. Conclusions In summary, the novel protein-based nanoparticles were fabricated by supramolecular assembly method. Two biomolecules, tumor necrosis factor-related apoptosis-inducing ligand and diphenylalanine, were employed as the building blocks for the formation of functionalized TRAIL-FF nanoparticles with potential anticancer activity. The size of as-prepared TRAIL-FF nanoparticles could be simply modulated by varying the concentration and the ratio of the two components. Moreover, the nanoparticles located around the cytomembrane after 60 min’s co-culture, facilitating the apoptotic signal transduction into MCF-7 cells though binding with the death receptors. Thus, these TRAIL-FF nanoparticles showed distinct killing effect on the cancer cells, and the IC50 of the nanoparticles on H460 cells was about 260 ng/ mL. For the future work, the TRAIL-FF nanoparticles may be combined with other chemotherapeutics like doxorubicin, carboplatin, and fluorouracil to realize the synergistic anticancer effect.
Fig. 3. Size distributions of TRAIL-FF nanoparticles prepared with different ratios of TRAIL to FF from 1:1 (curve 1, red), 2:1 (curve 2, green), 5:1 (curve 3, blue) to 5:2 (curve 4, pink). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
CRediT authorship contribution statement Hong Li: Investigation, Formal analysis, Writing - original draft. Jie Zhao: Investigation, Validation, Writing - review & editing. Anhe Wang: Validation, Visualization. Qi Li: Data curation, Investigation. Wei Cui: Conceptualization, Methodology, Funding acquisition, Supervision.
Declaration of Competing Interest
Fig. 4. UV–vis spectra of TRAIL-FF nanoparticles prepared with different ratios of TRAIL to FF.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 4
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Fig. 5. A) Cell viability of MCF-7 cells cultured in different conditions for 24 h: Group 1, the cells cultured in normal state (red); Group 2, the cells cultured with TRAIL-FF nanoparticles (green); Group 3, the cells cultured with free TRAIL (blue). B) Cell viability of H460 cells treated with TRAIL-FF nanoparticles of different concentrations from 8 × 10−6 to 2 × 10-3 mg/mL for 24 h. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 6. CLSM images of A) TRAIL-FF nanoparticles (labeled with DTAF in red), B) the overlapped image of TRAIL-FF nanoparticles and MCF-7 cells, in which the nuclei and the membrane were stained by DAPI (blue) and Alexa 488 (green), respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Acknowledgments
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