Article Cite This: ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX
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Plant-Derived Single-Molecule-Based Nanotheranostics for Photoenhanced Chemotherapy and Ferroptotic-Like Cancer Cell Death Jipsa Chelora,†,‡ Jinfeng Zhang,*,⊥,† Yingpeng Wan,†,‡ Xiao Cui,†,‡ Junfang Zhao,‡,§ Xiang-Min Meng,‡,§ Pengfei Wang,‡,§ and Chun-Sing Lee*,†,‡
Downloaded by UNIV AUTONOMA DE COAHUILA at 19:51:14:239 on June 02, 2019 from https://pubs.acs.org/doi/10.1021/acsabm.9b00311.
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Center of Super-Diamond and Advanced Films (COSDAF) & Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong SAR, P. R. China ‡ Nano-organic Photoelectronic Laboratory (NOPEL), TIPC, CAS-CityU Joint Laboratory, Dongguan, Guangdong 523000, P. R. China ⊥ School of Life Science, Beijing Institute of Technology, Beijing 100081, P. R. China § Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China S Supporting Information *
ABSTRACT: Although piperinean extract from pepperhas a mild chemotherapeutic effect, its poor water solubility has limited its applications for cancer therapy. With self-assembling of piperine into nanoparticles along with PEG (Pip NPs), both the water dispersibility and the chemotherapeutic efficacy can be substantially enhanced. It is further shown that the NPs can generate reactive oxygen species (ROS) with or without additional white light irradiation. Interestingly, the Pip NP induced cell death can be suppressed by ferroptosis inhibitors such as liproxstatin-1 and deferoxamine. Lipid ROS production is also observed in Pip NP treated cells. In addition to their cancer cell killing ability, the Pip NPs also show strong green fluorescence. These multiple functions make the Pip NPs a promising and low-cost nanotheranostic agent with herbal origin. KEYWORDS: plant-derived single molecule, nanotheranostic, nanodrug, chemotherapy, ferroptosis
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INTRODUCTION Drugs from plant origin are of great interest due to their low side effects even at high dosages.1In fact, 60% of approved anticancer drugs are of natural origin.2 Vinca alkaloids (vincristine, vinblastine), taxanes (taxol, docetaxel), podophyllotoxins (etoposide, teniposide), and camptothecins (topotecan, irinotecan) are some of the plant-based anticancer drugs which are in clinical use today.2,3 Piperine, the king of spices, is an alkaloid obtained from black pepper and long pepper which has been used in traditional Chinese and Indian medicines.1,4,5 Piperine exhibits multiple bioactivities including anti-inflammatory, arthritic, antibacterial, neuroprotective, and antidepressant properties.1,4,6−9 Apart from these properties, it has been reported to exhibit anticancer properties.1,4,7,10−13 Despite piperine’s remarkable antidisease characteristics, its extremely poor water solubility and lack of effective delivery system are impeding its wide clinical use.14 Fortunately, advances in nanocarrier-based technologies have provided an appealing strategy to solve their issues of water solubility and drug delivery.15−21 Nevertheless, potential systemic toxicity, complicated synthesis process, and excessive production cost of the nanocarriers are challenges that seriously impede their further clinical translations.20,22−24 © XXXX American Chemical Society
Furthermore, most drugs from plant origin can only exhibit a single chemotherapeutic effect which lacks theranostic and multifunctional capacities, thus requiring physical or covalent incorporation of various diagnostic and therapeutic agents together, further hindering their translation to clinics. Therefore, development of an intrinsically “all-in-one” singlemolecule-based plant-derived theranostic nanoplatform for cancer treatment is of great significance, but rare. Herein, we have prepared water-soluble Pip NPs which make drug delivery easier through passive targeting. Interestingly, Pip NPs have the ability to produce reactive oxygen species (ROS) and show good therapeutic effect toward HeLa cancer cells. We have observed that cell death is intercepted by the use of liproxstatin-1 and iron chelator which suggests the possibility of ferroptotic cell death in HeLa cells. Imagingassisted therapy is another advantageous characteristic of Pip NPs. Together these data indicate that Pip NPs can serve as an effective theranostic agent by inducing photoenhanced chemotherapy as well as ferroptotic-like cell death in cancer. The Received: April 12, 2019 Accepted: May 20, 2019
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DOI: 10.1021/acsabm.9b00311 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX
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ACS Applied Bio Materials
Figure 1. (a) Schematic illustration of the Pip NP preparation via nanoprecipitation. (b) Mechanism of the Pip-NP-induced cell death as an effective nanotheranostic agent. distribution were measured with a DLS (dynamic light scattering) instrument (Malvern Zetasizer Nano ZS) employing a 4 mW helium− neon laser and equipped with a thermostatic sample chamber. UV− visible spectra and fluorescence spectra were measured with an ultraviolet visible scanning spectrophotometer (Shimadzu 1700) and a spectrofluorometer (Fluormax-4). Two-Photon Absorption (TPA) Cross-Section Measurement. The TPA cross section (σPip) of the Pip NPs was measured by comparing Rhodamine B with a TPA-induced fluorescence method. TPA-induced upconverted fluorescence of the Pip NPs was compared with TPA-induced upconverted fluorescence of Rhodamine B in methanol at a concentration of 2 × 10−5 mol L−1. σPip was determined with the equation
development of such water-dispersible nanoplatforms based on a single building block will open new avenues for exploring novel nanotheranostics for biomedical applications.
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EXPERIMENTAL SECTION
Materials. Piperine and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), liproxstatin-1, deferoxamine, C11BODIPY, HOOC-PEG-COOH, poly(maleic anhydride-alt-1-octadecene) (C18PMH), and methoxy polyethylene glycol amine (mPEGNH2) were obtained from Sigma-Aldrich. Dulbecco’s modified Eagle’s medium (DMEM), Dulbecco’s phosphate-buffered saline (PBS), trypsin/ethylene diamine tetraacetic acid (0.5% trypsin, 5.3 mM EDTA tetrasodium), fetal bovine serum (FBS), and antibiotic agents such as penicillin and streptomycin (100 U/mL) were purchased from Life Technologies. Deionized water with a conductivity of 18.2 MΩ·cm−1 was collected from an in-line Millipore RiOs/Origin water purification system. All chemicals were collected from commercial suppliers and used as received without further purification. Preparation of C18PMH−PEG and Pip NPs. C18PMH−PEG was synthesized by following the reported procedure.25 Amounts of 10 mg of C18PMH and 143 mg of mPEG-NH2 were added in 5 mL of dichloromethane, followed by addition of triethylamine (6 μL) and 1ethyl-3-(3-(dimethylamino)propyl) carbodiimide (EDC-143 mg). This mixture was stirred for 24 h, and leftover solvents were evaporated by blowing dry N2. Solid obtained after the reaction was dissolved in deionized water and dialyzed for 3 days (molecular weight cutoff of dialysis bag used is 14 000 Da). The final C18PMH− PEG polymer was obtained by freeze-drying. The Pip NPs were prepared in aqueous solution by using a nanoprecipitation method. Piperine (1 mg mL−1) was first dissolved in THF followed by adding HOOC-PEG-COOH (0.5 mg mL−1) and PMHC18−mPEG (0.5 mg mL−1). An amount of 0.2 mL of this piperine−PEG stock solution was quickly added to 5 mL of milli-Q water under vigorous stirring. The mixture was then sonicated to evaporate THF at room temperature. Pip NPs were then obtained by centrifugation. Characterization of the Pip NPs. Size and morphology of the Pip NPs were examined using SEM (Philips XL-30 FEG) and TEM (FEI/Philips Tecnai 12 BioTWIN). Zeta potential and size
jij η C RdBnRdB zyzijj [F(t )]Pip yzz zzj z σPip = σRdBjjj RdB jj η C PipnPip zzzjj [F(t )]RdB zz { k Pip {k
where η is the fluorescence quantum yield; C is the concentration; n is the refractive index; and [F] is the integrated area of the upconverted fluorescence signal.26,27 The subscripts “Pip” and “RdB” refer, respectively, to Pip NPs and Rhodamine B. Cell Culture and Imaging. HeLa cells were cultured in a DMEM medium containing 10% FBS and 1% penicillin/streptomycin. The cells were seeded in 6-well plates with a density of 104 cells per well, and culture plates were incubated at 37 °C in a 5% CO2 humidified atmosphere for 24 h. Aqueous dispersions of the Pip NPs of different concentrations were added to culture plates, carefully mixed, and incubated at 37 °C and 5% CO2. Fluorescent images of the cells were acquired using a Nikon ECLIPSE 80i fluorescent microscope and Leica TCS SP5 laser scanning confocal microscope. Cell Viability. Cell viability of Pip-NP-treated HeLa cells was measured by an MTT assay. The HeLa cancer cells were seeded on 96-well plates and in Dulbecco’s modified Eagle’s medium (DMEM) containing 10% FBS and 1% penicillin/streptomycin. The cells were first grown overnight in the incubator at 37 °C. Pip NP dispersions of different concentrations were then added to the Hela cells and incubated for 24 or 48 h at 37 °C. The original culture medium was then replaced with a medium without FBS, and 20 μL of MTT stock solution (5 mg mL−1 in PBS) was added into each well. Medium B
DOI: 10.1021/acsabm.9b00311 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX
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Figure 2. (a) DLS spectrum and TEM image (inset: scale bar is 500 nm) of Pip NPs. (b) Zeta potential of Pip NPs in deionized water. (c) Absorption spectra of the Pip molecule (dashed line) and Pip NPs (solid line). (d) PL spectra of the Pip molecule (dashed line) and Pip NP (solid line) (inset: Mol and NPs are, respectively, photographs of the free molecule and Pip NPs under UV light). Excitation wavelength is 339 nm. (e) Size and PDI of Pip NPs for 120 hS. (f) Fluorescence stability of Pip NPs dissolved in DI water at different pH values.
ing.28 Photographs of piperine molecules dissolved in THF and Pip NPs under UV light are shown in the inset of Figure 2d. The stability of the nanoparticle is an important factor for their biomedical applications. Herein, we measured the stability of Pip NPs in terms of size and fluorescence. Size stability was measured in 24 h intervals for 120 h, and there are only modest variations in size and PDI (Figure 2e). The fluorescence stability of Pip NPs was measured at different pH, and there is no obvious fluorescence quenching from pH 2 to pH 8 (Figure 2f). Since it shows good fluorescence properties, imaging properties of Pip NPs were then studied. Initially, we explored a one-photon imaging capability of Pip NPs in HeLa cells. Imaging experiments were carried out after incubating the HeLa cells overnight with Pip NPs (15 μM). As shown in Figure 3, a green fluorescence signal was observed in the cytoplasm region. Two-photon optical properties of Pip NPs were studied by measuring TPA cross sections and TPE emission spectra of the Pip NPs under excitation from 710 to 770 nm using a femtosecond laser. Rhodamine B in methanol is used as the reference for the measurements. At an excitation of 740 nm, Pip NPs have a TPA cross section of 140 GM which is significantly higher than that of Rhodamine B (80 GM). Figure 4b shows a TPE emission spectrum of Pip NPs under 740 nm excitation. Two-photon imaging properties of the Pip NPs were investigated by using confocal scanning microscopy in HeLa cells (Figure 4c). To evaluate the therapeutic efficiency of the Pip NPs, cell viability was measured with MTT assay in a time-dependent manner in Pip-NP-treated HeLa cells for 24/ 48 h (Figure 5). Several groups have shown that piperine has cytotoxicity and can have possible applications of chemotherapy of cancer.1,4,7,10−13 Figure 5a shows that the piperine molecule (blue bar) does not have obvious toxicity for
containing MTT was completely removed after 4 h incubation, and 200 μL of DMSO was added to each well. The plate was gently shaken for 10 min at room temperature to dissolve precipitates, and five replicate wells were run for each concentration. A microplate reader (BioTek Power wave XS microplate reader) was used to determine absorbance of MTT at 540 nm.
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RESULTS AND DISCUSSION
The preparation of Pip NPs and their induced cell death mechanism are illustrated in Figure 1. The Pip NPs were fabricated via a well-documented self-assembly method, in which two hydrophilic polymers HOOC-PEG-COOH and PMHC18−mPEG were mixed to improve water dispersibility and bioavailability of the hydrophobic piperine molecules. Pip NPs can be taken up by cells through endocytosis and then act as a single-molecule-based theranostic integrated with one-/ two-photo imaging, photodynamic therapy, and ferroptotic-like cell death. DLS measurements show that the Pip NPs have an average diameter of 90 nm, a polydispersity index (PDI) of 0.157 (Figure 2a), and a zeta potential of −27.5 mV (Figure 2b). These parameters are suitable for passive targeting of cancer tissues. TEM and SEM studies show that the nanoparticles have spherical morphologies (inset of Figures 2a and S1). Photophysical properties of the piperine molecule and the Pip NPs are shown in Figure 2c and 2d. Piperine molecules in THF and Pip NP aqueous dispersion exhibit similar absorption peaks at ∼339 nm (Figure 2c). Emission peaks of the piperine molecule in THF peaks at 410 nm and Pip NPs show a red shift of 79 nm due to the strong intermolecular π−π interactions. It is worth noting that the Pip NPs have a large Stokes shift of 150 nm. This can minimize self-absorption and improve signal-to-noise ratio for bioimagC
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irradiation (100 mW cm−2 for 50 min; source Xe lamp after filtering out the UV part). Figure 5c shows that the fluorescence of SOSG increases by ∼8 times after irradiation. The inset of Figure 5c shows time evolution of the SOSG fluorescence intensity for the Pip NP sample and the control sample without any nanoparticles. These results confirm that ROSs can be generated by the Pip NPs upon irradiation with white light. Furthermore, we also have evaluated the viabilities of HeLa cells treated with Pip NPs with and without irradiation. As presented in Figure 5d, the as-prepared Pip NPs with light irradiation sample do show slightly higher toxicities than just using the NPs without irradiation. To further investigate cellular generation of ROS by the Pip NPs, cellular imaging was performed in Pip-NP-treated HeLa cells with and without white light irradiation (Figure 6). SOSG was chosen as the cellular singlet oxygen sensor. Before light irradiation, Pip NPs can induce some toxicities to HeLa cells which is indicated with blue arrows in Figure 6a. Interestingly, green fluorescence can be observed in dyed cells with shrunk morphology in the SOSG channel (Figure 6a, SOSG channel). It is interesting to observe that while no green fluorescence can be observed from the control sample (i.e., no Pip NPs added) with or without white light irradiation green fluorescence can be clearly observed after incubation with Pip NPs with or without irradiation. Green fluorescence without irradiation may be due to the ability of Pip nanoparticles to produce singlet oxygen in cells. This further confirms that Pip NPs can increase cellular ROS level to achieve a chemotherapeutic effect. There are reports about ROS generation of phytochemicals.1,7,13 A possible explanation for this is reduction of intracellular ferric ions and thereby enhancement of the catalytic action which results in ROS generation.1,7,13 This explains the results in Figure 5d that the extra irradiation only has a mild effect on the cell killing ability. On the other
Figure 3. Cellular imaging of Pip NPs (top row) with fluorescent microscope in HeLa cells, bright-field channel at left, Pip NP channel at the center, and overlap images at the right. The bottom row shows the control sample without any Pip NPs. Concentration of nanoparticle used is 10 μM. Scale bar is 50 μm.
concentration below 50 μM. This is consistent with results from previous reports that a relatively high concentration is required for obvious therapeutic effect.1,4,11−13 On the other hand, Pip NPs (green bar in Figure 5a) show much higher efficacy and can kill more than 50% of cancer cells at a concentration of 50 μM. Figure 5b further shows that cell viability decreases as the incubation time increases from 24 to 48 h. To investigate the ability of Pip NPs to generate ROS, we used singlet oxygen sensor green (SOSG) as a probe, in which green fluorescence would increase upon exposure to singlet oxygen. Here we added SOSG to Pip NP dispersion and monitored the fluorescence spectra before and after white light
Figure 4. (a) TPA cross section of Pip NPs dispersed in deionized water in comparison with Rhodamine B dissolved in methanol. (b) Normalized emission spectra of Pip NPs under TPE at 740 nm. (c) Two-photon cellular imaging of Pip NPs (top row) with a laser scanning confocal microscope in HeLa cells, bright-field channel on the left, Pip NP channel in the center, and overlap images on the right. The bottom row shows the control sample without any Pip NPs. Concentration of nanoparticle used is 10 μM. Scale bar is 50 μm. D
DOI: 10.1021/acsabm.9b00311 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX
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Figure 5. (a) Viability of HeLa cells incubated for 24 h with piperine free molecules and with Pip NPs (b) Effect of Pip NPs’ incubation time on the cell viability. (c) Fluorescence intensity enhancement of SOSG with Pip NPs after white light irradiation for 50 min. Inset shows the corresponding time evolution of the SOSG fluorescence intensities in Pip NPs and DI water as control. (d) Cell viability comparison in Pip NPs treated HeLa cells with and without white light irradiation after 24 h of incubation.
Since Pip NPs show the ability to induce ROS in HeLa cells even without external irradiation, we proposed a ferroptotic cell death pathway. Ferroptosis is a newly described cell death mechanism in which iron and lipid ROSs are the two important causes for cell death.29 Liproxstatin-1 is a pharmacological inhibitor of ferroptosis and scavenger of lipid ROS.29 We first tested whether Liproxsatin-1 can suppress Pip-NP-induced cell death through an MTT assay. As shown in Figure 7a, s3 Liproxstatin-1 does suppress cell death at all concentrations. To examine the lipid ROS accumulation, we have imaged Pip-NP-treated cells in the presence of lipid oxidation indicator C11-BODIPY. This result is compared with the control sample (i.e., no nanoparticle added) which does not show fluorescence at the C11-BODIPY channel (Figure 7b). In the presence of Pip NPs, some of the cell morphology shrank to small dots, which are probably completely dyed cells (Figure 7b). The small dyed cells show high intensity fluorescence in the C11-BODIPY channel. Lipid ROS accumulation before cell death is also observed with mild green fluorescence (Figure 7b). For comparison, we repeat the C11-BODIPY imaging experiment with NIH/3T3 cells. In contrary to the results of using Hela cells, no lipid ROS can be generated in the NIH/3T3 cell incubated with the Pip NPs (Figure S2). This hints that Pip NPs can produce lipid ROS only in HeLa cancer cells but not in NIH/3T3 normal cells. In addition, the viability of Pip-NP-treated NIH/3T3 cells is tested and compared with Pip-NP-treated HeLa cells (Figure S4). Results show that NIH/3T3 cells are more viable than the HeLa cells. Free iron level in cancer cells is significantly higher than the normal cells.30 Excess free iron is mostly being utilized for cancer growth by cytosolic and mitochondrial iron enzymes.30,31 Exceeding the amount of iron in the cells is capable of producing a free radical via Fenton chemistry.30,31 A
Figure 6. Cellular imaging with SOSG to confirm the presence of ROS in Pip-NP-treated HeLa cells (a) before irradiation and (b) after irradiation. HeLa cells without Pip NPs are used as control; brightfield channel on the left, SOSG channel in the center, and overlap images on the right. Concentration of nanoparticle used is 60 μM. Scale bar is 50 μm.
hand, the bottom row of Figure 6 does show that much more ROSs are generated upon white light irradiation. E
DOI: 10.1021/acsabm.9b00311 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX
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Figure 7. (a) Cell viabilities of Pip NPs at different concentrations in the presence of liproxstatin-1 (Lip) and deferaxoamine (DFO) after 24 h of treatment. (b) Lipid ROS accumulation detection with C11-BODIPY in HeLa cells. Bright-field channel on the left, BODIPY-C11 channel in the center, and overlap images on the right. Concentration of nanoparticle used is 60 μM. Scale bar is 50 μm.
Notes
higher amount of iron level leads to more free radical production and cell death.30,31 Sung et al. reported that a noniron nanoparticle can adsorb extracellular iron which leads to ferroptosis.29 To examine further, we used deferoxamine (DFO) which is an iron chelator reported to block ferroptosis.29 Interestingly, cell death is also suppressed in the presence of deferoxamine (Figure 7a, s3). In fact, Srinivasan et al. have reported that several herbal-originated compounds including piperine can absorb iron, zinc, and calcium.32 These results suggest that Pip NPs may bind with iron and induce ferroptosis in HeLa cancer cells. Combined with the photoenhanced chemotherapeutic effect, the asprepared Pip NPs can serve as a highly effective theranostic agent for cancer combination therapy.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The work was supported by a grant from the Hong Kong Innovation and Technology Commission (Project No. ITS/ 372/17) and the City University of Hong Kong Applied Research Grant (Project No. ARG 9667160).
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CONCLUSION In this study, Pip NPs are found to act as an effective nanotheranostic agent for cancer treatment by inducing imaging-assisted photoenhanced chemotherapy. It has been explored as a fluorescent probe for one-photon and twophoton excited cellular imaging. Owing to its abilities to create oxidative stress, the cell death of HeLa cancer cells was enhanced. Cell death was reversed in the presence of an iron chelator, liproxstatin-1, and it produces lipid ROS. These observations indicate that Pip NPs may induce ferroptotic cell death. Development of such plant-derived nanomedicine possesses greater significance for cancer treatment by integrating real-time diagnosis and therapeutic function.
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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/acsabm.9b00311. SEM image of Pip NPs, testing of lipid ROS accumulation with C11-BODIPY in NIH/3T3 cells, and cell viabilities of Pip NPs in HeLa cells and NIH/ 3T3 cells after 24 h of incubation (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected] (C.S.L.). *E-mail:
[email protected] (J.Z.). ORCID
Pengfei Wang: 0000-0002-8233-8798 Chun-Sing Lee: 0000-0001-6557-453X F
DOI: 10.1021/acsabm.9b00311 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX
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