Green Synthetic Nanoarchitectonics of Gold and Silver Nanoparticles Prepared Using Quercetin and Their Cytotoxicity and Catalytic
You Jeong Lee and Youmie Park∗
Quercetin is a flavonoid and is abundant in the plant kingdom. Green nanoparticles (gold and silver) were synthesized by using quercetin as a reductant via a green route for their potential nanoar- chitechtonic applications. There were no toxic chemicals involved during the synthesis. The gold and silver nanoparticles exhibited surface plasmon resonance at 527 nm and 401 nm, respectively. Both nanoparticle solutions retained excellent colloidal shelf stability for 7 days and in cell culture medium. The crystal structure of the nanoparticles was observed by X-ray diffraction analysis. Field emission transmission electron microscopy images revealed that spherical nanoparticles were syn- thesized, with an average size of 20.2 4.8 nm for gold nanoparticles and 32.4 14.0 nm for silver nanoparticles. Observation of clear lattice fringes in the microscopic images suggested that both types of nanoparticles pIPos: s5e.s6s2e.d15a5f.a1c9e-Ocenn: tMeroend,c0u6bicJasntru2c0tu2r0e.0C2a:1ta6ly:3ti3c activity was evaluated with respect to 4-nitrophenoCl orepdyurcigtiohnt: aAnmd emreicthaynl oSrcainegnetidfiecgPraudbaltiisohne. Wrshen increasing the amount of gold or silver nanoparticles used aDs ealivcaetraeldysbt,ythInegreantetaconstant of the catalytic reaction was also increased. Cytotoxicity assessment on cancer cells demonstrated that both types of nanoparticles can be appropriate candidates for delivery vehicles of biologically active molecules, such as anticancer agents.
Keywords: Quercetin, Flavonoid, Green Synthesis, Gold Nanoparticles, Silver Nanoparticles, Catalysis, Cytotoxicity.
For discovering useful nanomaterials, the concept of nanoarchitectonics play an important role in nanotechnol- ogy [1–3]. Applications of nanoarchitectonics have been proposed in many areas of research including nanomaterial production, analyte sensing and detection, energy storage and conversion, drug delivery, catalysis and biomedical applications [1, 3]. Specifically, sophisticated molecular imprinting techniques of nanoparticles is the most promis- ing aspect of nanoarchitectonics. For exploring future functional nanomaterials, we prepared metallic nanopar- ticles by a green synthetic route in which quercetin was used as a reductant. In this strategy, quercetin is a reduc- tant as well as a functional part of metallic nanopar- ticle surfaces for their potential applications. Metallic nanoparticles, particularly gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs), have attracted great atten- tion owing to their major applications in theranostics . AuNPs have been found to possess anticancer and antian- giogenic activities. AgNPs have potential antimicrobial activity together with antiviral activity and anticancer activity in the treatment of lung cancer, breast cancer, hepatocellular carcinoma and skin carcinoma . These nanoparticles can be synthesized by physical, chemical and biological (or green) methods. The green method employs natural products to reduce metal ions to metal- lic nanoparticles. No other noxious chemicals are intro- duced in the synthetic step, providing a completely green and eco-friendly method. Among natural products, plant extracts and pure compounds from plants have been used as reducing and capping agents for the green synthesis of AuNPs and AgNPs. Extensive reviews regarding this matter can be found elsewhere [5, 6]. In the authors’ lab- oratory, pure compounds from plants have been used for the green synthesis of AuNPs and AgNPs, including cate- chin , caffeic acid [8–10], resveratrol , chlorogenic acid [12, 13], gallic acid , tannic acid [15–17] and rosmarinic acid . Applications of the resulting AuNPs and AgNPs were focused on catalytic, antibacterial and anti-inflammatory activities.
Nearly half of the medicines presently used are derived from natural products. Extracts and pure compounds from plants, such as resveratrol, curcumin, rutin, quercetin and silymarin, are considered drug candidates . However, limitations such as low hydrophilicity and physical/chemical instability are major problems when pursuing drug discovery. Nanocarriers are designed to overcome these limitations and provide sustained release and enhanced bioavailability . It has been reported that nanocarriers of paclitaxel, artemisinin and resveratrol improved the water solubility, stability, efficacy and safety profiles . Flavonoids are natural polyphenol com- pounds and are widely distributed in the plant kingdom. Flavonoids have become the main source of nutraceuti- cals and herbal medicine owing to their diverse biological activities. Nanocarriers such as micelles, biodegradable nanoparticles, nanoemulsions and vesicles have been applied to flavonoids to improve their bio-efficacy . Specifically, applications of nanocarriers with natural polyphenols have demonstrated enhanced efficacy for can- cer therapy .
Quercetin (3,3∗,4∗,5,7-pentahydrIoPx:y5fl.a6v2o.n1e5, 5s.t1ru9ctOurne: iMn on, 0Q6-AJuNaPns 2(b0l2ac0k 0lin2e:)1a6n:d33Q-AgNPs (red line). The inset shows digi- Fig. 1(a)) is a flavonoid with fiveCohpyydrrigoxhyt:l Agmroeurpicsa, n Sctaileinmtaifgiecs Pofuebaclihshnaenrosparticle solution: Q-AuNPs (left) and Q-AgNPs which contribute to its biological activity. QuercDeteinlivpeorse-d by(rIinghgte).nta sesses antioxidant and anticancer activities. The effects of quercetin on cancer cell biology include the following: (i) inhibition of cell growth, (ii) inhibition of metasta- sis, and (iii) induction of apoptosis . The bioavailabil- ity and bioactivity of quercetin in cancer treatment and diagnosis are improved by adopting nanocarrier systems such as silica nanoparticles, poly(lactic-co-glycolic acid) (PLGA), poly(D,L-lactic acid) (PLA), chitosan nanoparti- cles, and liposomes .
Quercetin-mediated green synthesis of AuNPs and AgNPs can be found in several articles [22, 23]. Jain and Mehata have reported enhanced antibacterial activ- ity of AgNPs against Escherichia coli strains by the minimal inhibitory concentration method . However, green synthetic AuNPs and AgNPs obtained by using quercetin are uncommon. Some articles have employed cetyltrimethylammonium bromide or NaBH4 in the pres- ence of quercetin to reduce Ag ions to AgNPs; how- ever, these approaches are not completely green. Thus, in the present report, only quercetin was employed to reduce/stabilize nanoparticles in the presence of Au or Ag ions (referred to hereafter as Q-AuNPs and Q-AgNPs).
No other chemicals were introduced during the synthe- sis, which was totally eco-friendly. UV-visible spectra of the Q-AuNPs and Q-AgNPs confirmed the synthe- sis of nanoparticles with characteristic surface plasmon resonance (SPR) bands. The colloidal stability of the nanoparticles was also evaluated by acquiring UV-visible spectra. Information about size and shape was obtained from field emission transmission electron microscopy. The applications of Q-AuNPs and Q-AgNPs were focused on catalysis and cytotoxicity on cancer cells. An excellent review can be found elsewhere regarding Au and Ag catalysis . The review covers Au and Ag catalysis in the following reactions: aerobic oxidation, activation of C–H bonds, activation of C–C multiple bonds and bio- conjugation. Au catalysts might be comparable to H+ catalysts and are sometimes unique to many organic reac- tions . Thus, the catalytic activity of Q-AuNPs and
Q-AgNPs was evaluated for further catalytic applications. For Q-AuNPs, a 4-nitrophenol (4-NP) reduction reaction was used as a model reaction. In the case of Q-AgNPs, the methyl orange (MO) degradation reaction was selected as a model reaction. These model reactions were selected as the reaction progress can be easily followed by record- ing UV-visible spectra. The major application of AuNPs and AgNPs is in cancer diagnostics and therapeutics . Specifically, green nanoparticles synthesized from plants have been emerging as effective treatments for cancers owing to their aspects of safety, simplicity, energy effi- ciency, less toxicity and environmental friendliness . Thus, the cytotoxicity of Q-AuNPs and Q-AgNPs on can- cer cells was assessed to investigate the possibility of using these nanoparticles as future nanocarriers for cancer treatment.
2. EXPERIMENTAL DETAILS
Methyl orange and fetal bovine serum (FBS) were pur- chased from Fluka (AG, Buchs, Switzerland) and GE Healthcare HyClone™ (Victoria, Australia), respectively. 4-Nitrophenol, silver nitrate, sodium borohydride, sodium hydroxide, potassium gold (III) chloride and quercetin were obtained from Sigma-Aldrich (St. Louis, MO, USA). Cell culture reagents were purchased from Gibco (Thermo Fisher Scientific, MA, USA). All other reagents were of analytical grade and used as received.
A UV-visible spectrophotometer was utilized to record the SPR of the nanoparticles, evaluate colloidal stabil- ity and follow catalytic reactions (UV-2600, Shimadzu Corporation, Kyoto, Japan). The crystal structure of the nanoparticles was assessed using a high resolution X-ray diffractometer (HR-XRD) with a CuKα radiation source (h 0.154056 nm) (Ultima IV, Rigaku, Japan). Filed emis- sion transmittance electron microscopy (FE-TEM) was
used to observe the size and shapIPe :o5f.6th2e.1n5a5n.1op9aOrtinc:leMs on,
2.5. Cell Culture and Cytotoxicity
Three cancer cell lines (AGS, HT-29 and PANC-1) were purchased from the Korean Cell Line Bank (Seoul, Repub- lic of Korea). Cell culture was conducted according to our previous report [27–29]. Briefly, cells were grown and incubated at 37 ◦C (under 5% CO2) with 80% conflu- ence prior to trypsinization. Each cancer cell line (5.0 103 cells per well) was seeded on 96-well plates. Next, incubation was conducted in a 37 ◦C oven under CO2 (5%) for 24 h. Q-AuNPs and Q-AgNPs with four different con- centrations were applied to the cells: 2.5, 5, 10 and 20 µM Au and Ag. The nanoparticle-treated cells were further incubated in the 37 ◦C oven under CO2 (5%) for an addi- tional 24 h. After the addition of MTT reagent (10 µL, 5 mg/mL in PBS), incubation was performed in a 37 ◦C oven under CO2 (5%) for an additional 3 h. Absorbance at 570 nm was measured using a multi-detection microplate reader (Synergy HT, Bio Tek Instruments, Winooski, VT, USA). The cells that were not treated with nanoparticle solutions were used as a control and was operated at 200 kV (JEM-21C0o0pF,yrJiEgOhtL: ,ATmoekyrioc,an S Japan). A NanoBrook 90Plus Zeta was used to mea- sure zeta potentials (Brookhaven Instruments Corporation, New York, USA).
2.3. Green Synthesis of Q-AuNPs and Q-AgNPs
In a 4 mL glass vial, either KAuCl4 solution (final concentration of 0.4 mM, 80 µL, for the synthesis of Q-AuNPs) or AgNO3 solution (final concentration of 0.2 mM, 40 µL, for the synthesis of Q-AgNPs) was mixed with sodium hydroxide (final concentration of 1 mM, 20 µL). Next, quercetin solution (final concentration of 0.1 mM, 80 µL in 50% ethanol) was added to the mix- ture. The quercetin solution was always freshly prepared prior to use. The final mixture was vortexed for 5 sec, and incubation was performed in an 80 ◦C dry oven for
4 h. UV-visible spectra were recorded in the range of 300∼800 nm.
2.4. Colloidal Stability
Assessment of colloidal stability was performed accord- ing to our previous report: (i) stability in salt, buffer and cell culture medium was determined with deionized water, PBS (pH 7.4), NaCl (0.9%), DMEM and full medium, and (ii) shelf stability was assessed for 7 days at ambient temperature in the dark [27–29]. UV-visible spectra were obtained at 300∼800 nm.
3. RESULTS AND DISCUSSION
3.1. Green Synthesis of Q-AuNPs and Q-AgNPs
The reduction reaction of Au and Ag ions by quercetin was monitored by UV-visible spectrophotometry. The SPR of both nanoparticles was observed at 527 nm for Q-AuNPs and at 401 nm for Q-AgNPs (Fig. 1(b)). As shown in dig- ital photographs in Figure 1(b), the color of the colloidal solution was ruby red for Q-AuNPs (left image) and dark yellow for Q-AgNPs (right image). The color change of each solution confirmed that the synthesis of nanoparticles was successful. Jain and Mehata have reported that the high reduction potential of quercetin leads to the reduc- tion of metal ions . They also proposed a mechanism that occurs through the –OH functional group of the cate- chol moiety in quercetin. The bond dissociation energy of –OH in the catechol moiety is lower than that of the other –OH functional groups. This induces successful reduction reactions of metal ions with quercetin .
3.2. HR-XRD Analysis
The crystal structure of both nanoparticles was elucidated by HR-XRD analysis, as shown in Figure 2. The Q-AuNPs showed four peaks, which confirmed a face-centered cubic structure, as shown in Figure 2(a): 37.99◦ for (111), 44.17◦ for (200), 64.52◦ for (220), and 77.45◦ for (311). Two byproducts (KCl and NaCl) of the reaction generated the other ten remaining peaks. KCl was found at 28.29◦ for (200), 40.35◦ for (220), 50.08◦ for (222), 58.56◦ for (400) and 73.59◦ for (422). NaCl exhibited five peaks as fol- lows: 31.57◦ for (200), 45.25◦ for (220), 56.23◦ for (222), 66.30◦ for (400) and 75.16◦ for (420). The size informa- tion was obtained from HR-XRD analysis by using the
Scherrer equation, and the Q-AuNP size was determined to be 10.90 nm. In the case of Q-AgNPs, a face-centered cubic structure was also confirmed from the four peaks at 37.83◦ for (111), 44.19◦ for (200), 64.23◦ for (220), and 77.17◦ for (311). One peak from NaNO3, which was a byproduct, was observed at 29.06◦ for (004). The Scherrer equation was also applied to the Q-AgNPs, and the size
was measured as 11.09 nm based on the HR-XRD peaks.
3.3. FE-TEM Images
FE-TEM is an essential tool to determine the size and morphology of nanoparticles. FE-TEM images of Q-AuNPs were obtained, and the shape was observed to be spherical (Figs. 3(a–c)). Lattice fringes were clearly observed, suggesting that Q-AuNPs possess crystal struc- tures (Fig. 3(c)). This result was well corroborated by the HR-XRD analysis in the previous section, confirming the crystal structure of Q-AuNPs. The average size of Q-AuNPs was 20.2 4.8 nm, which was obtained from two hundred and eleven discrete nanoparticles in FE- TEM images (Fig. 3(d)). Spherical-shaped Q-AgNPs were also observed, and their FE-TEM images are displayed in Figures 4(a)–(c). Similar to the results for Q-AuNPs, clear lattice fringes were also observed, as shown in Figure 4(c), and this image further confirmed the crys- tal structure of Q-AgNPs. HR-XRD analysis also con- firmed the face-centered cubic structure of Q-AgNPs in the previous section. One hundred and twenty-four discrete nanoparticles were selected to measure the average size (32.4 ± 14.0 nm, Fig. 4(d)). The dispersion state of both types of nanoparticles was quite decent, demonstrating that quercetin played a role as a stabilizing agent as well as a reductant.
3.4. Colloidal Shelf Stability
Colloidal stability is an important requisite for nanoparti- cles for further in vitro and in vivo applications. As shown in Figure 5, the colloidal stability was assessed by UV- visible spectrophotometry for 7 days at ambient temper- ature in the dark. After 5 days, a new SPR of Q-AuNPs appeared at approximately 610 nm together with the orig- inal SPR at 527 nm (Fig. 5(a)). The absorbance decreased with increasing shelf time. In the case of Q-AgNPs, the shape of the SPR was retained with decreased absorbance at 401 nm and increasing shelf time (Fig. 5(b)). In both nanoparticle solutions, no aggregation of colloidal solu- tion was observed, which suggested that both nanoparticles possessed reasonable shelf stability for 7 days at ambient temperature in the dark. The zeta potential of Q-AuNPs was measured to be 22.33 mV. In the case of Q-AgNPs, the zeta potential was 35.76 mV. Both nanoparticles had large negative values of their zeta potentials, suggesting that the colloidal stability was reasonably high.
3.5. Colloidal Stability in Various Solutions
Five different solutions were tested for colloidal stabil- ity: deionized water, PBS (pH 7.4), NaCl (0.9%), DMEM and full medium. The results for Q-AuNPs are displayed in Figure 6(a). The control was a colloidal solution of Q-AuNPs immediately after synthesis. Under all solutions, SPR was decreased, and the digital images of each solu- tion are shown in the inset. The colloidal stability was the best retained in two solutions: full medium and deionized water. After mixing with deionized water, the colloidal solution had a violet color, and a purple color appeared in the full medium. The NaCl and DMEM solutions exhib- ited light blue and light gray colors, respectively. Their SPR maximum wavelengths were 686 nm for NaCl and 675 nm for DMEM solution. With PBS solution, a pink color appeared, and the lowest SPR was exhibited. In the case of Q-AgNPs, the UV-visible spectra are shown in Figure 6(b). Similar to Q-AuNPs, the SPR was reduced compared with that of the control. Digital images of each solution are shown in the inset. When mixed with full medium (yellow color) and deionized water (light yel- low color), SPR was well retained among the five solu- tions tested. In DMEM, there was a redshift in SPR at approximately 550 560 nm with a pinkish color. How- ever, SPR was not observed for PBS and NaCl solutions, suggesting that the colloidal stability was the lowest in these two solutions. In fact, the solution turned colorless due to the aggregation or agglomeration of nanoparticles in these solutions. Among the five solutions, the full medium displayed the highest absorbance, with a violet color for Q-AuNPs and yellow color for Q-AgNPs. Furthermore, no aggregation was observed in the full medium solution, indicating that full medium could be used for cytotoxicity experiments in the current report.
3.6. Catalytic Activity
The catalytic reduction of 4-NP to 4-aminophenol (4-AP) by using Q-AuNPs as a catalysis in the presence of excess sodium borohydride is shown in Figure 7. With excess sodium borohydride, 4-NP was changed to 4-nitriphenolate anion, which had an absorbance at 400 nm with a yellow color. When the Q-AuNP catalyst was added, the absorbance at 400 nm decreased. Simultaneously, the absorbance at 300 nm increased, which indicated the formation of the product 4-AP (Figs. 7(a and b)). In the absence of Q-AuNPs, the absorbance of the 4-nitrophenolate anion at 400 nm did not change. In our previous report, 4-AP was purified from the reaction mix- ture, and the structure was elucidated by 1H-NMR . The reaction rate was determined from the plot between ln(Ct /C0) and time (sec) (Fig. 7(c)). The 4-NP concen- trations at time 0 and time t were expressed as C0 and Ct , respectively. A linear relationship was observed in Figure 7(c). Two different amounts of Q-AuNPs (63 µL and 125 µL) were tested for catalytic activity. As expected, a larger amount (125 µL) of Q-AuNPs showed a larger rate constant (4.0 10−3/sec). Moreover, when the amount of Q-AuNPs was smaller (63 µL), the rate constant was also smaller (2.1 10−3/sec). The time for reaction com- pletion was 2-fold longer when a smaller amount of Q-AuNPs was added: 1,800 sec for 63 µL and 900 sec for 125 µL.
MO absorbed at 460 nm, and this absorbance decreased with time in the presence of the Q-AgNP catalyst (Figs. 8(a and b)). Similar to the 4-NP reduction reaction, a linear relationship between ln(Ct /C0) and time (sec) was observed (Fig. 8(c)). The rate constant of theMO degradation reaction also demonstrated that a larger amount of Q-AgNPs yielded a larger rate constant: 4.3 10−3/sec for 45 µL and 3.4 10−3/sec for 20 µL. When a smaller amount (20 µL) of Q-AgNPs was added, the reaction was completed at 1,260 sec, while a shorter time
for reaction completion was observed for a larger amount (45 µL) of Q-AgNPs. The catalytic activity was dependent on the amount of catalyst that was added. These results suggested that both Q-AuNPs and Q-AgNPs have capabil- ities as nano-catalysts.
AuNPs and AgNPs have arisen as cancer diagnostics and therapeutics. Thus, we selected cancer cells to evaluate the cytotoxicity of Q-AuNPs and Q-AgNPs. The cytotoxicity results on cancer cells are shown in Figure 9. Q-AuNPs mostly retained cell viability in a concentration range of 2.5 20 µM Au, as shown in Figure 9(a). Like Q-AuNPs, Q-AgNPs also retained cell viability in the tested con- centration range of Ag. At the highest concentration of 20 µM, both nanoparticles showed slight cytotoxicity on PANC-1 cells (94.1% cell viability with Q-AuNPs and 93.6% cell viability with Q-AgNPs). Within the tested con- centration ranges, both nanoparticles are potential candi- dates for drug delivery vehicles for anticancer agents. Specifically, an excellent review regarding the cyto- toxicity of metallic nanoparticles synthesized by plant- mediated routes can be found . The authors of the review reported that most of the plant-mediated synthe- sized metallic nanoparticles were cytotoxic; however, some were noncytotoxic to cancer cells. In the case of Q-AuNPs and Q-AgNPs, non-cytotoxicity was observed on the three cancer cell lines. Cytotoxicity is dependent on time and/or dose and is related to nanoparticle size and morphol- ogy . Metallic nanoparticles with spherical or quasi- spherical shapes were more cytotoxic than nanoparticles with other shapes, such as triangles, rods and hexagons.
MO methyl orange AgNPs silver nanoparticle SPR surface plasmon resonance.
Acknowledgments: This work was supported by the National Research Foundation of Korea (NRF) through a grant funded by the Korean Government by the Ministry of Education (NRF-2018R1D1A1B07041709). This work was partially supported by the National Research Founda- tion of Korea (NRF) and Center for Women In Science, Engineering and Technology (WISET) grant funded by the Ministry of Science and ICT (MSIT) under the team research program for female engineering students.
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