Modified silica nanoparticles with an Aminonaphthoquinone

ARTICLE

Modified silica nanoparticles with an Aminonaphthoquinone

Gleiciani Q. Silveira^I; Célia M. Ronconi^I,*; Maria D. Vargas^I,*; Rosane A. S. San Gil^II; Alvicler Magalhães^III,IV

^IInstituto de Química, Universidade Federal Fluminense, Campus do Valonguinho, Centro, 24020-150 Niterói-RJ, Brazil

^IIInstituto de Química, Universidade Federal do Rio de Janeiro, Ilha do Fundão, 21945-970 Rio de Janeiro-RJ, Brazil

^IIIInstituto Oswaldo Cruz, FIOCRUZ, CP 926, 21045-900 Rio de Janeiro-RJ, Brazil

^IVInstituto de Química, Universidade Estadual de Campinas, CP 6154, 13083-970 Campinas-SP, Brazil

ABSTRACT

The synthesis and characterization of silica nanoparticles (NPs) covalently modified with an aminonaphthoquinone are reported. The aminopropylsilicagelnaphthoquinone (APSGNQ) was obtained by nucleophilic substitution of 2-methoxy-1,4-naphthoquinone with aminopropylsilicalgel (APSG) NPs. Solid state ¹³C and ²⁹Si nuclear magnetic resonance spectra confirmed that the naphthoquinone is covalently bonded to APSG. Due to the solubility of APSGNQ in common organic solvents, solution ultraviolet-visible spectroscopy was used to determine the amount of naphthoquinone on the NPs surface (0.56 mmol of incorporated naphthoquinone per gram of APSGNQ) by comparison with the spectrum of 2-aminobutyl-1,4-naphthoquinone (ABNQ). Elemental analysis indicated that about 8% of the surface propylamine remained unreacted in APSGNQ. These multifunctional silica NPs have potential in medical applications.

Keywords: multifunctional material, silica nanoparticles, naphthoquinones, solid state ¹³C and ²⁹Si NMR

RESUMO

Nanopartículas de sílica (NPs) modificadas covalentemente com uma aminonaftoquinona foram sintetizadas e caracterizadas. A aminopropilsilicagelnaftoquinona (APSGNQ) foi obtida por substituição nucleofílica do grupo metóxi da 2-metóxi-1,4-naftoquinona por NPs modificadas com o grupo aminopropil (APSG). Os espectros de ressonância magnética nuclear de ¹³C e ²⁹Si no estado sólido confirmaram que a naftoquinona encontra-se ligada covalentemente à aminopropilsilicagel. Como o composto APSGNQ é solúvel em solventes orgânicos comuns, foi possível quantificar o ancoramento da naftoquinona na superfície das NPs modificadas por espectroscopia no ultravioleta-visível (0,56 mmol de naftoquinona ancorada por grama de APSGNQ), por comparação com o espectro do composto análogo 2-aminobutil-1,4-naftoquinona (ABNQ). Os dados das análises elementares indicaram que aproximadamente 8% da propilamina presente na superfície do composto APSGNQ não reagiu com a metóxinaftoquinona. Essas NPs de sílica multifuncionais têm potencial para aplicações médicas.

Introduction

Silica nanoparticles (NPs) modified with organic groups have been studied extensively.^1-3 A large number of silanes carrying different organic functional groups have been used for the silica NPs surface modification,⁴e.g., 3-aminopropyltriethoxysilane² and 3-iodopropyltrimethoxysilane.^3,5 Amorphous silica NPs present high thermal and chemical stability and high surface area, which allows a variety of interactions with other materials.⁶ The modified compounds differ significantly from the original matrix and may have various technological applications, such as support for drug delivery,⁷ biosensors,⁸ biomarkers,⁹ magnetic devices,⁷ fabrication of electric and thermal insulators¹⁰ and in photodynamic therapy,¹¹ among others. Organically modified silica NPs are particularly interesting for medical applications because they present low toxicity,¹² are biocompatible^12,13 and can be excreted in the urine.¹⁴

The work described herein involves the modification of silica NPs surface with 3-aminopropyltriethoxysilane for the incorporation of naphthoquinones. This class of compounds exhibits a wide range of biological properties, e.g., bactericide,¹⁵ fungicide,¹⁶ trypanocidal,¹⁷ antimalarial,¹⁸ antileishmanial,¹⁸ anticancer,^19,20 antitubercular²¹ and against Aedes aegypti.²² These biological activities have been associated to the interference of quinones in the electron transport chain by electron reduction processes, generating semiquinone radical (Q·) and hydroquinone anion (Q^2-).²³ The presence of amino groups has been shown to potentiate some of these biological activities.^20,24

Herein we describe the successful anchoring of an aminonaphthoquinone on silica NPs. To the best of our knowledge, NPs containing covalently-bound naphtoquinones have not yet been reported in the literature.

Experimental

Materials and methods

The silica nanoparticles (NPs) (Aldrich, 15 nm, 637238) were pretreated under high vacuum at 180 ºC for 10 h to remove adsorbed water. 3-Aminopropyltriethoxysilane and butylamine, both from Aldrich, were used without prior treatment. Toluene (Vetec) was previously dried with sodium/benzophenone under argon; methanol and ethanol were used as received. 2-(3-Butylamino)-1,4-naphthoquinone²⁵ and 2-methoxy-1,4-naphthoquinone²⁶ were prepared according to the literature. Transmission infrared (IR) spectra were obtained from KBr pellets with a FTIR Spectrum One (Perkin Elmer) spectrophotometer. IR diffuse reflectance (DRIFT) spectra were obtained with a FTIR Spectrum One (Perkin Elmer) spectrometer coupled to: i) a Praying Mantis Harrick, which consists of a domo of three windows (two KBr and a quartz) that protects the sample, ii) a Harrick Scientific ATC-124 model temperature controller and iii) a Matheson 8270 model argon flow controller (30 cm³ min^-1). Thermogravimetric analyses were conducted with a Netzsch STA 409 PC TG/DTA equipment. Approximately 10 mg of sample were weighed in an alumina crucible and heated at 35-1100 ºC, at the heating rate of 5 ºC min^-1, under nitrogen flow (30 cm³ min^-1). Elemental analyses were carried out at the Central Analítica of the Instituto de Química, Universidade de São Paulo, Brazil. Solid-state ¹³C and ²⁹Si NMR experiments were performed on a Bruker DRX300 spectrometer (7.05 T), operating at Larmor frequencies of 75.4 and 59.3 MHz respectively and equipped with a 4 mm Bruker CPMAS probe and ZrO₂ rotors, spinning at 6 kHz (¹³C) and 5 kHz (²⁹Si). For ¹³C NMR spectra, the ¹H-¹³C cross polarisation magic angle spinning (CPMAS) pulse sequence was employed, with optimised contact time of 2 ms and a repetition time (D1) of 4 s. ²⁹Si MAS NMR spectra were acquired by using both ¹H-²⁹Si cross polarisation (CPMAS) with contact time of 4 ms²⁷ and direct polarisation with high power ¹H dipolar decoupling (HPDD) pulse sequences. In this case experiments were performed by using repetition times from 10 to 300 s based on literature data for similar samples.²⁸ The results obtained with commercial silica NPs indicated that the repetition time of 60 s could be used to obtain quantitative Si spectra with enough signal-to-noise ratio to integrate the spectra. The external references used for the chemical shifts were the CH₃ signal of hexamethylbenzene at 17.3 ppm for ¹³C and the Q³ Si sites of caulinite at -91.5 ppm for ²⁹Si. UV-Vis spectra were obtained with a diode array 8452A (Hewlett Packard - HP) spectrophotometer in spectroscopic grade dimethylsulfoxide (dmso).

Synthesis of the silica nanoparticles modified with aminopropyl groups (APSG) and functionalized with naphthoquinone groups (APSGNQ)

The reaction is illustrated in Scheme 1. Modification of the NPs surface with the aminopropyl group² was carried out by addition of 3-aminopropyltriethoxysilane (APTES) (3 g, 13.5 mmol) to a suspension of silica NPs (3 g) in refluxing toluene (50.0 mL) under stirring and argon atmosphere. After 1.5 h, a small ethanol-containing toluene fraction was distilled off and more 3-aminopropyltriethoxysilane (1.05 g, 4.78 mmol) was added to the toluene suspension. This procedure was repeated 3 times. After the reaction mixture was cooled down to room temperature, the white solid was filtered off and washed copiously in a Soxhlet apparatus with CH₂Cl₂ (500 mL) and acetone (500 mL). The white solid (APSG) was then collected and dried under vacuum at 60 ºC (yield: 2.9 g).

A mixture containing APSG (200 mg) and 2-methoxy-1,4-naphthoquinone (MNQ, 100 mg, 0.53 mmol) in MeOH (7.0 mL) was heated under reflux for 16 h. The orange solid product was filtered off, washed with EtOH until the washing was colorless and dried under vacuum (yield of 2-(3-aminopropyl silica gel)-1,4-naphthoquinone, APSGNQ: 182 mg), Scheme 1a. For the purpose of comparison, the ungrafted 2-(3-butylamino)-1,4-naphthoquinone (ABNQ) was also synthesized from MNQ and butylamine (Scheme 1b).²⁶

Results and Discussion

FTIR spectra

FTIR analyses of the previously heated NPs, APSG and of the final product APSGNQ (Scheme 1) were carried out at room temperature (Figure S1, Supplemantary Information - SI). Diffuse reflectance FTIR (DRIFT) spectra were obtained after heating at 180 ºC under N₂ for 20 min (Figure 1), in order to remove all adsorbed water from the surface. The presence of water was evidenced in the spectra obtained at 100º and 150 ºC.

The bands at about 1097 and 804 cm^-1 refer to asymmetric and symmetric Si-O-Si stretches, respectively, which dominate the spectra of all samples (Figure S1, SI). The main differences between the spectra of NPs and APSG (Figures 1a and b, respectively) were due to the bands attributed to ν(C-H) stretches, clearly identified at 2975 and 2879 cm^-1, and weak bands due to ν(N-H) stretches at 3352 and 3294 cm^-1, associated to the presence of the aminopropyl group. Incorporation of the naphthoquinone to APSG (Figure 1c) resulted in the appearance, in the spectrum of APSGNQ, of bands at 3380, 1682 and 1607 cm^-1 assigned to ν(N-H), ν(C=O) and ν(C=C) stretches, respectively; the ν(N-H) band could only be observed upon heating the sample at 180 ºC, due to the presence of the stretching vibration band of adsorbed water, ν(O-H), observed at 3444 cm^-1. As expected the infrared spectra of APSGNQ and of a pure sample of ABNQ are very similar (Figure S2, SI) thus confirming the anchoring of the naphthoquinone moiety.

Elemental and thermogravimetric analyses

The nitrogen contents in the APSG and APSGNQ samples were assessed from elemental analysis and in the first case also by argentometry,³⁰ and the results are summarized in Table 1. Elemental analysis³¹ and argentometry of APSG gave respectively 0.61 and 0.59 mmol g^-1of amine groups on the surface. Considering that the C/N obtained was the expected one, it can be assumed that no silicon carbide was produced under the conditions employed for the elemental analysis (inert gas flow). Furthermore the elemental analysis of APSGNQ indicates that not all the amine groups have reacted with the naphthoquinone (see UV-Vis and NMR results below).

Thermogravimetric analysis was used to assess the thermal stability of APSG and APSGNQ (Figure 2). There is an initial weight loss that can be assigned to the release of adsorbed water from APSG and APSGNQ, respectively. Subsequently, there is a weight loss for both samples over the approximate temperature range of 200-600 ºC that can be assigned to both decomposition of the aminopropyl groups and thermal condensation of residual silanol groups. The total weight loss at 1100 ºC was 11.0, 19.0 and 17.0% for the silica NPs, APSG and APSGNQ samples respectively.

UV-Vis spectra

Quantification of the naphthoquinone content in APSGNQ was carried out by UV-Vis spectroscopy measurements. Both APSGNQ and ungrafted ABNQ were soluble in common organic solvents and exhibited very similar spectra. The spectra of APSGNQ (1.2 mg per 10 mL of dmso) and of ABNQ in the same solvent (2.86 × 10^-5 mol L^-1, Figure 3) showed a band around 334 nm corresponding to the aromatic system π-π* transitions, and a broad band in the visible region around 457 nm due to the quinone carbonyls π-p* transition.³² The naphthoquinone concentration in the APSGNQ solution was determined using the absorption band in the visible region, which resulted in 0.56 mmol of incorporated naphthoquinone per gram of APSGNQ. This result is in accordance with the elemental analyses and suggests that about 8% of the surface propylamine remained unreacted in APSGNQ. Thus, UV-Vis spectroscopy has been a valuable and quick method to determine the naphthoquinone content in this material.

Figure 4 shows the ²⁹Si CPMAS spectra obtained for the NPs, APSG and APSGNQ samples, whereas the ¹³C CPMAS spectra obtained for APSG, APSGNQ and 2-methoxy-1,4-naphthoquinone are depicted in Figure 5. With the pulse sequence employed (see Experimental), the ²⁹Si and ¹³C signals are related to the magnitude of the dipolar interaction with protons, which depends on geometrical factors, namely, the ¹H-²⁹Si and ¹H-¹³C internuclear distances, respectively, by factors r_SiH^-3 and r_CH*^-3. In this way Q⁴, Q³ and Q²²⁹Si sites are observed. Similarly, in the ¹³C NMR spectra, protonated and non-protonated carbon atoms can be observed.³³

In the ²⁹Si CPMAS spectrum of NPs (Figure 4a), signals due to SiO₂(OH)₂ (Q² sites) at -84 ppm, SiO₃-OH (Q³ sites) at -96 ppm and SiO₄ (Q⁴ sites) at -111 ppm were observed. The spectra of APSG and APSGNQ (Figures 4b and c, respectively) indicated the absence of the Q² sites and showed the presence of Tⁿ sites: in the -50 to -60 ppm range (T² site, C-Si(OSi)₂OH), and -60 to -75 ppm (T³ site, C-Si(OSi)₃), in addition to the Q³ and Q⁴ sites, at -98 and -107 ppm, respectively, thus confirming the presence of the aminopropyl group covalently bound to the silica NPs.³⁴ The relative increase in the intensity of peak Q⁴ in the spectrum of APSG in comparison with that of NPs (Figures 4b and c, respectively) indicates that further condensation has also occurred between unreacted hydroxy groups of silane molecules bound to the silica surface and hydrolyzed ethoxy groups from APTS or from bound -OSi(OEt)_×(CH₂)₃NH₂, resulting in oligomerized and polymerized layers, as described previously.²⁹

The concentration of functional groups in APSG and APSGNQ was measured from the relative intensities of Tⁿ and Qⁿ silicon groups observed by ²⁹Si MAS NMR under direct polarization and high power proton decoupling. The results indicated in both cases that about 3 molar % of Si-O sites corresponded to Tⁿ sites, i.e., that 3% of silicon atoms were bound to aminopropyl groups. This value, which is lower than those given by elemental analysis and argentometry (see above), is probably obtained because the low aminopropyl content of both materials makes quantitative analysis difficult.

¹³C CPMAS spectra of APSG and APSGNQ (Figures 5a and b) confirmed the results obtained from the ²⁹Si CPMAS NMR spectra. The carbon chemical shifts of CH₂-NH₂ (44 ppm), C-CH₂-C (23 ppm) and CH₂-Si (11 ppm) in the spectrum of APSG are similar to those obtained by Rahman et al.³⁵ The spectrum of APSGNQ exhibits the resonances of APSG together with a peak due to CH₂-NH-naphthoquinone (52 ppm) and those attributed to the naphthoquinone carbon atoms, thus confirming the presence of unreacted amine groups. The spectrum of 2-methoxy-1,4-naphthoquinone (MNQ) was included for comparison (Figure 5c) and presented well resolved signals, evidencing the crystalline nature of this compound. Displacement of the methoxy group by the surface amine of APSG was confirmed by the absence, in the spectrum of APSGNQ, of the peak associated to the MNQ O-CH₃ carbon, at 58 ppm, besides the clear shift of the C_ar-O signal at 161 ppm, in the spectrum of MNQ, to 149 ppm in the spectrum of APSGNQ. Furthermore, shifts of the signals attributed to the C=O groups (at 185 and 180 ppm) and C_ar (between 120 and 140 ppm) are also observed. We conclude, therefore, that the incorporation of 1,4-naphthoquinones onto modified silica NPs is easily carried out via the same route used for the synthesis of amino-substituted 1,4-naphthoquinones.^26,36 The fact that some amine groups remained unreacted might be associated to the oligomerization or polymerization of silane molecules bound to the silica surface (see above NMR discussion)²⁹ making it difficult for the amine to react with the naphthoquinone.

Conclusions

Our work has demonstrated that the reaction of aminopropylsilicalgel NPs with labile 2-methoxy-1,4-naphthoquinones is a good route to silica NPs containing bound amino-naphthoquinones. The material was fully characterized by a combination of techniques that established that the 1,4-naphthoquinone is covalently bound to the silica NPs. Even though the methodology proved itself efficient, further investigation is necessary to produce material with larger amounts of aminonaphthoquinone groups on the silica surface. Considering that modification of the 1,4- and 1,2-naphthoquinone nuclei with amines has resulted in increased cytotoxic activity²⁰ and that surface modified NPs can be efficiently endocytosed in vitro by a variety of mammalian cells including cancer and non cancer cells,¹³ it is possible that the binding of naphthoquinone onto NPs may help to increase the concentration of this compound inside the cells and therefore its cytotoxicity.

Supplementary Information

Supplementary information associated with this paper contains the FTIR spectra of the synthesized materials. It is available free of charge at http://jbcs.sbq.org.br as PDF file.

Acknowledgements

Authors gratefully acknowledge FAPERJ (Primeiros Projetos and Jovens Emergentes), Pronex-FAPERJ (grant number E-26/171.512/2006) and CAPES (G. Q. S. fellowship) for financial support. M. D. V and C. M. R. are recipients of CNPq research fellowships. We thank Dr. A. Faro (IQ-UFRJ, Brazil) for the DRIFT spectra and Dr. Ana Maria Rangel de Figueiredo Teixeira and Wildson Vieira Cerqueira (IQ-UFF) for the TGA analyses.

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Submitted: July 19, 2010

Published online: February 10, 2011

FAPESP has sponsored the publication of this article.

Supplementary Information

Figure S2 - Click to enlarge

Publication Dates

• Publication in this collection
  16 May 2011
• Date of issue
  May 2011

History

• Accepted
  10 Feb 2011
• Received
  19 July 2010