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Adsorption and Release of 5-Fluorouracil (5FU) from Mesoporous Silica Nanoparticles
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ScienceDirect Materials Today: Proceedings 19 (2019) 1722–1729
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ICCSE 2018
Adsorption and Release of 5-Fluorouracil (5FU) from Mesoporous Silica Nanoparticles Nur Syazaliyana Azali1, Nur Hidayatul Nazirah Kamarudin1,2,*, Ainul Rasyidah Abdul Rahim1, Norzaidhatul Syifa’a Jamal Nasir2, Sharifah Najiha Timmiati3, Nur Farhana Jaafar4 1
2
Research Centre for Sustainable Process Technology (CESPRO), Faculty of Engineering and Built Environment, Universiti Kebangsaan
Malaysia, 43600 UKM Bangi, Selangor, Malaysia. Chemical Engineering Programme, Faculty of Engineering and Built Environment, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia. 3 Fuel Cell Institute (SELFUEL), Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia. 4 School of Chemical Sciences, Universiti Sains Malaysia, 11800 USM Penang, Malaysia.
Abstract Recently, nanoparticle technology have attracted widespread interest among researchers as it is very suitable to be applied in many industrial areas especially in pharmaceuticals. Due their physical characteristic, it will lead to a significant advantage in industry specifically in drug delivery system (DDS). Hence, MSNs was synthesized by using sol-gel method and used to carry an anticancer drug, 5-Fluorouracil (5FU). The samples were analyzed and characterized by using X-ray Diffraction (XRD), Transmission Electron Microscope (TEM) and Fourier Transform Infrared (FTIR). From data obtained, the MSNs was confirmed in hexagonal structure with increased of porosity and diameter. For adsorption of drug, different mediums of drug by which in ethanol medium and deionized water medium and various concentration of 5FU were used as parameter to measure the loading capacity of 5-FU into MSNs. An adsorption data showed that 95.27% of 5FU in ethanol medium was success to load into MSN after 24 hours of adsorption and with concentration of 20 ppm, 96.35% was adsorbed. For release analysis of 5FU from MSN5FU, the activity was held under body temperature condition with pH of 7.4. The result showed that after 24 h of drug released analysis, 9% of drug from ethanolic adsorption while 23% of drug from deionized water adsorption was released. © 2019 Elsevier Ltd. All rights reserved. Selection and peer-review under responsibility of the scientific committee of the International Conference on Chemical Sciences and Engineering: Advance and New Materials, ICCSE 2018. Keywords: Drug Delivery System (DDS);adsorption; release; Mesoporous Silica Nanoparticles (MSNs); 5-Fluorouracil (5-FU) .
* Corresponding author. Tel.: +6017-7304857 E-mail address: [email protected] 2214-7853 © 2019 Elsevier Ltd. All rights reserved. Selection and peer-review under responsibility of the scientific committee of the International Conference on Chemical Sciences and Engineering: Advance and New Materials, ICCSE 2018.
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1. Introduction Drug delivery system (DDS) specialized in controlled release technology has been introduced since 1970s and continuously expand until now with various product has produced and recently, many studies regarding to silica nanostructured have gained a widespread attention to researchers in various fields especially in pharmaceuticals as it seem able to carry drug to target tissues via systemic circulation [1]. Silica nanostructured is an atomic microscopic sized less than 100 nanometer and have a very reactive surface that will guarantee an adsorption of therapeutic agent into its pore [2]. Silica nanostructured is an atomic microscopic sized less than 100 nanometer and have a very reactive surface that will guarantee an adsorption of therapeutic agent into its pore [3, 4]. There are several advantages of using MSNs as the carrier for DDS. Among these advantages are ordered porous structure which help a better control in drug loading and released mechanism, larger than 1 cm3/g pore volume and 700 m2/g surface area, particle size can be tune from 50 to 300 nm which suitable for facile endocytosis by living cells, surface functionalization for achieving better guard in drug loading and release, good biocompatibility which means it will excreted through faeces and urine without mending in the body and nontoxicity [5-9]. Regarding to the advantages of MSNs, this show that MSNs is the best carrier for DDS as compared to other nanostructured carrier to carry various kind of drug such as 5-Fluorouracil (5FU) drug for treatment purpose. 5FU is commonly used to treat various kind of cancer such as breast, pancreas, gastrointestinal and liver [10-12]. 5FU is a water soluble in the mean of hydrophilic acidic drug and as antineoplastic agent that extensively used in cancer chemotherapy treatment especially for treatment of solid tumours. 5FU also being known as one of the antimetabolic drug that will act as antimetabolite to avoid reoccurring subsequent scarring from trabuculomy and helps to prevent long-term retinal reattachment of prognosis [13]. 5FU has been used widely in clinical application but due to resistance and low bioavailability of 5FU lead to ample limitations of its usage [14]. Other than that, 5FU will metabolized inside body easily and in order to remain in the body, high demand of 5FU will continuously demanded. Despite of treating cancer cells, the consumers will affected from high toxicity in their body [15-17]. Pressure over bone marrow that is important in immunity production, decreases of white blood cells, diarrhea and vomit are the other side effect of consuming higher dose of 5FU [18]. This shows that MSNs is important ifor carrying drug like 5-FU in order to reduce dosage intake and thus reduce their side effect towards consumers. There are various methods in synthesizing MSNs and one of them is sol- gel method which offers money saving, exclusive and simple method. On the other hands the MSNs produced are non- toxic and biocompatible [1]. Tetraethyl orthosilicate (TEOS) usually been used as a forming agent which will produced a sample with moderate reactivity and good control of robust network [19]. The MSNs were combined with different kind of materials and turns into different formulation before drug loading in order to gain better release rate and higher bioavailability of the drug [20]. Modification of MSNs by using 3-aminopropyltriethoxysilane (APTES) showed an enlargement of pore size thus improved the ability of MSNs to load the drug [21]. In DDS, drug will be load into MSNs involving drug stirring or suspension, immersing the drug into MSNs for certain period until reach the equilibrium, involving vacuum, formation of emulsion, gravimetric method [22], pressure method, evaporation of solvent within carrier to contain drug and delivery process [23]. Once the drug been loaded into its carrier by mean MSNs, the drug needed to be release at targeted cancer cells. There are few factor that can influence the rates of drug release such as support structural properties, features of drug, simulated biological fluid and drug- linker- support system interaction properties, condition of release and support surface properties by binding functional organic group modification. The other few factor that will influence release rate include temperature, acidic condition, redox agents, light and enzymes [3]. And also variety of primary methods in releasing the drug from its carrier like diffusion, degradation and swelling followed by diffusion [23]. The objective of this study was to synthesis MSNs as a carrier for anticancer drug 5FU and synthesis of MSNs was confirmed through X- Ray Diffraction (XRD) to identify the crystalinility of MSNs and Transmission Electron Microscopy (TEM) to confirm the shape and arrangement of MSNs. Other than that, MSNs sample also being analysed through Fourier Transform Infrared Spectroscopy (FTIR) to determine functional group or cross-linked of atom. Next, MSNs were used to measure its ability to load and release the anticancer drug 5FU. The loading analysis of 5FU into MSNs was held in different medium conditions and concentration of 5FU. The medium conditions of 5FU were prepared in deionized water medium and ethanol medium in order to measure the most suitable condition for drug adsorption into its carrier. Furthermore, different concentrations 20 ppm, 40 ppm, 60 ppm, 80 ppm and 100 ppm of 5FU were prepared to measure the optimum concentration needed for 5FU to be
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loaded into MSNs. All the analysis were using Perkin Elmer Lambda 35 UV- Vis and concentration of 5FU were measured. 2. Experimental 2.1. Materials Cetyltrimethylammonium bromide (CTAB), ethylene glycol (EG), tetraethylortho-silicate (TEOS), and 3aminopropyl trieth-oxysilane (APTES) were purchased from Sigma Aldrich. Am-monium hydroxide (NH4OH) was obtained from Qrec. All the chemicals were used as received without further treatment. 2.2. Synthesis of mesoporous silica nanoparticles (MSNs) MSNs were prepared according to the procedure reported in the literature [21, 24]. The synthesis procedure was as follows. CTAB, EG, and NH4OH were dissolved in water with the fol-lowing molar composition and the mixture were stir vigorously. In order to get white micelles solution, TEOS were added to the mixture followed by addition of APTES to the mixture. The mixture was kept under continuous stirring condition and then centrifuged to collect sample. Then the sample was heated for 24h to obtain the gel. Next, the powder was calcined to remove the surfactant. Infrared spectroscopy (FTIR) was checked to ensure complete removal of the surfactant which did not reveal the presence of any residual organic species. 2.3. Materials characterization The crystallinity of the catalysts was measured with a Bruker Advance D8 X-ray powder diffractometer (XRD) with radiation of Cu Kά (λ= 1.5418Å) and the monochromatic beam diffrac-tion at 40 kV and 40 mA. Transmission Electron Microscope (TEM) was carried out by using a Philips TEMCM12 in order to get the close up image of MSNs. For observing the functioning group held in the sample, KBr method with range between 400 to 4000 cm-1 Fourier Transform Infra- red (Perkin Elmer Spec-trum GX FTIR Spectrometer) was performed. 2.4. 5FU loading measurement in different medium Powdered mesoporous samples soaked into ethanol solution of 5FU for sample loading. Then stirred continuously for 24 h at 310K. A MSN and 5FU were poured into conical flask in 1:1 (by weight) ratio by mean practically 150 mg of 5FU was dis-solved in ethanol and 150 mg of dried MSNs. Mixed the solu-tion for 24 h at temperature of 37oC and MSN-5FU obtained. The 2mL aliquots was withdrawn from mixture in every 5 h and centrifuged to detect the concentration of 5FU in the solution and then by using UV-Vis spectrophotometer (Perkin Elmer, Lambda 35) in order to determine residual concentration of 5FU. Next, the samples were recovered through filtration, ethanol washed and dried for 24 h at 313 K. 5FU adsorption band was taken at its maximum wavelength (λ). The whole method was repeat by soaking 5FU into deionized water medium. 2.5. 5FU loading measurement in different concentration Powdered mesoporous samples soaked into 100ppm concen-tration of 5FU for sample loading. Then stirred continuously for 24 h at 310K. A MSN and 5FU were poured into conical flask in 1:1 (by weight) ratio by mean practically 150 mg of 5FU was dissolved in ethanol and 150 mg of dried MSNs. Mixed the solution for 24 h at temperature of 37oC and MSN-5FU ob-tained. The 2mL aliquots was withdrawn from mixture in every 5 h and centrifuged to detect the concentration of 5FU in the solution and then by using UV-Vis spectrophotometer (Perkin Elmer, Lambda 35) in order to determine residual concentration of 5FU. Next, the samples were recovered through filtration, ethanol washed and dried for 24 h at 313 K. 5FU adsorption band was taken at its maximum wavelength (λ). The whole method was repeat by 80 ppm, 60 ppm, 40 ppm and 20 ppm different concentration of 5FU.
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2.6. 5FU release measurement For releasing of 5FU profile, MSN-5-FU was added to 200 mL round bottom flask with 100 mL simulated body fluid (SBF) at 37oC under continuous stirring for 24 h. UV-Vis was used to determine concentration of 5FU in release fluid at different release time. For every 3mL of release fluid were taken out for analysis, replaced again with fresh SBF. 3. Results and Discussion 3.1. Characterization In this study, an anticancer drug, 5FU was chosen as drug model to test the use of carrier MSNs in DDS. The DDS procedure was prepared by soaking MSNs powdered into 5FU liquid and it required 5FU to diffuse into hexagonally mesopore of MSNs available within the framework. Since 5-FU is a soluble type of drug, so loading the drug into MSNs carrier using mixing method is better than any other methods [23]. 3.2. Crystallinity study According to XRD data of MSN in the low 2Ө region, it is shown in Figure 1 that MSNs is in hexagonally shaped. At angle 2Ө, the diffraction showed at well- resolved Bragg diffraction peaks at 2.5o, 4.4o and 5.0o as assigned to (100), (110) and (200) angle of diffraction reflect the hexagonal structure of MSNs. The sharp peak at 2.5o indicate the high order crystalline structure of MSNs was revealed [24]. The result obtained from XRD data is a typical XRD result for MSNs type materials [25]. Thus, from XRD data, it can be confirmed that MSNs is in hexagonal structure due to peaks obtained. Next, with the addition of APTES during synthesis of MSNs enhanced its hexagonally shaped and the structure obtained is in orderly arrangement [21]. 14000
Intensity (a.u)
12000 10000 8000 6000 4000 2000 0
0
2
4
6
8
10
2 theta (°) Fig. 1: XRD analysis result of MSNs.
3.3. Morphology study The morphology of MSNs was observed by using TEM analysis. According to data obtained from TEM analysis, the MSNs has pore size of 50 nm by which obeyed the characteristic of MSNs where the pore size should be less than 50 nm to be considered as mesoporous particles [26]. The TEM image as shown in Figure 2, it can be seen clearly that MSNs structure were in depict hexagonal arrays in which pore was similar to bee-hive structure with hundreds of empty frameworks. The mesopore of MSNs were in high volume and also in orderly arrangement. The
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empty frameworks then will be loaded with drug 5-FU. Based on the image obtained from TEM, the MSNs showed hexagonally and relatively rough structure by mean a typical image for MSNs [27].
50 nm Fig. 2: TEM image of MSNs
3.4. Functional group study
Transmittance [%]
Figure 3 showed the functional group contained in the particle can be determine through FTIR analysis in the range from 400 to 4000 cm-1. In the synthesis of MSNs, the formation of MSNs was modified with APTES and CTAB which means from analysis of FTIR will gave the amination of MSNs C-H deformation vibration at 2926 and 2851 cm-1 and peak of 1485 cm-1 indicate C-H deformation vibration as existed of CTAB [3]. As refer to FTIR analysis of MSNs, those peaks were not observed. This does mean that all the peaks attribute to CTAB has been disappeared as during synthesis MSNs, all CTAB were flushed out during calcination. Analysis of MSNs showed that MSNs was successfully prepared according to few peaks that indicate functional group contained in the carrier. A O-H stretching and bending vibration was observed at broad band peak 3418.2 cm-1. There is also a peak observed at wavenumbers of 1081.3 cm-1 in very high intensity by which every MSNs compulsory to exhibit this peak. This peak attribute to Si-O-Si assymetric stretching [24, 28-30]. Moreover, there is another peak being detected at 808.7 cm-1 where these peaks indicate the presence of Si-O vibration modes for MSNs.
3500
2500 1500 Wavenumber [cm-1] Fig 3: FTIR spectra of MSNs
500
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3.5. MSNs adsorptivity toward 5-FU 5-FU was used as a model drug to evaluate the loading capacity and drug storage ability of the synthesized MSNs. The final product obtained containing MSNs loaded with drug and solvent residual [31]. For the analysis of drug 5-FU load into MSNs, there are two mediums were set in order to testify the ability of MSNs to load drug into its pore. The two conditions are 5-FU was dissolve in ethanol medium and deionized water medium by mean the analysis of drug loading will be held in both conditions. According to UV-Vis analysis of drug loaded, the highest peak of spectrum was observed at 264 nm and the loading analysis was held about 24 h. The UV-Vis result showed differences in both loading medium. The loading rate of 5FU was differ for both deionized water medium and ethanol medium of drug solvent as the drug loading in ethanol medium showed higher loading percentage as compared with drug loading in deionized water medium. According to Figure 4, the drug loading capacity of ethanol condition is about 96.35% by mean almost complete load of drug into MSNs. For hydrophilic type of drug, ethanol condition method is more suitable due to smaller vesicles and efficiency of drug load will be higher to achieve [32]. This is due to dispersion theory of solid. As the 5FU being dissolved in ethanol, the drug was dispersed completely in the solvent solution. Thus, increase the tendency of drug being loaded into MSNs s this solid dispersion technique is very helpful especially in pharmaceuticals for drug adsorption [33]. Other than that, the presence of OH group in ethanol medium played a role of increased that electronegativity of solution medium and thus help in bonding mechanism between MSNs and drug model 5FU.
Adsorption percentage (%)
120 100 80 60 40 20
%DL Air Ternyah Ion Deionized water
Ethanol %DL Etanol 0 0
5
10
15 Time (h)
20
25
30
Fig. 4: Adsorption of 5-FU into MSNs in ethanol and deionized water.Evaluation of MSNs on 5-FU release behavior
The simulated body fluid was used to study the MSNs release performance in DDS. For drug release analysis, the drug release was held for 24 h under continuous stirring and body temperature indication of 37oC. According to UVVis analysis for 5-FU release from MSNs, in ethanol medium of MSN-5FU as shown in Figure 5, the release rate percentage was slower than MSN-5FU in deionized water medium in which 9% and 23% respectively. Hence, thus showed that the presence of OH ion concentration of ethanol increase the molecular bond between MSNs and 5FU. According to Peretti 2018 [34] the presence of OH ion in the solution also improved the drug interaction with its carrier and make the deprotonation between drug and its carrier become harder thus lead to slow release of drug from carrier. As the drug being dissolved in ethanol medium, the presence of silanol group increase the bonding between 5FU and MSNs and thus slower the rate of release percentage as compared to dionized water medium where might have no ion concentration in between the interaction of MSNs and 5FU hence, it will loosen the bonding of 5FU and MSNs and lead to the deprotonation between MSNs and 5FU become easier and increase the release rate of 5FU. As seen on data analysis for drug released, drug release in deionized water condition of MSN5FU has higher release rate as compared to ethanol condition which will determine the release rate in human body later.
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Release percentage (%)
25 20 15 10 5 Deionized water Ethanol 0 0
5
10
15
20
25
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Time (h) Fig. 5: Release behavior of 5-FU from MSNs in ethanol and deionized water.
4. Conclusion From this study, the physical characteristic of MSNs such as high pore volume and size, functional surface and large surface area become a crucial factor for delivering 5FU. Furthermore, in order for 5FU fully loaded into its carrier MSNs, solvent medium such as ethanol and concentration of drug 5FU plays a vital loading factors of 5FU into MSNs. In ethanol medium of MSN-5FU, the release rate percentage was slower than MSN-5FU in deionized water medium, which is 9% and 23% respectively. Lastly, a modern technology of DDS could be tailored for a slower release to suit the anti-cancer drug delivery. Acknowledgement The authors are grateful for the financial support by the Research University Grant from Universiti Kebangsaan Malaysia (GUP-2018-046) for their support. References [1] Z. Z. Li, L. X. Wen, L. Shao, and J. F. Chen, "Fabrication of porous hollow silica nanoparticles and their applications in drug release control," J Control Release, vol. 98, pp. 245-54, Aug 11 2004. [2] Y. S and G. U, "Nanoparticle Based Delivery of miRNAs to Overcome Drug Resistance in Breast Cancer," Journal of Nanomedicine & Nanotechnology, vol. 07, 2016. [3] X. Chen, X. Yao, C. Wang, L. Chen, and X. Chen, "Mesoporous silica nanoparticles capped with fluorescence-conjugated cyclodextrin for pH-activated controlled drug delivery and imaging," Microporous and Mesoporous Materials, vol. 217, pp. 46-53, 2015. [4] I. Munaweera, B. Koneru, Y. Shi, A. J. Di Pasqua, and J. K. J. Balkus, "Chemoradiotherapeutic wrinkled mesoporous silica nanoparticles for use in cancer therapy," APL Materials, vol. 2, p. 113315, 2014. [5] Y. He, S. Liang, M. Long, and H. Xu, "Mesoporous silica nanoparticles as potential carriers for enhanced drug solubility of paclitaxel," Mater Sci Eng C Mater Biol Appl, vol. 78, pp. 12-17, Sep 1 2017. [6] D. Sen Karaman, G. Patrignani, E. Rosqvist, J. H. Smatt, A. Orlowska, R. Mustafa, et al., "Mesoporous silica nanoparticles facilitating the dissolution of poorly soluble drugs in orodispersible films," Eur J Pharm Sci, vol. 122, pp. 152-159, Sep 15 2018. [7] X. Xu, S. Lü, C. Wu, Z. Wang, C. Feng, N. Wen, et al., "Curcumin polymer coated, self-fluorescent and stimuli-responsive multifunctional mesoporous silica nanoparticles for drug delivery," Microporous and Mesoporous Materials, vol. 271, pp. 234-242, 2018. [8] E. Yamamoto and K. Kuroda, "Preparation and Controllability of Mesoporous Silica Nanoparticles," 2018. [9] Y. Zhou, G. Quan, Q. Wu, X. Zhang, B. Niu, B. Wu, et al., "Mesoporous silica nanoparticles for drug and gene delivery," Acta Pharm Sin B, vol. 8, pp. 165-177, Mar 2018. [10] C. Focaccetti, A. Bruno, E. Magnani, D. Bartolini, E. Principi, K. Dallaglio, et al., "Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes," PLoS One, vol. 10, p. e0115686, 2015.
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ICCSE 2018
Adsorption and Release of 5-Fluorouracil (5FU) from Mesoporous Silica Nanoparticles Nur Syazaliyana Azali1, Nur Hidayatul Nazirah Kamarudin1,2,*, Ainul Rasyidah Abdul Rahim1, Norzaidhatul Syifa’a Jamal Nasir2, Sharifah Najiha Timmiati3, Nur Farhana Jaafar4 1
2
Research Centre for Sustainable Process Technology (CESPRO), Faculty of Engineering and Built Environment, Universiti Kebangsaan
Malaysia, 43600 UKM Bangi, Selangor, Malaysia. Chemical Engineering Programme, Faculty of Engineering and Built Environment, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia. 3 Fuel Cell Institute (SELFUEL), Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia. 4 School of Chemical Sciences, Universiti Sains Malaysia, 11800 USM Penang, Malaysia.
Abstract Recently, nanoparticle technology have attracted widespread interest among researchers as it is very suitable to be applied in many industrial areas especially in pharmaceuticals. Due their physical characteristic, it will lead to a significant advantage in industry specifically in drug delivery system (DDS). Hence, MSNs was synthesized by using sol-gel method and used to carry an anticancer drug, 5-Fluorouracil (5FU). The samples were analyzed and characterized by using X-ray Diffraction (XRD), Transmission Electron Microscope (TEM) and Fourier Transform Infrared (FTIR). From data obtained, the MSNs was confirmed in hexagonal structure with increased of porosity and diameter. For adsorption of drug, different mediums of drug by which in ethanol medium and deionized water medium and various concentration of 5FU were used as parameter to measure the loading capacity of 5-FU into MSNs. An adsorption data showed that 95.27% of 5FU in ethanol medium was success to load into MSN after 24 hours of adsorption and with concentration of 20 ppm, 96.35% was adsorbed. For release analysis of 5FU from MSN5FU, the activity was held under body temperature condition with pH of 7.4. The result showed that after 24 h of drug released analysis, 9% of drug from ethanolic adsorption while 23% of drug from deionized water adsorption was released. © 2019 Elsevier Ltd. All rights reserved. Selection and peer-review under responsibility of the scientific committee of the International Conference on Chemical Sciences and Engineering: Advance and New Materials, ICCSE 2018. Keywords: Drug Delivery System (DDS);adsorption; release; Mesoporous Silica Nanoparticles (MSNs); 5-Fluorouracil (5-FU) .
* Corresponding author. Tel.: +6017-7304857 E-mail address: [email protected] 2214-7853 © 2019 Elsevier Ltd. All rights reserved. Selection and peer-review under responsibility of the scientific committee of the International Conference on Chemical Sciences and Engineering: Advance and New Materials, ICCSE 2018.
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1. Introduction Drug delivery system (DDS) specialized in controlled release technology has been introduced since 1970s and continuously expand until now with various product has produced and recently, many studies regarding to silica nanostructured have gained a widespread attention to researchers in various fields especially in pharmaceuticals as it seem able to carry drug to target tissues via systemic circulation [1]. Silica nanostructured is an atomic microscopic sized less than 100 nanometer and have a very reactive surface that will guarantee an adsorption of therapeutic agent into its pore [2]. Silica nanostructured is an atomic microscopic sized less than 100 nanometer and have a very reactive surface that will guarantee an adsorption of therapeutic agent into its pore [3, 4]. There are several advantages of using MSNs as the carrier for DDS. Among these advantages are ordered porous structure which help a better control in drug loading and released mechanism, larger than 1 cm3/g pore volume and 700 m2/g surface area, particle size can be tune from 50 to 300 nm which suitable for facile endocytosis by living cells, surface functionalization for achieving better guard in drug loading and release, good biocompatibility which means it will excreted through faeces and urine without mending in the body and nontoxicity [5-9]. Regarding to the advantages of MSNs, this show that MSNs is the best carrier for DDS as compared to other nanostructured carrier to carry various kind of drug such as 5-Fluorouracil (5FU) drug for treatment purpose. 5FU is commonly used to treat various kind of cancer such as breast, pancreas, gastrointestinal and liver [10-12]. 5FU is a water soluble in the mean of hydrophilic acidic drug and as antineoplastic agent that extensively used in cancer chemotherapy treatment especially for treatment of solid tumours. 5FU also being known as one of the antimetabolic drug that will act as antimetabolite to avoid reoccurring subsequent scarring from trabuculomy and helps to prevent long-term retinal reattachment of prognosis [13]. 5FU has been used widely in clinical application but due to resistance and low bioavailability of 5FU lead to ample limitations of its usage [14]. Other than that, 5FU will metabolized inside body easily and in order to remain in the body, high demand of 5FU will continuously demanded. Despite of treating cancer cells, the consumers will affected from high toxicity in their body [15-17]. Pressure over bone marrow that is important in immunity production, decreases of white blood cells, diarrhea and vomit are the other side effect of consuming higher dose of 5FU [18]. This shows that MSNs is important ifor carrying drug like 5-FU in order to reduce dosage intake and thus reduce their side effect towards consumers. There are various methods in synthesizing MSNs and one of them is sol- gel method which offers money saving, exclusive and simple method. On the other hands the MSNs produced are non- toxic and biocompatible [1]. Tetraethyl orthosilicate (TEOS) usually been used as a forming agent which will produced a sample with moderate reactivity and good control of robust network [19]. The MSNs were combined with different kind of materials and turns into different formulation before drug loading in order to gain better release rate and higher bioavailability of the drug [20]. Modification of MSNs by using 3-aminopropyltriethoxysilane (APTES) showed an enlargement of pore size thus improved the ability of MSNs to load the drug [21]. In DDS, drug will be load into MSNs involving drug stirring or suspension, immersing the drug into MSNs for certain period until reach the equilibrium, involving vacuum, formation of emulsion, gravimetric method [22], pressure method, evaporation of solvent within carrier to contain drug and delivery process [23]. Once the drug been loaded into its carrier by mean MSNs, the drug needed to be release at targeted cancer cells. There are few factor that can influence the rates of drug release such as support structural properties, features of drug, simulated biological fluid and drug- linker- support system interaction properties, condition of release and support surface properties by binding functional organic group modification. The other few factor that will influence release rate include temperature, acidic condition, redox agents, light and enzymes [3]. And also variety of primary methods in releasing the drug from its carrier like diffusion, degradation and swelling followed by diffusion [23]. The objective of this study was to synthesis MSNs as a carrier for anticancer drug 5FU and synthesis of MSNs was confirmed through X- Ray Diffraction (XRD) to identify the crystalinility of MSNs and Transmission Electron Microscopy (TEM) to confirm the shape and arrangement of MSNs. Other than that, MSNs sample also being analysed through Fourier Transform Infrared Spectroscopy (FTIR) to determine functional group or cross-linked of atom. Next, MSNs were used to measure its ability to load and release the anticancer drug 5FU. The loading analysis of 5FU into MSNs was held in different medium conditions and concentration of 5FU. The medium conditions of 5FU were prepared in deionized water medium and ethanol medium in order to measure the most suitable condition for drug adsorption into its carrier. Furthermore, different concentrations 20 ppm, 40 ppm, 60 ppm, 80 ppm and 100 ppm of 5FU were prepared to measure the optimum concentration needed for 5FU to be
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loaded into MSNs. All the analysis were using Perkin Elmer Lambda 35 UV- Vis and concentration of 5FU were measured. 2. Experimental 2.1. Materials Cetyltrimethylammonium bromide (CTAB), ethylene glycol (EG), tetraethylortho-silicate (TEOS), and 3aminopropyl trieth-oxysilane (APTES) were purchased from Sigma Aldrich. Am-monium hydroxide (NH4OH) was obtained from Qrec. All the chemicals were used as received without further treatment. 2.2. Synthesis of mesoporous silica nanoparticles (MSNs) MSNs were prepared according to the procedure reported in the literature [21, 24]. The synthesis procedure was as follows. CTAB, EG, and NH4OH were dissolved in water with the fol-lowing molar composition and the mixture were stir vigorously. In order to get white micelles solution, TEOS were added to the mixture followed by addition of APTES to the mixture. The mixture was kept under continuous stirring condition and then centrifuged to collect sample. Then the sample was heated for 24h to obtain the gel. Next, the powder was calcined to remove the surfactant. Infrared spectroscopy (FTIR) was checked to ensure complete removal of the surfactant which did not reveal the presence of any residual organic species. 2.3. Materials characterization The crystallinity of the catalysts was measured with a Bruker Advance D8 X-ray powder diffractometer (XRD) with radiation of Cu Kά (λ= 1.5418Å) and the monochromatic beam diffrac-tion at 40 kV and 40 mA. Transmission Electron Microscope (TEM) was carried out by using a Philips TEMCM12 in order to get the close up image of MSNs. For observing the functioning group held in the sample, KBr method with range between 400 to 4000 cm-1 Fourier Transform Infra- red (Perkin Elmer Spec-trum GX FTIR Spectrometer) was performed. 2.4. 5FU loading measurement in different medium Powdered mesoporous samples soaked into ethanol solution of 5FU for sample loading. Then stirred continuously for 24 h at 310K. A MSN and 5FU were poured into conical flask in 1:1 (by weight) ratio by mean practically 150 mg of 5FU was dis-solved in ethanol and 150 mg of dried MSNs. Mixed the solu-tion for 24 h at temperature of 37oC and MSN-5FU obtained. The 2mL aliquots was withdrawn from mixture in every 5 h and centrifuged to detect the concentration of 5FU in the solution and then by using UV-Vis spectrophotometer (Perkin Elmer, Lambda 35) in order to determine residual concentration of 5FU. Next, the samples were recovered through filtration, ethanol washed and dried for 24 h at 313 K. 5FU adsorption band was taken at its maximum wavelength (λ). The whole method was repeat by soaking 5FU into deionized water medium. 2.5. 5FU loading measurement in different concentration Powdered mesoporous samples soaked into 100ppm concen-tration of 5FU for sample loading. Then stirred continuously for 24 h at 310K. A MSN and 5FU were poured into conical flask in 1:1 (by weight) ratio by mean practically 150 mg of 5FU was dissolved in ethanol and 150 mg of dried MSNs. Mixed the solution for 24 h at temperature of 37oC and MSN-5FU ob-tained. The 2mL aliquots was withdrawn from mixture in every 5 h and centrifuged to detect the concentration of 5FU in the solution and then by using UV-Vis spectrophotometer (Perkin Elmer, Lambda 35) in order to determine residual concentration of 5FU. Next, the samples were recovered through filtration, ethanol washed and dried for 24 h at 313 K. 5FU adsorption band was taken at its maximum wavelength (λ). The whole method was repeat by 80 ppm, 60 ppm, 40 ppm and 20 ppm different concentration of 5FU.
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2.6. 5FU release measurement For releasing of 5FU profile, MSN-5-FU was added to 200 mL round bottom flask with 100 mL simulated body fluid (SBF) at 37oC under continuous stirring for 24 h. UV-Vis was used to determine concentration of 5FU in release fluid at different release time. For every 3mL of release fluid were taken out for analysis, replaced again with fresh SBF. 3. Results and Discussion 3.1. Characterization In this study, an anticancer drug, 5FU was chosen as drug model to test the use of carrier MSNs in DDS. The DDS procedure was prepared by soaking MSNs powdered into 5FU liquid and it required 5FU to diffuse into hexagonally mesopore of MSNs available within the framework. Since 5-FU is a soluble type of drug, so loading the drug into MSNs carrier using mixing method is better than any other methods [23]. 3.2. Crystallinity study According to XRD data of MSN in the low 2Ө region, it is shown in Figure 1 that MSNs is in hexagonally shaped. At angle 2Ө, the diffraction showed at well- resolved Bragg diffraction peaks at 2.5o, 4.4o and 5.0o as assigned to (100), (110) and (200) angle of diffraction reflect the hexagonal structure of MSNs. The sharp peak at 2.5o indicate the high order crystalline structure of MSNs was revealed [24]. The result obtained from XRD data is a typical XRD result for MSNs type materials [25]. Thus, from XRD data, it can be confirmed that MSNs is in hexagonal structure due to peaks obtained. Next, with the addition of APTES during synthesis of MSNs enhanced its hexagonally shaped and the structure obtained is in orderly arrangement [21]. 14000
Intensity (a.u)
12000 10000 8000 6000 4000 2000 0
0
2
4
6
8
10
2 theta (°) Fig. 1: XRD analysis result of MSNs.
3.3. Morphology study The morphology of MSNs was observed by using TEM analysis. According to data obtained from TEM analysis, the MSNs has pore size of 50 nm by which obeyed the characteristic of MSNs where the pore size should be less than 50 nm to be considered as mesoporous particles [26]. The TEM image as shown in Figure 2, it can be seen clearly that MSNs structure were in depict hexagonal arrays in which pore was similar to bee-hive structure with hundreds of empty frameworks. The mesopore of MSNs were in high volume and also in orderly arrangement. The
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empty frameworks then will be loaded with drug 5-FU. Based on the image obtained from TEM, the MSNs showed hexagonally and relatively rough structure by mean a typical image for MSNs [27].
50 nm Fig. 2: TEM image of MSNs
3.4. Functional group study
Transmittance [%]
Figure 3 showed the functional group contained in the particle can be determine through FTIR analysis in the range from 400 to 4000 cm-1. In the synthesis of MSNs, the formation of MSNs was modified with APTES and CTAB which means from analysis of FTIR will gave the amination of MSNs C-H deformation vibration at 2926 and 2851 cm-1 and peak of 1485 cm-1 indicate C-H deformation vibration as existed of CTAB [3]. As refer to FTIR analysis of MSNs, those peaks were not observed. This does mean that all the peaks attribute to CTAB has been disappeared as during synthesis MSNs, all CTAB were flushed out during calcination. Analysis of MSNs showed that MSNs was successfully prepared according to few peaks that indicate functional group contained in the carrier. A O-H stretching and bending vibration was observed at broad band peak 3418.2 cm-1. There is also a peak observed at wavenumbers of 1081.3 cm-1 in very high intensity by which every MSNs compulsory to exhibit this peak. This peak attribute to Si-O-Si assymetric stretching [24, 28-30]. Moreover, there is another peak being detected at 808.7 cm-1 where these peaks indicate the presence of Si-O vibration modes for MSNs.
3500
2500 1500 Wavenumber [cm-1] Fig 3: FTIR spectra of MSNs
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3.5. MSNs adsorptivity toward 5-FU 5-FU was used as a model drug to evaluate the loading capacity and drug storage ability of the synthesized MSNs. The final product obtained containing MSNs loaded with drug and solvent residual [31]. For the analysis of drug 5-FU load into MSNs, there are two mediums were set in order to testify the ability of MSNs to load drug into its pore. The two conditions are 5-FU was dissolve in ethanol medium and deionized water medium by mean the analysis of drug loading will be held in both conditions. According to UV-Vis analysis of drug loaded, the highest peak of spectrum was observed at 264 nm and the loading analysis was held about 24 h. The UV-Vis result showed differences in both loading medium. The loading rate of 5FU was differ for both deionized water medium and ethanol medium of drug solvent as the drug loading in ethanol medium showed higher loading percentage as compared with drug loading in deionized water medium. According to Figure 4, the drug loading capacity of ethanol condition is about 96.35% by mean almost complete load of drug into MSNs. For hydrophilic type of drug, ethanol condition method is more suitable due to smaller vesicles and efficiency of drug load will be higher to achieve [32]. This is due to dispersion theory of solid. As the 5FU being dissolved in ethanol, the drug was dispersed completely in the solvent solution. Thus, increase the tendency of drug being loaded into MSNs s this solid dispersion technique is very helpful especially in pharmaceuticals for drug adsorption [33]. Other than that, the presence of OH group in ethanol medium played a role of increased that electronegativity of solution medium and thus help in bonding mechanism between MSNs and drug model 5FU.
Adsorption percentage (%)
120 100 80 60 40 20
%DL Air Ternyah Ion Deionized water
Ethanol %DL Etanol 0 0
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15 Time (h)
20
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Fig. 4: Adsorption of 5-FU into MSNs in ethanol and deionized water.Evaluation of MSNs on 5-FU release behavior
The simulated body fluid was used to study the MSNs release performance in DDS. For drug release analysis, the drug release was held for 24 h under continuous stirring and body temperature indication of 37oC. According to UVVis analysis for 5-FU release from MSNs, in ethanol medium of MSN-5FU as shown in Figure 5, the release rate percentage was slower than MSN-5FU in deionized water medium in which 9% and 23% respectively. Hence, thus showed that the presence of OH ion concentration of ethanol increase the molecular bond between MSNs and 5FU. According to Peretti 2018 [34] the presence of OH ion in the solution also improved the drug interaction with its carrier and make the deprotonation between drug and its carrier become harder thus lead to slow release of drug from carrier. As the drug being dissolved in ethanol medium, the presence of silanol group increase the bonding between 5FU and MSNs and thus slower the rate of release percentage as compared to dionized water medium where might have no ion concentration in between the interaction of MSNs and 5FU hence, it will loosen the bonding of 5FU and MSNs and lead to the deprotonation between MSNs and 5FU become easier and increase the release rate of 5FU. As seen on data analysis for drug released, drug release in deionized water condition of MSN5FU has higher release rate as compared to ethanol condition which will determine the release rate in human body later.
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Release percentage (%)
25 20 15 10 5 Deionized water Ethanol 0 0
5
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Time (h) Fig. 5: Release behavior of 5-FU from MSNs in ethanol and deionized water.
4. Conclusion From this study, the physical characteristic of MSNs such as high pore volume and size, functional surface and large surface area become a crucial factor for delivering 5FU. Furthermore, in order for 5FU fully loaded into its carrier MSNs, solvent medium such as ethanol and concentration of drug 5FU plays a vital loading factors of 5FU into MSNs. In ethanol medium of MSN-5FU, the release rate percentage was slower than MSN-5FU in deionized water medium, which is 9% and 23% respectively. Lastly, a modern technology of DDS could be tailored for a slower release to suit the anti-cancer drug delivery. Acknowledgement The authors are grateful for the financial support by the Research University Grant from Universiti Kebangsaan Malaysia (GUP-2018-046) for their support. References [1] Z. Z. Li, L. X. Wen, L. Shao, and J. F. Chen, "Fabrication of porous hollow silica nanoparticles and their applications in drug release control," J Control Release, vol. 98, pp. 245-54, Aug 11 2004. [2] Y. S and G. U, "Nanoparticle Based Delivery of miRNAs to Overcome Drug Resistance in Breast Cancer," Journal of Nanomedicine & Nanotechnology, vol. 07, 2016. [3] X. Chen, X. Yao, C. Wang, L. Chen, and X. Chen, "Mesoporous silica nanoparticles capped with fluorescence-conjugated cyclodextrin for pH-activated controlled drug delivery and imaging," Microporous and Mesoporous Materials, vol. 217, pp. 46-53, 2015. [4] I. Munaweera, B. Koneru, Y. Shi, A. J. Di Pasqua, and J. K. J. Balkus, "Chemoradiotherapeutic wrinkled mesoporous silica nanoparticles for use in cancer therapy," APL Materials, vol. 2, p. 113315, 2014. [5] Y. He, S. Liang, M. Long, and H. Xu, "Mesoporous silica nanoparticles as potential carriers for enhanced drug solubility of paclitaxel," Mater Sci Eng C Mater Biol Appl, vol. 78, pp. 12-17, Sep 1 2017. [6] D. Sen Karaman, G. Patrignani, E. Rosqvist, J. H. Smatt, A. Orlowska, R. Mustafa, et al., "Mesoporous silica nanoparticles facilitating the dissolution of poorly soluble drugs in orodispersible films," Eur J Pharm Sci, vol. 122, pp. 152-159, Sep 15 2018. [7] X. Xu, S. Lü, C. Wu, Z. Wang, C. Feng, N. Wen, et al., "Curcumin polymer coated, self-fluorescent and stimuli-responsive multifunctional mesoporous silica nanoparticles for drug delivery," Microporous and Mesoporous Materials, vol. 271, pp. 234-242, 2018. [8] E. Yamamoto and K. Kuroda, "Preparation and Controllability of Mesoporous Silica Nanoparticles," 2018. [9] Y. Zhou, G. Quan, Q. Wu, X. Zhang, B. Niu, B. Wu, et al., "Mesoporous silica nanoparticles for drug and gene delivery," Acta Pharm Sin B, vol. 8, pp. 165-177, Mar 2018. [10] C. Focaccetti, A. Bruno, E. Magnani, D. Bartolini, E. Principi, K. Dallaglio, et al., "Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes," PLoS One, vol. 10, p. e0115686, 2015.
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