Mesoporous Silica Nanoparticles and Waste Derived-Siliceous Materials for Doxorubicin Adsorption and Release

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ScienceDirect Materials Today: Proceedings 19 (2019) 1420–1425

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ICCSE 2018

Mesoporous Silica Nanoparticles and Waste Derived-Siliceous Materials for Doxorubicin Adsorption and Release Jafreena Adira Jaafarb, Nur Hidayatul Nazirah Kamarudina,b*, Herma Dina Setiabudic, Sharifah Najiha Timmiatid, Teh Lee Penge a

Chemical Engineering Programme, Faculty of Engineering and Built Environment, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia. Research Centre for Sustainable Process Technology (CESPRO), Faculty of Engineering and Built Environment, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia. c Faculty of Chemical & Natural Resources Engineering, Universiti Malaysia Pahang, Lebuhraya Tun Razak, 26300 Gambang, Kuantan, Pahang, Malaysia. d Fuel Cell Institute (SELFUEL), Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia. e Centre for Advanced Materials and Renewable Resources, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia. b

Abstract Mesoporous silica nanoparticles (MSN) have been widely used for the drug delivery system due to their unique properties such as porous structure, high and tailorable internal and external surface area, as well as functionalizable surface. Due to the abundance of rice husk ash waste (RHA), extensive research had been conducted to convert these wastes to a useful resources. As RHA had been reported to contain high silica content (96.34%), it was seen as potential adsorbent as other silica materials. In this study, we have synthesized nano-silica materials from RHA (RHA-silica) to compare the potential of this waste-derived material with MSN for drug delivery application. RHA-silica was applied to the adsorption and release of model anti-cancer drugs, doxorubicin, and the performance was compared with the synthesized mesoporous silica nanoparticles (MSN). The characterization of the material was also compared and it was observed that the adsorption of doxorubicin was 65% on RHA-silica and MSN was 79.5% and 90.8%, while the total release percentage was 30.7% and 48.8%, respectively. From the result, it is expected that the waste-derived silica material could be further modified and optimized for the drug delivery application, as well as the appropriate modification and functionalization to suite the need for adsorption and release of drugs, but with lower cost and significant contribution to a greener chemistry. © 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: mesoporous silica, siliceous material, rice husk ash, doxorubicin, drug adsorption, drug release * Corresponding author. Tel.: +03-89215555 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 The method of drug delivery nowadays has several disadvantages such as suffering from patients with repetitive injection and drug dosage. Various methods have been studied in improving the drug delivery method, one of which is to use a special device that can release medicines using certain mechanisms. Prescription errors involving drug dosage formulations often occur in hospitals and no systematic assessment of the errors associated with taking medication doses has been performed. Nanotechnologies such as MSN are expected to assist these problems as a replacement for effective drug delivery today [1]. The integration between the chemical and biomedical engineering fields on the study of the potential of nanosized materials is growing. Nano particles are nano-sized substances that are capable of embedding drugs, imaging agent, and genes [2]. Mesoporous silica is a unique combination of nanostructures and mesostructured materials, especially for [3], sensing and drug delivery [4] and catalysis [5] activities due to the pore abilities and rapid molecular diffusion. Besides, Zhu Y. et al [6] states that the control drug delivery system (CDDS) has been studied extensively and has attracted the attention of the public as the system offers many advantages such as effectiveness, reducing toxicity and side effects while reducing the dose intake MSN is composed of mesoporous structures that are structurally uniform but are adjusted by pore size, making them the best candidate to accommodate guest molecule, to provide a physical emphasis to protect abandoned medicines from degradation and denaturation. Based on this study, drug delivery is more focused on the treatment of cancer cells that are more acidic than a normal cell. One of the ways to achieve the target and the release of selective medicines is with drug emission by responsive stimuli. Specific stimuli on the target site is such as a low pH, elevation levels of certain enzymes, and externally used physical signals such as high temperatures, magnetic fields and ultrasound. Amongst all these internal and external stimuli, high temperatures are one of the best signals in terms of convenient and secure medical applications [7]. For more than a decade, porous silica materials in various shapes have been studied as drug carriers due to the chemical instability, biocompatibility properties and better physical chemistry properties. Aerogel silica is a special porous silica material consisting of nanostructures with high mesoporous. As a result of the formation of this structure, aerogel offers a high specific surface area, a high pore volume, high fracture and low density required for efficient drug delivery. Recent studies show that aerogel usage for drug delivery applications is expected to grow in the future [8]. Waste materials such as rice husk ash was also had been extensively studied to produce siliceous materials. The rice husk ash waste-derived silica compound (RHA-silica), has been produced by sol-gel technique using a source of rice husk ash which has been used in the drug delivery system [9]. In this study, the adsorption and release of doxorubicin drug will be compared from the chemically synthesized MSN and waste-derived RHA-silica. 2. Experimental 2.1. Materials Cetyltrimethylammonium bromide (CTAB) and ethylene glycol (EG) were obtained from R&M Chemical, 3aminopropyl triethoxysilane (APTES) and tetraethyl orthosilicate (TEOS) were purchased from Sigma Aldrich. Ammonium hydroxide (NH4OH) from JT Baker/USA. All chemicals were reagent grade and used without further purification 2.2. Synthesis of Mesoporous Silica Nanoparticles (MSN) The method to synthesize MSN were referred to a sol-gel method by the previous study. The procedure was as follows, CTAB, EG, and NH4OH were dissolved in 720 mL of water with the following ratio composition of 0.0065: 0.17: 0.04 in water, respectively. The mixture was heated and stirred vigorously for 30 min. Then TEOS and

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APTES were added to the mixture to give a white homogenous solution. The mixture was kept under continuous stirring for another 2 h and the sample was collected by centrifugation. The obtained samples were dried at 110°C for 24 h and proceed to calcination at 550°C for 3 h to yield a white powder MSN. The similar procedure was used to synthesis MSN by excluding the calcination process. 2.3. Synthesis of RHA-silica The rice husk ash (RHA) was collected from local rice mill located at Kedah, Malaysia. The RHA will be washed thoroughly with water to remove adhering dust and soil, and then dried at 120 °C overnight. Then, RHA was calcined at 600 ºC for 6 h to remove organic impurities in RHA. Acid-soluble elements were removed by acid leaching whereby the calcined RHA and 100 mL of 2 M HCl solution was stirred at 60 °C for 3 h. The mixture was filtered and the solid residue was dried at 120 °C overnight followed by calcination at 550 °C for 3 h. 2.4. Material Characterization The crystallinity of MSN and RHA-silica were measured with a Bruker Advance D8 X-ray powder diffractometer with Cu Kα (λ = 1.5418 Ǻ) radiation as the diffracted at 40 kV and 40 mA. TEM was performed using a Philip TEMCM12 microscope. The samples were ultrasonically dispersed in acetone and deposited on an amorphous, porous carbon grid. The surface morphology and surface elemental analysis of the samples were performed using FESEM-EDX (Merlin/Merlin Compact/Supra 55VP) with an accelerating voltage of 15 kV. FT-IR (Perkin Elmer Spectrum FT-IR/FT-NIR Spectrometer & Spotlight 400 Imaging System) was carried out using the KBr method with a scan range of 400–4000 cm−1. Adsorption and profile release studies been analyzed using Perkin Elmer/Lamda 35 at wavelength of 380 nm. 2.5. Doxorubicin (DOX) loading and release measurement MSN samples were loaded with DOX in a ratio of 1:3 by soaking them into diluted NaOH solution and followed by continuous stirring for 24 h at 25oC. The concentration of DOX been fixed to 80 ppm for the loading which 110 mg of DOX was dissolved in 1 L of diluted NaOH and 100 mg of dry MSN were added into the solution. The wasted DOX has been separated by filtration process by washing in ethanol and been dried in an oven overnight at 105oC. The samples of aliquots 2 ml were taken at the pre-defined time interval and been centrifuged. The experiment was repeated for three times for analyzing the wavelength using UV-Vis spectrophotometer at adsorption band 380 nm. The release profile was obtained by adding 0.25 g of sample to 200 mL round-bottom flask containing 100 mL of phosphate buffer saline (PBS) at 37oC under continuous stirring. The samples have been analyzed by UV–Vis spectrophotometer to measure the DOX been released within the time interval and the same method been used to RHA-silica. 3. Result and discussion 3.1 Characterization Fig. 1 shows the XRD patterns of MSN and RHA-silica. The small-angle XRD patterns exhibit a strong diffraction peak corresponding to (100) reflection and two smaller peaks assigned to (110) and (200) Bragg reflections. The diffraction of the samples occurred at 2θ = 2.2°, 3.9° and 4.5°, indicating well-ordered hexagonal arrays of mesopores [10]. For RHA-silica, the peak shows typical form of crystalline silica, which proved that the silica material had been successfully synthesized from the RHA.

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Fig. 1. X-Ray diffraction of MSN and RHA-silica Fig. 2 shows the TEM images of the MSNs at different microwave power levels, respectively. Comparing both of the materials, the MSN spherical particles demonstrate the clusters of hexagonally-ordered silica nanoparticle approximately of 30–45 nm in size, while RHA-silica shows fibrous surface with a core inside the particles. The surface properties of both materials are displayed in Table 1. MSN had obviously higher surface area than RHAsilica, which is 1107 m2/g, while 220 m2/g for the latter. Pore volume of MSN was also bigger, which is 2.14 cm3/g, while 0.94 cm3/g for RHA-silica. On the contrary, the pore size of RHA-silica shows much more wide and bigger than MSN, which is 17.37 nm, with only 3.43 nm for MSN.

MSN

Fig. 2. TEM images of MSN and RHA-silica

Table 1. Surface properties of MSN and RHA-silica Properties Surface area (m2/g) Total Pore Volume (cm3/g) Pore size (nm)

MSN 1107 2.14 3.43

RHA-silica 220 0.94 17.37

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Fig. 3 shows the FTIR spectra of both materials. MSN and RHA-silica functional groups were described through the FT-IR spectrum in the range 400 – 4000 cm-1. All MSNs will exhibit infrared (IR) peaks on the path associated with Si-O-Si symmetry stretch at 779 cm-1 and SI-OH group at 986 cm-1. Si-O-Si assymmetric stretching was observed at 1076 cm-1, while 1627 cm-1 and 3405 cm-1 representing the O-H bending and O-H stretching that associated with the Si-OH in both materials [11].

Fig. 3. FTIR spectra of MSN and RHA-silica 3.2 Adsorption and release study The performance of both materials with respect to DOX adsorption was investigated and compared (Fig. 4). For the first 60 mins, the adsorption preceded rapidly for both materials, with MSN demonstrated almost 80% adsorption of DOX, while almost 70% for RHA-silica. Despite of having low surface area, RHA-silica had the comparable adsorption of DOX, which is most probably due to its large pore opening that allows more DOX molecules to enter. The release behaviour of DOX from both materials were also observed. For the first 10 hours, both materials exhibited slow release for about 40% from MSN, while 27% from RHA-silica. After 60 hours, DOX release was achieved for almost 50% for MSN, while not more than 30% from RHA-silica. In this case, it is speculated that DOX on RHA-silica was attracted stronger than on MSN, most probably due to the fibrous RHAsilica’s structure that permits the diffusion of DOX to deeper inside the particles, and near to the core. This results shows that the RHA-silica has the potential to be further improved to be a good host of drug molecules,

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Fig. 4. Adsorption and release study of DOX from MSN and RHA-SIlica 4. Conclusion MSN and RHA-silica was compared for the properties, adsorption and desorption behavior. Both materials shows different kind of crystallinity, morphology and surface properties, however the same functional groups present in both materials. It was observed that the adsorption of doxorubicin was 79.5% on RHA-silica and 90.8% on MSN while the total release percentage was 30.7% and 48.8%, respectively. From the result, it is expected that the wastederived silica material could be further modified and optimized for the drug delivery application, as well as the appropriate modification and functionalization to suite the need for adsorption and release of drugs, but with lower cost and significant contribution to a greener chemistry. Acknowledgement The authors was grateful and appreciate the Ministry of Higher Education for the Fundamental Research Grant Scheme (FRGS/1/2016/STG07/UKM/03/1) for the financial support throughout this study. References [1] T.S. Lesar, Medscape Pharm, 2 (2001) 2 [2] O. C. Farokhzad, R. Langer, ACS Nano. 3 (2009) 16–20 [3] L. Hou, F. Feng, W. You, P. Xu, F. Luo, B. Tian, H. Zhou, X. Li. J Chromatogra A. 1552 (2018) 73-78 [4] I.I. Slowing, B.G. Trewyn, S. Giri, V. Y. Lin. Adv Funct Mater, 17 (2007) 1225-1236 [5] R.M. Rioux, H. Song, J.D. Hoefelmeyer, P. Yang, G.A. Somorjai. J. Phy Chem. 109 (2005) 2192-2202 [6] Y. Zhu, J. Bioanal Biomed. 5 (2013) 117 [7] M. Nakayama, T. Okano, T. Miyazaki, F. Kohori, K. Sakai, M.Yokoyama, J. Control. Release. 115 (2006) 46-56 [8] S. K. Rajanna, D. Kumar, M. Vinjamur, M. Mukhopadhyay. Ind Eng Chem Res. 54 (2015) 949-956 [9] P. Prawingwong, C. Chaiya, P. Reubroycharoen, C. Samart. Journal of Metals, Materials and Minerals. 19 (2009) 61–65. [10] N. H. N. Kamarudin, A. A. Jalil, S. Triwahyono, M.R. Sazegar, S. Hamdan, S. Baba, A. Ahmad. RSC Adv. 5 (2015) 30023-30031 [11] N. H. N. Kamarudin, A. A. Jalil, S. Triwahyono, V. Artika, N. F. M. Salleh, A. H. Karim, N. F. Jaafar. J. Colloid Interface Sci. 421 (2014) 6–13.