The Oral Curcumin via Hydrophobic Porous Silicon Carrier

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Biological and Medical Applications of Materials and Interfaces

The Oral Curcumin via Hydrophobic Porous Silicon Carrier: Preparation, Characterization and Toxicological Evaluation in Vivo Yue Zhang, Wei Li, Di Liu, Yafang Ge, Mengyuan Zhao, Xuerui Zhu, Weiwei Li, Longfeng Wang, Tiesong Zheng, and Jianlin Li ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.9b10368 • Publication Date (Web): 20 Aug 2019 Downloaded from pubs.acs.org on August 21, 2019

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ACS Applied Materials & Interfaces

The Oral Curcumin via Hydrophobic Porous Silicon Carrier: Preparation, Characterization and Toxicological Evaluation in Vivo Yue Zhang a, Wei Li

b, c,

Di Liu

a,c,

Yafang gea, Mengyuan Zhaoa, Xuerui Zhua, Weiwei Lia,

Longfeng Wanga, Tiesong Zheng a* and Jianlin Li a* a

School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210024, China

b

Department of Electronic and Electrical Engineering, The University of Sheffield, Sheffield, S3 7HQ, United Kingdom

c These

authors contributed to this work equally and should be regarded as co-first authors

*Corresponding authors. Tel.: +86 25 83598286; fax: +86 25 83598901. E-mail addresses: [email protected], [email protected]

1

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Abstract Curcumin has antioxidant, anti-inflammatory, antimicrobial and anticarcinogenic activities. However, the clinical application of curcumin has been restricted by the poor water solubility and low bioavailability of this molecule. In the work, hydrophobic porous silicon (pSi) particles were prepared by electrochemical etching method and grafted with the different hydrophobic groups on their surfaces. The loading efficiency of curcumin in pSi has been investigated. The properties of pSi particles have been characterized by scanning electron microscopy (SEM) and Fourier transform-infrared spectroscopy (FTIR). The highest loading efficiency of curcumin can be obtained with pSi surface modified with the octadecyl silane group. The release properties of curcumin in hydrophobic pSi have been researched in vitro and in vivo. The curcumin in the hydrophobic pSi surface keeps a high antioxidant bioactivity. The toxicological evaluation of the hydrophobic pSi particles indicates they have a high in vivo biocompatibility within the observed dose ranges. The hydrophobic pSi particles could provide an effective and controlled release delivery carrier for curcumin, which may provide a new tool platform for the further development of curcumin. Keywords: hydrophobic porous silicon, curcumin, drug delivery, release, toxicological evaluation

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1.Introduction Curcumin(1,7-bis(4-hydroxy-3-methoxy-phenyl)-1,6-heptadiene-3,5-dione;diferuloylmethane), a yellow polyphenol substance from the rhizomes of the plant curcuma longa, has been used as a food additive and traditional medicine in Southeast Asia countries. It exhibits multiple pharmacological activities, including antioxidant, anti-inflammatory, anti-viral, anti-bacterial activities and anticancer1,2. Curcumin can inhibit cell proliferation, metastasis and induce apoptosis by modulating several signaling pathways including pro-inflammatory factors, growth factors, receptors and transcription factors3-4. In addition, it is pharmacologically safe compound for human being even at a high single dose oral administration of 12 g per day5. It has been suggested as a potential reagent for both prevention and treatment of a great variety of different cancers, including gastrointestinal melanoma, genitourinary, breast, lung, hematological, head and neck, neurological and sarcoma6. Despite of all the potential therapeutic characteristics, the clinical applications of curcumin are limited because of its extremely low solubility in aqueous solution (30 pmoL/mL), the poor instability, rapid metabolism, short half-life and the poor oral bioavailability 2, 7, 8, 9. Developing delivery vehicles for curcumin is one of the most practical and effective methods to overcome the above problems10. For examples, liposomes11,12, polymeric micelles2,13, peptide/protein carriers14,15-16, polymeric nanoparticles17, cyclodextrin18 and inorganic materials7, 19,20

have been proposed as carriers to improve the circulation time, permeability, stability and

pharmacological activities of curcumin. Controllable release systems of drug have been widely used in drug industry because they can prevent potential degradation and toxic effects of the active molecules and improve their release performances21. For instance, chitosan-polyethylene glycol22 and hollow silica particles23 have been used as the controllable release carriers for curcumin. Among the controllable release systems, the degradable porous silicon (pSi) carriers have more and more attracted attention because of their high porosity/large pore volume (50-80%/0.5-2.0 cm3/g), tailored pore size (5-150 nm), high specific surface area (up to 580 m2/g), high biocompatibility, nontoxic degradation, large of loading capacity, versatile surface modification and intrinsic photoluminescence24-26. pSi can completely degrade into nontoxic orthosilicic acid [Si(OH)4], which is naturally present in the 3



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human body27-28. In addition, silicon is an essential trace element that plays a role in our metabolic process and its oxidized product, silica has been used as a food additive in various products and generally recognized as safe by the Food and Drug Administration (FDA) for over 50 years29. Recent research indicated that silicon particles may be used as a nutritional food additive30-31. Due to these properties, pSi could provide a real-time and online monitoring platform for the effect of drugs on their targets and make the precise medicine possible. Therefore, pSi has been used to deliver various drugs and image the tumor28. However, there are few reports on curcumin delivery carrier with pSi. Especially, the fundamental issues on the properties of loading, release and toxicological evaluation for curcumin on the different surfaces of pSi have been not addressed. Here, we prepared the pSi microparticles by electrochemistry etching method and grafting the surfaces of pSi with the different chemical groups. A controlled release delivery system with high loading efficiency for curcumin was established by the hydrophobic pSi vehicles. The release properties, bioactivity of curcumin in the pSi and toxicological evaluation in vivo were investigated. The work has a great significance in the clinical application of curcumin, which may provide a new tool platform for the further development of curcumin. 2. Experimental and methods 2.1. Materials Octadecyl silane and pentaf were purchased from TSI AI Chemical Industry Development Co., Ltd (Shanghai, China). 48% Hydrofluoric acid and sodium dodecyl sulfonate (SDS) were bought from Aladdin Reagent Co., Ltd (Shanghai, China). 1,1-diphenyl-2-picrylhydrazyl (DPPH) and Nitroblue tetrazolium (NBT) were bought from Sangon Biotech. Co., Ltd (Shanghai, China). Ammonium hydroxide, hydrogen peroxide, hydrochloric acid, acetone, methyl alcohol, methylbenzene, disodium hydrogen phosphate, sodium dihydrogen phosphate methionine and sodium chloride were purchased from Nanjing Chemistry Reagent Co., Ltd (Nanjing, China). Ascorbic acid (Vc), curcumin (≥98%, HPLC grade), emodin (≥98%, HPLC grade), pepsase, pancreatin and sodium carboxymethylcellulose (CMC-Na) were bought from Sinopharm Chemical Reagent Co., Ltd (Beijing, China). Silicon wafers (0.0008-0.0012 Ω-cm resistivity, polished on the (100) face, B-doped) were obtained from Siltronix Co. (Archamps, France). 0.01M, pH7.4 Phosphate buffer solution (PBS) was purchased from Nanjing Keygen Biotech Co., Ltd. (Nanjing, China). 4


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2.2. Preparation of pSi film and microparticles pSi film was prepared by the electrochemistry etching method28,32. Firstly, silicon wafer was cut into 3 cm×3 cm wafer and then respectively washed with acetone, ethanol and deionized water with ultrasonic (300 w) for 15 min. The wafer was etched with 1:1(v/v0) mixture aqueous 48% HF and absolute ethanol at a constant current density of 40 mA/cm2 for 30 min. The film was respectively washed with absolute ethanol for 3 times. The pSi film was stripped off from the Si substrate by a current density of 4 mA/cm2 for 200 s in 3.3% aqueous hydrofluoric acid in ethanol. Finally, the pSi film was fractured into microparticles by water bath ultrasonication (300 w) for 2 h. 2.3. The surface modification of pSi The silica surface of pSi was obtained by the thermally oxidized pSi (TOPSi) method in tube furnace at 500 °C for 2 h. Octadecyl silane and pentaf were grafted on the surface of pSi (pSiSi(C18) and pSi-PFPS) according to the reference33. Briefly, pSi microparticles in a 10 mL vial were dried under nitrogen. 1.6 mL of methylbenzene and 0.4 mL of octadecyl silane or pentaf were added in the vial and homogeneously mixed by vortex. Then, the grafting reaction was performed in 80 °C water bath for 24 h. The pSi was transferred in a 10 mL centrifuge tube and centrifuged at 1914 × g for 10 min. The liquid supernatant was removed and pSi microparticles were respectively washed with methylbenzene and ethanol for three times. The pSi microparticles were dried at 60 °C tube furnace in vacuum for 2 h. 2.4. The surface properties of pSi film and microparticles The surface properties of pSi film and pSi microparticles were characterized with scanning electron microscopy (SEM) (FEI XL30 microscope equipped with a field emission gun and through-the-lens detector) and Fourier transform-infrared spectroscopy (FTIR) (Nicolet Nexus670, Thermo-Scientific) using KBr disks in the range of 400-4000cm-1 with a resolution of 0.125cm-1. The contact angle image of pSi film was detected by digital camera after 5 μL deionized water was dropped on the surface of pSi film. Surface area analysis of pSi samples was characterized by N2 adsorption-desorption isotherm on a Micromeritics ASAP 2050 system (Micromeritics, USA) according to the Brunauer-Emmett-Teller (BET) and Barrett-Joyner-Halenda (BJH) method34. 2.5. Curcumin Ultra Violet (UV)-visible spectrometry analysis A series of concentrations of curcumin (2-20 μg/mL) in absolute ethanol solution were detected 5



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by Ultraviolet visible spectrophotometer (UV 6100A, Shanghai Yuanxi instrument co., Ltd, China) at 426 nm. The standard curve of curcumin was obtained (Figure S1). 2.6. Preparation of curcumin-load pSi microparticles and drug loading (DL) 1 mL of curcumin (1 mg/mL in ethanol solution) and 1 mL of double distilled water were added in a 10 mL centrifuge tube containing with 10 mg pSi microparticles and mixed under water bath ultrasonication (300 w) for 30 min. The sample was placed at 50°C water bath for 16 h. The control sample without pSi microparticles was performed in the same conditions. The sample was centrifuged at 1914 × g for 10 min and the supernatant was transferred into a 10 mL brown glass flask volumetric. The sediment was respectively washed with 40% ethanol and double distilled water and then the washing liquid was added into the brown glass flask volumetric. The solution in the brown flask was adjusted to a constant volume with ethanol and then was filtered with a 0.45 μm filter membrane. The filtrate was collected and the concentration of unloaded curcumin was measured according to the above UV method. DL is calculated according to before and after 1mL, 1 mg/mL of curcumin solution is added in 10 mg pSi, which is as follows: DL = (Total amount of added curcumin - amount of free curcumin)/(Total amount of added curcumin)×100%

(equation 1)

2.7. The optimal conditions of loading curcumin with pSi microparticles The optimal conditions of loading curcumin with pSi microparticles were investigated, which included etching current density (constant current etching wafer at 30,40,50 and 60 mA/cm2, respectively), temperature (loading curcumin in pSi microparticles at 25,37,50, and 65°C water bath for16 h, respectively), time (loading curcumin time for 2,4,8,16 and 24 h, respectively), and the stirring methods (loading curcumin at still water bath, magnetic stirring and table oscillation). 2.8. The release properties of curcumin from pSi microparticles in vitro The release properties of curcumin from pSi microparticles in vitro were carried out in different pH buffer solutions (pH 5.0,7.4 and 8.5 PBS) and in simulated gastric fluid (SGF, pH 1.5) and intestinal fluid (SIF, pH 6.8) according to previous studies22, 35-36. Briefly, 5 mg of curcumin-pSi (0.1 mg curcumin) was immersed in 50 mL PBS containing 0.5% SDS at different pH values in conical flask and kept at 37 °C with gentle shaking at 0.1 × g. After certain time intervals, the solutions were centrifuged at 2000× g for 10 min and 2 mL of the supernatants were periodically 6


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withdrawn from the samples. At the same time, 2 mL of the release medium solution was added in the samples in order to keep the volume of release medium constant. The curcumin release was analyzed using the above UV method and its concentration was quantified by a standard curve of curcumin established for each dissolution medium. 2.9. The release properties of curcumin from pSi microparticles in vivo All experiments involving animals were approved by the Institutional Animal Ethics Committee of Nanjing Normal University, China. Male Institute of Cancer Research (ICR) mice (mean body weight of 26 ±2 g) from the Animal House, Jiangsu provincial hospital animal feeding center (Experimental animal license number SYXK 2007-0017) were used in this experiment. The animals were kept in the animal room (23 ±2°C, 50 ± 5% humidity) under a 12 h light/dark cycle and fed with diet. 40 mice were randomly divided into four groups with 10 mice per each group: control, low dose, medium dose and high dose groups. 1 mL, 0.5% CMC-Na solution, 1 mL of CMC-Na solution contained 0.5, 1.0 and 5.0 mg of curcumin-pSi were respectively fed to the mice as control, low dose, medium dose and high dose groups. The mice were fed the samples after they were fed for 5 days to adapt to the environment. After mice were fasted for solids for 12 h, mice were taken gavage. 0.3 mL of plasma samples were taken from posterior orbital vein at a certain time and immediately transferred to a heparinized microcentrifuge tube and centrifuged at 4000×g for 20 min at 4 °C. The supernatant plasma was stored at -20 °C for the next experiment. The quantification determination of curcumin was performed by HPLC analysis according to the reference37. 4 μg/mL, 50 μL of emodin (in methanol) was added into 100 μL of plasma sample and vortexed for 3min. Then 0.25 mL of ethyl acetate was added into the sample and vortexed for 3 min. The sample was centrifuged at 4000×g for 20 min at 4 °C. The supernatant was collected and dried under nitrogen. The sample was dissolved in the solution of acetonitrile-2% acetic acid (58:42, v/v), vortexed and centrifuged at 4000×g for 20 min at 4 °C. The supernatant was collected and filtered through a 0.45 μm membrane filter. The filtrate was used for HPLC assay (blank plasma sample in Figure S2 and plasma sample spiked curcumin and emodin in Figure S3). The HPLC conditions were as follows: HPLC system (Agilent,1100, USA) with Kromasil-C18 column (250mm×4.6mm,5μm), acetonitrile-2% acetic acid (58:42,v/v) as the mobile phase, 1.0 mL/min flow rate, 10 μL of injection volume, temperature at 30 °C and the detection wavelength at 426 nm. 7



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To prepare the standard curve of curcumin, a series of different concentrations of curcumin (10 μL, 10-5000 ng/mL) was added into the plasma samples. The plasma samples were pretreated and detected according to the above method. The ratio of curcumin peak area (Y) to the internal standard emodin peak area (Y) was used as the ordinate and the concentration of curcumin (X) was used as the abscissa. The standard curve was obtained to be as Y=0.5465X+0.0371, R2=0.998(Figure S4). 2.10. DPPH free radical scavenging assay DPPH free radical scavenging activities were determined according to the reference38. Firstly, curcumin in pSi microparticles was extracted by ethanol solution. 10 mg of curcumin-pSi was placed into a 10 mL centrifuge tube and extracted by 2 mL of ethanol under oscillation for 10 min. Then the sample was centrifuged at 1914 × g for 10 min. 20 μL of supernatant solution or curcumin and 180 μL, 60 μmol/L of DPPH were added into a 96 well microplate and uniformly mixed under oscillation for 5 min. The absorbance value (AX) of sample was detected by 96 well microplate reader at 530 nm and recorded for 40 min at intervals of 5 min. The background absorbance value (AX0) of 200 μL of mixture solution (20 μL of curcumin and 180 μL of ethanol) was obtained in the same conditions. The control sample without curcumin extraction was detected and used as the absorbance value A0. The scavenging DPPH free radical was calculated according to the formula: The scavenging DPPH ratio (%) = [A0-(AX-AX0)]/A0×100%

(equation 2)

Here, A0, AX, and AX0 are the absorbance value of the control sample, sample and the background solution, respectively. 2.11. Superoxide anion scavenging assay 0.1 mL, 130 mmol/L methionine in PBS and 0.1 mL, 20 μmol/L riboflavin in double distilled water and 0.2 mL, 750 μmol/L NBT in PBS and 3.2 mL, 50 mmol/L pH 7.8 PBS were added into a 10 mL centrifuge tube. 0.4 mL of curcumin extraction from pSi (the same as above method) or curcumin or ascorbic acid with different concentrations was added in the centrifuge tube and then the samples were placed under ultraviolet radiation for 2 min. The absorbance value of the sample was scanned from 300-800 nm and the absorbance value at 590 nm position was recorded as As. The absorbance value of the sample without ultraviolet radiation was used as Ac. The scavenging O2-• ratio was calculated according to the formula: The scavenging O2-• ratio (%) = (Ac-As)/Ac×100% 8


(equation 3)

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2.12. Hematological analysis 40 mice were randomly divided into four groups with 10 mice per each group: control, low dose, medium dose and high dose groups. 1 mL, 0.5% CMC-Na solution, 1mL CMC-Na solution contained 0.5, 1.0 and 5.0 mg pSi microparticles were respectively fed to the mice as control, low dose, medium dose and high dose groups. The mice were fed the samples after they were fed for 5 days to adapt to the environment. After mice were fasted for solids for 12 h, mice were taken gavage. In the seventh day, blood samples were taken by removing eyeball and divided into two groups: one is in a heparinized microcentrifuge tube for routine analysis, other is in a microcentrifuge tube without heparinizing for biochemical analysis. The red and white cells (RBC, WBC) were counted. The determination of the hemoglobin in level (HGB), platelets (PLT), and lymphocytes (LYM) were performed with Cell-Dyn Sapphire. 2.13. Biochemical analysis of blood The blood samples were determined for triglyceride (TG), total cholesterol (CHO), glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) using an automatic analyzer (ARTAX Menarini Diagnostics, Florence, Italy) with enzymatic colorimetric assay reagent strips (human, Wiesbaden, Germany). 2.14. Histopathological section observation of internal organs of mice The mice were fed according to 2.12 method for seven days and dislocation was executed. Liver, kidney, spleen and heart of mice were immediately taken and placed in the 10% formaldehyde solution for morphology and pathological section observation. 2.15. Statistical Analyses Results are expressed as mean ± standard error of at least three different measurements. Statistical analysis was performed by means of one-way analysis of variance (ANOVA). 3. Results and discussion 3.1. The preparation, surface modification and properties of pSi film and microparticles

9



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Scheme 1. The process of preparation and release of hydrophobic microparticle pSi carrier for curcumin. The mouse image was taken by the experimenter during experiment using mobile phone. The scheme 1 shows the whole process of preparation and curcumin release of hydrophobic microparticle pSi carrier. pSi was prepared and moved from silicon substrate by electrochemical etching method. The microparticles were obtained by sonication and then their surfaces were grafted with hydrophobic groups. Curcumin was introduced into the surfaces of microparticles by hydrophobic interaction. Curcumin was slowly released after microparticle pSi was degraded in mice. The bioactivity of curcumin would be well kept in microparticle pSi and oral bioavailability of curcumin will be great improved.

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100

Absorbance intensity (a.u)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


E

1527

75

14601633

798

2090 2848 2918

623

PSi-Si(C18) TOPSi PSi-PFPS

50 471

3343

25 1076

0

800

1600 2400 Wavenumber (cm-1)

3200

4000

Figure1.The properties of pSi film and particles. SEM images of pSi film: A, cross-section, B, top surface, C, thickness of pSi film, D, pSi microparticles; Spectra of FTIR of the pSi surfaces modified with the different groups (E); The hydrophobic properties of pSi surfaces grafted with the different groups: F, TOPSi, G, pSi-PFPS, H, pSi-Si(C18). The SEM images of pSi film and microparticles are shown in Figure 1 A-D. Figure 1A is the cross-section image of pSi film, which indicates the pore size of pSi is about 30-80 nm. Figure 1B is the top surface image of pSi film, which displays that the pSi film has reticular sponge structure. The thickness of pSi film is about 10 μm (Figure1C). Figure1D is the image of pSi microparticles, which shows the width × length is less than 50 μm×100 μm. Three different groups were respectively grafted on the surfaces of pSi. The FTIR spectra of pSi surfaces are shown in Figure 1E. The peak positions at 471 and 1076 cm-1come from the stretching vibration of silanol group. The peak positions at 2958,2918 and 2848 cm-1 result from C-H stretching vibration and 2090 cm-1 assigns to Si-H stretching vibration. The peak position at 11



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1633 cm-1 comes from H-O-H bending vibration. This indicates octadecyl silane has been grafted on the surface of pSi. The peak position at 1527 cm-1 is C=C stretching vibration and 1460 cm-1 ascribes to C-H bending vibration, which shows the pentaf has been grafted the surface of pSi. The hydrophobic surface properties of pSi microparticles grafted with the different groups were investigated. The results are shown in Figure 1F-H. The surface of thermally oxidized pSi film shows an obvious hydrophilicity (Figure 1F), which is attributed to the hydrophilicity of Si-OH. The surfaces of pSi films grafted with pentaf and octadecyl silane show high hydrophobicity and their contact angles are 131.3 (Figure 1G) and140.7 (Figure 1H), respectively. The results are in agreement with the properties of these groups. 3.2. The influence of the pSi surfaces modified with the different groups on DL of curcumin Figure 2 shows the influence of the pSi surfaces modified with the different groups on curcumin loading. The pSi microparticles grafted with hydrophobic surfaces show a markedly higher DL of curcumin than pSi microparticles with hydrophilic surface. DL of curcumin in hydrophobic surfaces of pSi microparticles is almost double as much as that in hydrophilic surface. The result may be ascribed to the strong hydrophobic interaction between the curcumin and hydrophobic pSi surfaces. In addition, the pore size of pSi would become small after it is thermally oxidized39, which obstructs curcumin entering into the surface of pSi. Compared with the pSi surface grafted with pentaf group, the pSi surface grafted with octadecyl silane group has shown higher DL of curcumin. Therefore, the pSi modified with octadecyl silane group has been used in the next experiments. The optimal conditions for loading curcumin in the pSi microparticles grafted with octadecyl silane group were investigated, which include etching current, temperature, time, and stirring methods. The results are shown in Figure S5. The optimal conditions are as follows: 40 mA/cm2 etching current density for 30 min, temperature at 50 °C and magnetic stirring for 16 h. Under the optimal conditions, DL of curcumin in pSi microparticles can reach to 22.3%.

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16

12 DL percentage (%)

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8

4

0

TOPSi PSi-Si(C)18 PSi-PFPS The surfaces of pSi with the different grafting groups

Figure 2. The influence of the pSi surfaces modified with different groups on curcumin DL. The repeatability of the preparation of curcumin-pSi has been investigated by loading the low, medium and high concentration of curcumin in the pSi according to the above optimal conditions. The curcumin in pSi is recovered by ethanol extraction and detected by the above UV method. The recovery rates are shown in Table S1. All recovery rates are more than 90% and the relative standard deviation (RSD) is less than 5%. The result indicates the protocol for preparation of curcumin-pSi has a good repeatability. The physicochemical properties of the hydrophobic pSi before and after curcumin loading are shown in Figure S6 and Table S2. The pores of pSi have not been completely blocked after curcumin loading (Figure S6 A and B). Thus, loading of curcumin on the pSi was performed mainly in the inner surface of pores without affecting the pore structure. The representative N2 adsorption-desorption isotherms of hydrophobic pSi before and after curcumin loading are shown in Figure S6 C, which displays a typical Ⅳ-type isotherm. The surface area, pore volume and pore size diameters are seen in Table S2. The BET surface areas, pore volume and pore size of hydrophobic pSi before and after curcumin loading are 259.31 m2/g, 1.14 cm3/g, 18.90 nm; 119.00 m2/g, 0.44 cm3/g and 17.04 nm, respectively. The results show that the pore diameter indeed 13



decreased after curcumin loading. Except for hydrophobic pSi, other hydrophobic surface materials including protein40-41, nanocrystalline cellulose42 and lipoprotein/pectin complex43 have been developed as delivery vehicles for curcumin by their hydrophobic interactions to improve its bioavailability. Although these hydrophobic delivery vehicles have shown good biocompatibility, they have some disadvantages such as complex preparation process, limited drug loading and lack of self-report photoluminescence. On the contrary, hydrophobic pSi delivery vehicles can overcome these disadvantages. 3.3. The curcumin release properties from pSi in vitro

A

pH5.0 pH7.4 pH8.5

80

Accumulated release rates (%)

80

Accumulated release rates (%)

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60

40

20

0

0

2

4

6 Time(h)

8

10

60 40 20 0 0 0.5 1

12

stomach pH 1.5 intestinal pH 6.8

B

2

3

4 5 6 Time(h)

7

8

9 10 11 12

Figure 3. Curcumin release profiles from pSi in different pH PBS: A, The curcumin release properties from pSi in vitro in different pH buffer medium solutions; B, The curcumin release properties from pSi in simulative stomach and intestine medium solutions in vitro. The release properties of curcumin from pSi in vitro were investigated. Figure 3A shows time-dependent in vitro curcumin release profiles from pSi in the different pH PBS. The accumulated release rates of curcumin increase as time increase and reach a plateau after 10 h in the different pH PBS. The accumulated release rates of curcumin in pH 5.0 PBS are higher than that in pH 7.4 and 8.5 PBS in the same time. The accumulated release rates of curcumin in pH 8.5 PBS are lower than that in pH 5.0 and 7.4 after 7 h. About 49.4, 53.8 and 60.8% of loaded curcumin were released within 3 h and then the remaining curcumin was gradually released in pH 5.0, 7.4 and 8.5 PBS, respectively. The faster release property of curcumin from hydrophobic pSi within 3 h is probably related to the diffusion of free curcumin molecules entrapped in the pore structure. 14


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The slow release after 3 h may come from the strong interaction between curcumin and hydrophobic surface of pSi and slow degradation of pSi. The release dynamics of curcumin from pSi have been investigated by monitoring the release rates of curcumin from pSi in the different time. The release dynamic property of curcumin from pSi was modeled, which displayed a RitgerMt

Peppas model (M = kttn) ∞

44,45

in the pH 5.0 and 7.4 medium solutions (Table S4-S5), deviated

Ritger-Peppas model in the pH 8.5 medium solutions (Table S3) (R2=0.888). This may result from the degradation or anionic form of curcumin in pH 8.5. In addition, the drug release properties from pSi still depend on pore size, surface characteristics, temperature, molecular interactions, as well as the pSi degradation profiles46. Figure 3B shows that the accumulated release rates of curcumin in simulative stomach and intestine medium solutions. The accumulated release rates of curcumin reach a plateau after 3 h and 7 h in simulative intestine and stomach medium solutions, respectively. The accumulated release rates of curcumin in intestine medium solutions are higher than that in stomach medium solutions in all observation time points from 0.5 to 12 h. This indicates that curcumin in pSi is released more easily in intestine medium solution than in stomach medium solution. The release dynamics of curcumin from pSi in simulative stomach and intestine medium solutions show the same model as that in pH 5.0 and 7.4 medium PBS solutions (Table S6 and S7). 3.4. The release property of curcumin from pSi in vivo The mice were fed with low, medium and high dose of curcumin-pSi. The curcumin in serum were detected by HPLC-UV. The results show that the curcumin cannot be detected in serum of mice which fed with low and medium dose curcumin-pSi in the all observation time. This result is ascribed to the low concentration of curcumin level in the samples. Figure 4 shows that the release property curcumin from pSi in the serum of mouse fed at high dose in the different times. The curcumin concentrations in the serum of mice increase and reach to the maximum value within 4 h and then quickly decrease, even cannot be detected after 8 h. Shoba et al. have reported that the concentration of curcumin would reach to the maximum value within 1 h and cannot be detected after 5 h in serum of mouse fed at 2g/kg dose47. Wu et al found that the highest concentration of curcumin can be detected after 1.5 h and cannot be detected after 7 h in serum of mouse fed at 100 mg curcumin/kg dose48. The doses in the previous reports are more a dozen times 15



than that in the work (3.8 mg curcumin/kg). Therefore, we believe that increase of oral dose could further improve the concentration of curcumin in serum of mouse in this work. One obvious difference from the above reports is that hydrophobic pSi is used as a curcumin carrier in this work. This result indicates that pSi can slowly release curcumin and improve the concentration of curcumin in serum. The concentration of curcumin (ng/mL)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 27

60

40

20

0 0

2

4 Time(h)

6

8

Figure 4. The release property of curcumin from hydrophobic pSi in mice serum. 3.5. The antioxidant activity of curcumin from pSi microparticles Figure 5A shows the scavenging effect of the different concentration of curcumin on DPPH free radical. As increases of curcumin concentration and time, the curcumin shows a better scavenging effect on DPPH free radical, which is consistent with antioxidant activity of curcumin49,50. Figure 5B shows that the scavenging effect of the same concentration of curcumin and curcumin extraction from pSi microparticles on DPPH free radical. Curcumin displays obviously higher scavenging effect on DPPH free radical than curcumin extraction from pSi microparticles in the all observation time, especially, during 10-30 min. The result can be attributed to the slow release of curcumin from pSi microparticles. Figure 5 C shows that the comparation of scavenging effect on O2-• free radical between the curcumin extraction from pSi microparticles and Vc at the different concentrations in 1 h. The curcumin extraction from pSi microparticles displays a far higher scavenging effect on O2-• free radical than Vc because the concentration of curcumin is lower an order of magnitude than that of Vc. The results indicate that curcumin in pSi microparticles keeps a good antioxidant bioactivity. 16


Page 17 of 27

20μg/mL 40μg/mL 60μg/mL 80μg/mL 100μg/mL 120μg/mL 140μg/mL

Scavenging rate (%)

60

80 μg/mLcurcumin curcumin-pSi

B 45 Scavenging rate (%)

A

45

30

30

15

15

0 0

10

C

20 Time (min)

30

40

0

10

20 Time (min)

30

40

Curcumin extraction from pSi (μg/mL) Vc (mg/mL)

75

Scavenging rates(%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


50

25

0

20

40

60 80 The concentration

100

Figure 5. The scavenging effect of curcumin(A), curcumin extraction from pSi microparticles (B and C) on DPPH free radical, and curcumin extraction from pSi microparticles and Vc (C) on O2-• free radical. 3.6. The influence of hydrophobic pSi microparticles on hematological analysis The oral safety assessment of hydrophobic pSi microparticles was performed in vivo in mice. The influence of hydrophobic pSi microparticles on the cells in blood is shown in the table 1. Though WBC in low dose group is remarkably higher than that in control group, there are not significant differences (p< 0.01) among the other groups. In addition, there are not significant differences among the all groups for LYM and PLT, RBC and HGB in high, medium and low dose groups although RBC at low dose group is obviously lower than that in control group. This could be attributed to hemolysis caused by improper shaking during blood collection. Table 1. Influence of hydrophobic pSi microparticles on blood routine of mice Groups

WBC

LYM

RBC 17


PLT

HGB


Page 18 of 27

（×109/L）

（%）

（×1012/L）

（×109/L）

(g/L)

Control

25.4±0.6bB

81.7±7aA

7.0±1.0aA

850.0±138.4aA

124.3±13.9aA

High dose

30.1±3.4bB

78.7±6.8aA

6.9±0.7aA

954.6±191.6aA

122.7±9.6aA

Medium dose

34.4±5.4abAB

82.6±4.4aA

6.6±1.0aA

896.0±144aA

116.5±14.7aA

Low dose

38.0±2.6aA

86.9±2.7aA

1.2±1.4bB

588.8±153.5aA

137.9±16.7aA

The data are present as mean ± S.D. The same letters (ab AB) mean no differences among the groups. The different letters indicate differences among groups. a,b P< 0.05 and A,BP< 0.01.

The influence of hydrophobic pSi microparticles on serum biochemical index of liver in mice is shown in table 2. Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), total protein (TP) and Albumin (ALB) in serum of liver in mice in high, medium and low dose groups have not shown the significant difference in the all groups. ALT and ALP are enzymes located in liver and heart cells that leak out into the general circulation when liver cells are injured51. The results indicate the pSi microparticles have not significant influence on liver of mice. Table 2. Influence of hydrophobic pSi microparticles on serum biochemical index of liver in mice Groups

ALT（U/L）

ALP(U/L)

TP(g/L)

ALB(g/L)

Control

31.87±1.59aA

103.50±81.9aA

58.73±3.63aA

40.09±1.63aA

High dose

36.23±9.64aA

137.27±24.69aA

56.12±3.54aA

39.70±2.07aA

Medium dose

36.77±9.28aA

117.93±13.80aA

58.59±3.21aA

39.20±2.58aA

Low dose

27.73±1.45aA

107.73±5.08aA

54.94±1.58aA

38.69±1.48aA

The data are present as mean ± S.D. The same letters (a A) mean no differences among the groups. The different letters indicate differences among groups. aP< 0.05 and AP< 0.01.

The influences of hydrophobic pSi microparticles on serum biochemical index of myocardial injury and kidney in mice have been investigated and the results are shown in table 3 and 4, respectively. Generally, LDH and AST are abundant in myocardial cell and they will release into the serum when myocardial cell is injured. LDH and AST are the two indexes for myocardial injury. CREA and BUN are the end products of organic matter containing nitrogen and protein metabolism, respectively. They are used as diagnostic and screening index of glomerular filtration 18


Page 19 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


function. When glomerular filtration function decreases, they will increase in serum of kidney. From the table 3 and 4, there are not significant differences for LDH, AST, CREA and BUN among the all groups. The results indicate that the hydrophobic pSi microparticles also have not significant influences on the myocardial cell and kidney of mice. Table 3. The influence of hydrophobic pSi microparticles on serum biochemical index of myocardial injury in mice Lactic dehydrogenase (LDH)

Aspartic acid aminotransferase

（U/L）

(AST)(U/L)

Control

1660.50±816.07aA

144.30±44.2aA

High dose

895.13±402.41aA

152.77±112.18aA

Medium dose

1446.80±300.17aA

127.77±47.86aA

Low dose

1081.00±206.94aA

105.83±28.79aA

Groups

The data are present as mean ± S.D. The same letters (a A) mean no differences among the groups. The different letters indicate differences among groups. a P< 0.05 and AP< 0.01.

Table 4. The influence of hydrophobic pSi microparticles on serum biochemical index of kidney in mice Groups

Blood creatinine(CREA)（μmol/L）

Urea nitrogen (BUN) (mmol/L)

Control

9.33±2.31aA

5.66±0.67aA

High dose

10.67±3.51aA

6.86±0.91aA

Medium dose

9.33±1.15aA

6.31±0.66aA

Low dose

10.00±2.65aA

6.50±0.68aA

The data are present as mean ± S.D. The same letters (aA) mean no differences among the groups. The different letters indicate differences among groups. a P< 0.05 and AP< 0.01.

3.7. Histopathological section observation of mice Figure 6 shows the representative histopathological sections of the liver, kidney, spleen and heart of mice of control and pSi microparticles groups at different dose of 0.5, 1.0 and 5.0 mg. There are no marked pathological changes among the control groups and their corresponding dose groups, indicating that the hydrophobic pSi microparticles have high in vivo biocompatibility 19



Page 20 of 27

within the observed dose ranges. Nano- and microparticles made from other delivery vehicles have been used to enhance the bioavailability and prolong the curcumin concentration in plasma48. Compared with previous reports about curcumin delivery vehicles, pSi shows several unique properties: easy preparation process, large internal surface area, controlled pore size, high drug loading (22.3%) and the intrinsic photoluminescence. Although the maximum allowable dose of curcumin-pSi in animal still needs to be further investigated, the preliminary results of hematological analysis and histopathological section observation of mice show that the hydrophobic pSi is a promising delivery vehicle for curcumin.

Figure 6. Physiological section of liver, kidney, spleen and heart from mice of control and pSi microparticle groups at different dose of 0.5, 1.0 and 5.0 mg (400×images for liver, kidney, 20


Page 21 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


heart and 100×images for spleen; Hematoxylin staining. 4. Conclusion In summary, we investigated the influence of the different surface properties of pSi microparticles on the loading efficiency of curcumin. The pSi microparticles modified with C-18 group show the highest loading curcumin efficiency. Curcumin from pSi microparticles can be effectively released in a controlled manner in vitro and in vivo. The antioxidant activity of pSicurcumin in vitro indicates curcumin from pSi microparticles could scavenge DPPH and O2-• free radical and has kept good bioactivity. The toxicological evaluation of the hydrophobic pSi microparticles in vivo indicates they have a high in vivo biocompatibility within the observed dose ranges. The hydrophobic pSi microparticles could provide a new drug delivery carrier for curcumin. ASSOCIATED CONTENT Supporting Information Additional information as noted in text. This material is available free of charge via the Internet at http://pubs.acs.org. Notes The authors declare no competing ﬁnancial interest. Acknowledgments The work was supported by National Natural Science Foundation of China no.31471642. References: (1) Huang, P.; Zeng, B.; Mai, Z.; Deng, J.; Fang, Y.; Huang, W.; Zhang, H.; Yuan, J.; Wei, Y.; Zhou, W. Novel Drug Delivery Nanosystems Based on Out-inside Bifunctionalized Mesoporous Silica yolk–shell Magnetic Nanostars Used as Nanocarriers for Curcumin. J.Mater. Chem. B 2016, 4 (1), 46-56. (2) Gong, C.; Deng, S.; Wu, Q.; Xiang, M.; Wei, X.; Li, L.; Gao, X.; Wang, B.; Sun, L.; Chen, Y.; Li, Y.; Liu, L.; Qian, Z.; Wei, Y. Improving Antiangiogenesis and Anti-tumor Activity of Curcumin by Biodegradable Polymeric Micelles. Biomaterials 2013, 34 (4), 1413-1432. 21



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For TOC only

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The Oral Curcumin via Hydrophobic Porous Silicon Carrier

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