polyacrylic acid

Journal Pre-proofs pH-triggered sustained drug release of multilayer encapsulation system with hollow mesoporous silica nanoparticles/chitosan/polyacrylic acid Qiaohua Qiu, Zhenzhen Quan, Hongnan Zhang, Xiaohong Qin, Rongwu Wang, Jianyong Yu PII: DOI: Reference:

S0167-577X(19)31539-3 https://doi.org/10.1016/j.matlet.2019.126907 MLBLUE 126907

To appear in:

Materials Letters

Received Date: Revised Date: Accepted Date:

20 July 2019 27 September 2019 28 October 2019

Please cite this article as: Q. Qiu, Z. Quan, H. Zhang, X. Qin, R. Wang, J. Yu, pH-triggered sustained drug release of multilayer encapsulation system with hollow mesoporous silica nanoparticles/chitosan/polyacrylic acid, Materials Letters (2019), doi: https://doi.org/10.1016/j.matlet.2019.126907

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pH-triggered sustained drug release of multilayer encapsulation system with hollow mesoporous silica nanoparticles/chitosan/polyacrylic acid Qiaohua Qiu a, Zhenzhen Quan a, b, *, Hongnan Zhang a, Xiaohong Qin a, *, Rongwu Wang a, Jianyong Yu b a. Key Laboratory of Textile Science & Technology of Ministry of Education, College of Textiles, Donghua University, Shanghai 201620, China; b. Innovation Center for Textile Science and Technology, Donghua University, Shanghai 201620, China.

Abstract Chitosan is one of the most important and commonly used pH stimuli-responsive polymer. However, the drug burst release when the pH values are in the sensitive range of CS makes the release of the drug unsustainable. To address this problem, the multilayer encapsulation of hollow mesoporous silica nanoparticles with chitosan and polyacrylic acid as outmost layer (SiO2@CS@PAA), is reported. The morphology and structure of the SiO2@CS@PAA are characterized and the release behaviors of drugs in different pH release medium are also studied. The results suggested that the decoration of PAA could reduce the burst release of drugs with pH-sensitivity. Keywords： Nanoparticles; Nanocomposites; Polyacrylic acid; Chitosan; Silica nanoparticles; Controlled-release

1. Introduction pH-responsive drug delivery systems have received particular attention in recent years [1, 2]. To develop such pH-sensitive drug delivery system, chitosan (CS) has been widely utilized because of its versatile characteristics, such as biocompatibility, biodegradability, and so on [3, 4]. Furthermore, the high charge density provided by the amino groups on chains of CS endows CS with pH-sensitivity [3, 5]. At the same time, hollow silica nanoparticles, with the adjustable size, excellent biocompatibility and abundant Si-OH bonds on the surface, are usually used as drug carriers for controlled release. Many researchers have reported the application of CS and SiO2 in pH-responsive drug delivery systems in the ____________ * Corresponding authors. E-mail address: [email protected] (Z. Quan, Ph.D.), [email protected] (X. Qin, Ph.D., Professor)

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past few years [3, 6, 7]. However, the sustained drug release behavior of the chitosan enclosed SiO2 (SiO2@CS) nanoparticles remains poor, when the pH values are in the sensitive range of CS. To address the above problem, in the present work, polyacrylic acid (PAA) has been attached to the surface of the SiO2@CS nanoparticles through the electrostatic interaction between PAA and CS, which enhanced the sustained release of triclosan (TR).

2. Experimental

2.1. Preparation of hollow mesoporous SiO2 nanoparticles

According to the Ref. [8], 0.15 g PAA aqueous solution was dissolved into ammonium hydroxide solution of 4.3 mL, and 87 mL absolute alcohol was added to above solution mixture and stirred for 1 h. Then, 1.4 mL tetraethyl orthosilicate (TEOS) was added into the stirred solution and stirred for another 12 h at room temperature, after which, the solution was centrifuged, washed and dried to obtain hollow mesoporous SiO2 nanoparticles.

2.2. Preparation of TR loaded SiO2 nanoparticles

TR was dissolved in ethanol solution at a concentration of 30 mg/mL, and 1g hollow mesoporous SiO2 nanoparticles were added. Then, the mixture was stirred at room temperature for 48 h, centrifuged and dried at 60 ℃ to obtain the TR loaded SiO2 nanoparticles (SiO2-TR).

2.3. Preparation of SiO2@CS@PAA nanoparticles

Chitosan solution (0.2% w/v) was prepared by dissolving chitosan in acetic acid aqueous and stirring at room temperature for 12 h, and the pH was adjusted to be 6 with 1M NaOH. The SiO2-TR nanoparticles were dispersed in 10 mL chitosan solution and stirred at room temperature for 12 h. The SiO2@CS nanoparticles were obtained after centrifuging, washing and drying. After that, SiO2@CS nanoparticles were added into PAA solution (0.2% w/v) and

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stirred at room temperature for 12 h. The TR loaded SiO2@CS@PAA nanoparticles were obtained after centrifuging and drying.

2.4 Measurement of triclosan release

Drug release behavior from the SiO2@CS@PAA nanoparticles was measured as follows. 0.5 g SiO2@CS@PAA nanoparticles were soaked in 15 mL of 0.01M phosphate buffer saline (PBS) solution (with pH 7.5 and 5.5) at 37 ℃ with mild shaking and observed for 7 days. Since TR was slightly soluble in PBS, 0.5% w/v sodium lauryl sulfate (SLS) was added to increase the solubility. At given time intervals, 1 mL of the solution was replaced with 1 mL of fresh PBS (with 0.5% w/v SLS) for measuring the TR concentration by ultraviolet spectrophotometer at 281 nm (UV, PerkinElmerLambda 35). To further demonstrate the release behavior, inhibition zone was observed at different pH release medium. The SiO2@CS@PAA nanoparticles were placed in deionized water with different pH to obtain the drug solution. And then, 20 μL of resulting solution was dispersed onto a sterilized circular filter paper, which was placed onto the cultural plate coated with the bacteria solution in advance. Inhibition zone was observed after incubation at 37 ℃ for 18 h.

3. Results and discussion

3.1. Characterization of the SiO2@CS@PAA nanoparticles

As shown in Figure 1b-d, the obtained hollow mesoporous SiO2 nanoparticles had a legible spherical shape and an obvious core-shell structure with a core of 65 nm in diameter and a shell of 18 nm in thickness. Compared to the SiO2 nanoparticles, the obtained SiO2@CS@PAA nanoparticles (Figure 1c-e) showed a more obvious inter-conglutination and an increased shell thickness of about 23 nm, which could be attributed to the existence of CS and PAA outside the silica core.

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Figure 1 (a) Illustration of the preparation of SiO2@CS@PAA nanocarriers and the drug release behavior at different pH values. (b-d) TEM and FESEM images of hollow mesoporous SiO2 nanoparticles. (c-e) TEM and FESEM images of SiO2@CS@PAA nanoparticles.

The TG analysis results are shown in Figure 2a. Pure TR began to degrade at 150 ℃, while for SiO2-TR nanoparticles, the degradation of TR experienced a comparatively long time, which may be attributed to the protection of

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SiO2 shell. In the case of SiO2-CS, the mass loss occurred at the range of 220-360 ℃, which was assigned to the degradation of CS portion [9]. For SiO2@CS@PAA nanoparticles, the first stage of mass loss appeared at 220-350 ℃, which was related to the degradation of CS portion and the other one appeared at 350-450 ℃, which was attributed to PAA degradation. As shown in Figure 2b, the vibrational peaks at 1055 cm-1 and approximately 3240 cm-1, attributed to the stretching vibration of Si-O and O-H bound, respectively [10, 11]. When the CS was covalently linked onto the surface of SiO2 nanoparticles, the spectra of SiO2@CS exhibited two peaks at about 1380 cm-1 and 1594 cm-1, which indicated the vibration of amide Ⅲ and amide Ⅱ, respectively [12]. Notably, these two peaks generated a shift compared with pure CS, which may be due to hydrogen bonding with the Si-OH on the silica surface. Compared with SiO2@CS, the appearance of the peak at approximately 1715 cm-1 in spectra of SiO2@CS@PAA was attributed to the carboxy group [13, 14], indicated that the PAA deposited on the surface of the SiO2@CS nanoparticles by electrostatic self-assembly. The N2 adsorption-desorption isotherms of SiO2 and SiO2@CS@PAA nanoparticles as shown in Figure S1 (Supporting Information). The isotherm of these samples showed a hysteresis loop on the desorption branch which is Type IV, characteristic for mesoporous materials. After SiO2 nanoparticles had been wrapped with CS and PAA, the reduction of the adsorption capacity of SiO2@CS@PAA due to the sealing effect of the outside CS and PAA layers. Consequently, the calculated surface area SBET reduced to 45.92 from 70.17 m2/g, moreover the pore volume Vp fell from 0.50 to 0.42 cm3/g. The zeta potential experiment showed that the SiO2 nanoparticles have a negative potential of about -10.4 mV, whereas the zeta potential of the SiO2@CS increased to +13.5 mV due to the cationic chitosan deposition. After decorating of PAA, the zeta potential decreased to -13.1mV because of the negatively charged of PAA (Table 1).

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Figure 2 (a) TGA curves and (b) FTIR spectra of SiO2, SiO2-TR, SiO2@CS, SiO2@CS@PAA, CS and TR.

Table 1 Zeta potential of SiO2, SiO2@CS and SiO2@CS@PAA under different pH conditions. Samples

Zeta Potential b(mV) pH: 5.5

pH: 7.5

SiO2

-10.4±1.5

-9.7±2.1

SiO2@CS

+13.5±2.6

+11±3.1

SiO2@CS@PAA

-13.1±1.9

-16±2.4

3.2. pH-controlled TR release from SiO2@CS@PAA nanoparticles To evaluate the pH-sensitive drug release properties, related samples were dispersed in the different release medium with pH 7.5 and pH 5.5, respectively. As shown in Figure 3a, TA was released rapidly from the hollow mesoporous SiO2 nanoparticles and about 75% of the loaded drug was released at 24 h and about 92% at 144 h. The amounts of released TR from SiO2@CS in pH 5.5 PBS solution were around 49% for 24 hours and 74% for 144 h, whereas the released TR in pH 7.5 solution was about 18% for 24 h and about 32% for 144 h. Most importantly, the SiO2@CS@PAA nanoparticles showed a much slower release of TA in pH 5.5 compared to SiO2@CS. At 144 h, only 67% of the total drug had been released in pH 5.5 solution, the possible reason may be that in this pH condition CS was in stretched state, while the PAA was in aggregated state, which blocks the release of some TR. In addition, the inhibition zone assays, as shown in Figure

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3b, also verified that the surface-coated PAA could effectively reduce the release of drug under acidic conditions.

Figure 3 (a) The release curves of TR from SiO2, SiO2@CS and SiO2@CS@PAA nanoparticles and (b) The inhibition zone of samples at different pH release medium.

4. Conclusions In conclusion, the release behaviors of SiO2, SiO2@CS and SiO2@CS@PAA indicated that the release of TR was controlled by the release medium pH value. More importantly, the TR release rate of SiO2@CS@PAA was reduced and can be sustained compared to SiO2@CS, which was due to the existence of PAA. As a result, the pH-responsive drug nanocarriers described here provide a novel strategy for controlling the drug release behavior.

Acknowledgments This work was partly supported by the Chang Jiang Youth Scholars Program of China and grants (51773037) from the National Natural Science Foundation of China to Prof. Xiaohong Qin as well as the “Innovation Program of Shanghai Municipal Education Commission”, “Fundamental Research Funds for the Central Universities” and “DHU Distinguished Young Professor Program” to her. This work has also been supported by grant (51803023, 61771123) from the National Natural Science Foundation of China to Dr. Hongnan Zhang and Prof. Rongwu Wang and the Shanghai Sailing Program (18YF 1400400), the Project funded by China Postdoctoral Science Foundation

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(2018M640317) and the Fundamental Research Funds for the Central Universities (2232018A3-11) to Dr. Zhenzhen Quan and the Fundamental Research Funds for the Central Universities and Graduate Student Innovation Fund of Donghua University (CUSF-DH-D-2018043) to Ms. Qiaohua Qiu.

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9 Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

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1.

The multilayer encapsulation of silica hollow nanoparticles is fabricated.

2.

The release behaviors of drugs are different in different pH release medium.

3.

The surface-coated PAA can prolong the drug release under acidic conditions.