Visible-Light-Responsive Surface Molecularly Imprinted Polymer for

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Cite This: ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

Visible-Light-Responsive Surface Molecularly Imprinted Polymer for Acyclovir through Chicken Skin Tissue Lantao Liu, Nan Li, Meijun Chen, Hailin Yang, Qian Tang, and Chengbin Gong* College of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China

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S Supporting Information *

ABSTRACT: The phototoxicity of UV light limits the application of conventional azobenzene-based photoresponsive molecularly imprinted polymers in the biomedical field. This paper reports a tetra-ortho-methoxy-substituted azobenzene, N-(4-((4-amino-2,6-dimethoxyphenyl)diazenyl)-3,5-dimethoxyphenyl)methacrylamide (ADDDM), whose photoswitching is induced by all visible-light irradiation (440 nm for trans form to cis form and 630 nm for cis form to trans form) in N,N-dimethylformamide and tetrahydrofuran (1:9, v/v). Using ADDDM as the monomer, a visible-light-responsive surface molecularly imprinted polymer (VSMIP) on silica microspheres was fabricated for acyclovir (ACV). VSMIP showed a higher drug loading capacity, better specificity, faster drug release rate, and faster photoisomerization rate constant to ACV than the corresponding visible-light-responsive surface molecularly nonimprinted polymer (VSNIP). The selectivity of VSMIP to ACV and competing materials (ganciclovir and triacetylganciclovir) was examined by ultraviolet−visible spectroscopy, and the VSMIP showed excellent specificity of recognition toward ACV. The VSMIP can realize a visible-light-triggered (440/630 nm) release and uptake of ACV through chicken skin tissue (1 mm in thickness). KEYWORDS: visible-light-responsive surface molecularly imprinted polymer, drug delivery system, azobenzene functional monomer, acyclovir

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INTRODUCTION Photoresponsive surface molecularly imprinted polymers (PSMIPs) are common carriers for drug delivery systems (DDSs). They are widely used in food testing,1 environmental monitoring,2 biological detection,3 controlled release,4−6 and other fields because of a good recognition ability, controllable photoresponsive rate, high binding stability, etc. The photoresponsive properties of PSMIPs are mainly based on azobenzene photoisomerization.7−10 The change from a trans to cis isomer for conventional azobenzene molecules is commonly obtained by UV irradiation, but phototoxicity of UV light limits their application in the biological and biomedical fields.11 Therefore, the design and development of visible-lightresponsive azobenzenes are the keys to achieving high biocompatibility control methods. Recent discoveries and applications of the visible- and red-light response of azobenzene molecules12−17 have brought major breakthroughs in photoresponsive biological systems, photopharmacology, and materials science. Three representative designs of visible-light-responsive © XXXX American Chemical Society

azobenzene derivatives are the tetra-ortho-fluoroazobenzene derivative designed by Hecht18 as well as the tetra-orthomethoxyazobenzene and tetra-ortho-chloroazobenzene reported by the Woolley team.19−22 These azobenzenes have an exciting light response in the visible region from 400 to 600 nm. These works have established the base for visible-light-responsive polymers. ACV is widely used to treat viral diseases.23−25 The oral bioavailability of ACV is poor (10−20%) and variable, and therefore, gram amounts are required per day, which can affect renal function. A straightforward method, topical delivery of ACV onto the anterior segment, is effective against superficial HSV infections, but it is not effective for deep infections. Moreover, the transport of ACV is efficiently restricted by skin tissue owing to its polarity and poor water solubility.23 Received: June 28, 2018 Accepted: August 21, 2018 Published: August 21, 2018 A

DOI: 10.1021/acsabm.8b00275 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

Article

ACS Applied Bio Materials

(98%), N,N-diisopropylethylamine (DIPEA, 99%), triethylamine (99%), triethanolamine (99%), tetraethyl orthosilicate (TEOS, 98%), 3-methacryloxypropyltrimethoxysilane (MPS, 97%), ACV (97%), ganciclovir (GCV, 98%), triacetylganciclovir (TCV, 98%), CuBr (99%), PMDETA (99%), ethyl α-bromoisobutyrate (98%), H2SO4, HNO3, acetone, methanol, ethanol, pyridine, HCl, acetic acid, propanoic acid, formic acid, tetrahydrofuran, ammonia hydroxide solution (28%), dichloromethane, urea, K2CO3, NaNO2, NaOH, and Na2S·9H2O were commercially provided by Aladdin Co. Ltd. (Shanghai, China). Measurements. The instruments used to obtain 1H NMR and 13 C NMR, ultraviolet−visible (UV−Vis) spectra, Fourier transform infrared (FT-IR) spectra, thermal gravimetric analysis (TGA), nitrogen adsorption−desorption analysis, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) were the same as in our previous report.28 Visible lights (440 and 630 nm) were used for photoirradiation. The intensity was measured to be 80 mW/cm2 with a full spectrum strong light power meter (CEL-NP2000-2, CEAULIGHT, Beijing, China). Synthesis of ADDDM and Triethanolamine Trimethacrylate (TEAMA). Scheme 2 shows the synthetic route for the functional monomer ADDDM. The detailed procedures were described in the Supporting Information. The acylation reagents methacryloyl chloride and hydrophilic cross-linker TEAMA (Scheme 1) were synthesized exactly according to our previous report.1 Synthesis of Silica Microspheres. The silica microspheres were prepared and activated by the modification of our previously reported method.26 The hydrolysis time was extended to 48 h to obtain a more uniform size with good reproducibility (yield 2.25 g). HCl (100 mL, 4 mol L−1) was used for silica microspheres (2.00 g) activation. The surface of the silica microspheres was modified using Tian’s method27 with a slight change: 2.00 g of activated silica microspheres, 1 mL of acetic acid, and 10.00 g of MPS in 10 mL of ethanol were used. Synthesis of VSMIP/VSNIP. The synthesis of VSMIP/VSNIP was performed according to the method reported in our previous report,28 with a few modifications: In a 100 mL flask, SiO2-MPS (320.0 mg) was dispersed in 1:5 H2O/THF (v/v; 40 mL), and the mixture was stirred for 5 min. Subsequently, ACV (18.0 mg, 0.08 mmol) and ADDDM (160.0 mg, 0.40 mmol) were added. A longer stirring time (12 h) was required to obtain a clear solution. TEAMA (700.0 mg, 2.00 mmol) was then added as the cross-linker. The reaction system was placed in the dark during polymerization. A temperature of 45 °C under a vacuum was adopted to dry ACV-VSMIP, and ACV was removed using 120 mL

Therefore, the clinical application of ACV faces two problems: low oral bioavailability and difficulty in delivering to deep tissue. It is necessary to develop a drug delivery material that can both achieve a controlled drug release in vitro and deliver the drug to deep tissue. To address the two problems, a VSMIP was prepared for visible-light-regulated release and uptake of ACV in vitro (through chicken skin tissue) by designing a visible-lightresponsive tetra-ortho-methoxy-substituted azobenzene (440 nm for trans → cis and 630 nm for cis → trans), N-(4-((4-amino-2,6dimethoxyphenyl)diazenyl)-3,5-dimethoxyphenyl)methacrylamide (ADDDM) (Scheme 1), as the functional monomer. For Scheme 1. Structural Formula of Cross-Linker, Functional Monomer, ACV, GCV, and TCV

ADDDM, the four ortho-methoxy substituent groups, the paraamino substituent group, and the para-amide substituent group help to realize the visible-light-responsive properties,19−22 and the CC is used as the polymerizing group with a cross-linker. The in-time release of ACV through skin tissue in vitro can be regulated by visible light, which is biocompatible.

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EXPERIMENTAL METHODS

Chemicals. Resorcinol (≥99%), 3,5-dimethoxyaniline (98%), dimethylsulfate (DMS, 98%), Pd/C (5 wt % Pd), p-toluenesulfonyl chloride (TsCl, 98%), α-methylacrylic acid (98%), thionyl chloride

Scheme 2. Synthetic Route for ADDDM

B


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Photoisomerization Investigation. Spectroscopic characterizations of ADDDM, VSMIP, and VSNIP followed the procedure reported by Gong.2 The solvent was a mixture of DMF and THF (1:9, v/v). Eq 1 was used to calculate the trans to cis and cis to trans photoisomerization kinetic rate constants (k).29

Scheme 3. Preparation Procedure for VSMIP

ln

A 0 − A∞ = kt A t − A∞

(1)

Binding Kinetics of VSMIP for ACV. Approximately 15.0 mg of VSMIP and 3 mL of 40 μmol L−1 ACV in DMF and THF (1:9, v/v) were added in a cuvette. The binding kinetics of VSMIP and VSNIP were investigated by UV−vis spectroscopy.28 The binding capacity was calculated using eq 2:30

Q=

(C0 − C)V W

(2)

Equilibrium Rebinding Study. An equilibrium rebinding was studied in the dark according to a previous method.28 Standard ACV solutions were prepared in DMF and THF (1:9, v/v), and the ACV concentrations ranged from 10 to 160 μmol L−1. VSMIP (15 mg) and a standard ACV solution (3 mL) were placed in a centrifuge tube and then incubated at room temperature for 40 min. After centrifugation at 5000 rpm for 5 min, the ACV concentration in the supernatant was analyzed with UV−vis spectroscopy. The Scatchard equation (eq 3)

of methanol and acetic acid (9:1, v/v) for 48 h. The other procedure was similar to the one in ref 28. The VSMIP material (yield 600.0 mg) was obtained as a brown powder after drying at 45 °C in a vacuum oven. A similar procedure was adopted to fabricate VSNIP, but without the addition of ACV. VSMIP and VSNIP were sealed to keep out air and moisture and were stored using Gong’s method.28

Figure 1. SEM microphotographs of silica (a), SiO2-MPS (b), VSMIP (c), and VSNIP (d). TEM microphotographs of silica (e), SiO2-MPS (f), VSMIP (g), and VSNIP (h).

Figure 2. FT-IR spectra (a) and TGA curves (b) of silica, SiO2-MPS, and VSMIP. C


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Figure 3. Nitrogen adsorption−desorption isotherms of VSMIP (a) and VSNIP (b) at 77 K. Insets: pore size distribution. Specificity of VSMIP Toward ACV. The binding specificity of VSMIP and VSNIP was investigated in the dark at room temperature using GCV and TCV as the competitive materials. The procedure was similar to the method reported by Yang.26 ACV, GCV, and TCV solutions with a concentration of 40 μmol L−1 in DMF and THF (1:9, v/v) were prepared. The mixture of VSMIP/VSNIP microspheres (15.0 mg) and 3 mL of ACV, GCV, or TCV solution was stirred for 40 min. The amounts of ACV, GCV, and TCV bound to the VSMIP/VSNIP was analyzed with UV−vis spectroscopy. Visible-Light-Induced Release and Uptake of ACV by VSMIP/VSNIP. The procedure was similar to previous methods,28 but with some differences. The mixture of VSMIP (15.0 mg) and ACV, GCV, or TCV solution (40 μmol L−1, 3 mL) in DMF and

Table 1. Surface Area, Pore Diameter, and Pore Volume of VSMIP and VSNIP materials

surface area (m2/g)

pore volume (cm3/g)

average pore size (Å)

VSMIP VSNIP

27.83 15.83

0.1422 0.0716

40.13 37.82

was used to calculate the equilibrium adsorption capacity of VSMIP for ACV (Q).31 Q −Q Q = max Cs Kd

(3)

Figure 4. UV−vis spectra of VSMIP (0.3 mg mL−1) in DMF and THF (1:9, v/v) upon irradiation at 440 nm (a) and then at 630 nm (b), and the absorbance at 364 nm versus irradiation time for ADDDM (30 μmol L−1) (c) and VSMIP (0.3 mg mL−1) (d). D


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Figure 5. Binding kinetics (a) and adsorption isotherms (b) of the VSMIP and VSNIP.

Figure 6. Scatchard plot of the batch-type rebinding assay of VSMIP (a) and VSNIP (b) with ACV.

3420, 1103, 953, and 471 cm−1 in the three curves demonstrate the presence of silica microspheres.31−33 The bands at 1638 cm−1 for SiO2-MPS and 1724 cm−1 for VSMIP were, respectively, ascribed to CC and CO groups. TGA analyses of silica, SiO2-MPS, and VSMIP (Figure 2b) showed that MPS and MIP were degradaed at above 250 °C, demonstrating that VSMIP was thermal stable. Type IV isotherms were observed for the adsorption isotherms of VSMIP and VSNIP (Figure 3). The pore size distribution (insets of Figure 3) indicated that VSMIP and VSNIP were mesoporous materials. The surface area, pore diameter, and pore volume of VSMIP were larger than those of VSNIP, owing to the formation of cavities during the removal of ACV (Table 1). Photoisomerization Analysis. ADDDM exhibited the best photoresponsive properties in THF. However, the solubility of ACV in THF was poor. A small fraction of DMF was added to solubilize ACV. Therefore, DMF−THF (1:9, v/v) was used. As inspired by Woolley’s,19−22 Wang’s,16,17 and Wu’s reports,34−36 photoisomerization of ADDDM was investigated under photoirradiation at wavelengths from 405 to 630 nm. Good results were obtained using 440 nm to induce trans to cis isomerization and 630 nm to induce cis to trans isomerization. The UV−vis spectra of ADDDM upon irradiation at 440 and 630 nm (Supporting Information, Figure S1a,b) in DMF and THF (1:9, v/v) showed a strong absorption peak at approximately 364 nm, which was attributed to the π−π* electron transition of azobenzene. VSMIP was also studied under the same irradiation conditions (Figure 4a, 440 nm; Figure 4b, 630 nm) in DMF and

THF (1:9, v/v) was stirred for 40 min, centrifuged at 5000 rpm, and analyzed by UV−vis spectroscopy. Irradiations at 440 nm for 0.5 h and 630 nm for 1.5 h were, respectively, adopted for the photoregulated release and uptake of ACV, GCV, and TCV. The same method was used to study the visible-light-responsive properties of VSNIP. Photoregulated Release and Uptake of ACV by VSMIP through Chicken Skin. The method described above was also used for this study, except that a piece of chicken skin (1 mm thick with an area of 20 × 30 mm) was placed between the light source and the cuvette.

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RESULTS AND DISCUSSION Synthesis of VSMIP/VSNIP. Scheme 3 illustrates the preparation procedure for VSMIP. The optimized polymerization conditions are as follows: solvent, H2O/THF (1:5, v/v); mass ratio of SiO2-MPS/ADDDM, 2:1; molar ratio of TEAMA/ ADDDM, 5:1. Characterization of the VSMIP/VSNIP. SEM and TEM analyses (Figure 1) showed that silica, SiO2-MPS, VSMIP, and VSNIP were spherical materials with a regular morphology, monodispersed, and a uniform size. The number-average diameters of silica, SiO2-MPS, and VSMIP were calculated to be 554, 652, and 769 nm (Supporting Information, Table S1), respectively. The VSMIP and VSNIP materials had a core− shell structure with a polymer layer thickness of 50 nm. These results illustrated that a MIP shell was successfully coated on the SiO2 core. No distinct difference was observed by the SEM microphotographs of VSMIP and VSNIP. The FT-IR spectra of SiO2, SiO2-MPS, and VSMIP are shown in Figure 2a. The bands observed at approximately E


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results illustrated that VSMIP had good visible-light-responsive properties for ACV. After alternate irradiation at 440 and 630 nm for four cycles, the absorbances at 364 nm for ADDDM (Figure 4c) and 348 nm for VSMIP (Figure 4d) were stable. Binding Kinetics and Equilibrium Rebinding Study. The binding kinetics of ACV with VSMIP and VSNIP were evaluated (Figure 5a). Compared with VSNIP, VSMIP had a larger binding capacity (4.26 μmol g−1 vs. 2.14 μmol g−1) and faster mass-transfer rate, owing to tailor-made binding sites.28 This result was consistent with the nitrogen adsorption− desorption analysis (Table 1 and Figure 3). Figure 5b shows the static binding isotherm of ACV on VSMIP and VSNIP. It was clear that the adsorption capacities of VSMIP and VSNIP increased as the initial concentration of ACV increased. The maximum adsorption of VSMIP for ACV (12.65 μmol g−1) was nearly three times larger than that of the corresponding VSNIP (4.50 μmol g−1). This demonstrates that VSMIP showed a better affinity to ACV compared with VSNIP. Scatchard Analysis. Scatchard analysis was used to calculate the binding affinity and theoretical binding site number for ACV of VSMIP (Figure 6a) and VSNIP (Figure 6b). Two intersecting lines in Figure 6a indicate that VSMIP contains both specific and nonspecific binding sites. The Qmax and Kd were 5.26 μmol g−1 and 4.15 μmol L−1, respectively. One line was observed in Figure 6b, which illustrated that VSNIP did not exhibit specific binding sites.

Figure 7. Absorption efficiency of ACV, GCV, and TCV with the VSMIP and VSNIP.

THF (1:9, v/v). The π−π* electron transition of azobenzene appeared at approximately 348 nm. Similar results were obtained for VSNIP (Supporting Information, Figure S1c,d). Compared to ADDDM, the ktrans→cis and kcis→trans of VSMIP were smaller (Supporting Information, Table S2) owing to rigid environment of MIP. The ktrans→cis of VSMIP was larger than that of VSNIP, and the kcis→trans was smaller than that of VSNIP. This was attributed to the fact that VSNIP did not contain imprinted cavities, the azobenzene functional groups suffered from large steric hindrance, trans to cis isomerization was difficult, and cis to trans isomerization was easier. These

Figure 8. Visible-light (440 and 630 nm)-induced release and uptake of ACV and competing materials (GCV and TCV) by VSMIP/VSNIP (a). Photographs of 440 nm blue light (left) and a 630 nm red light (right) penetrating a chicken skin tissue slice. Visible-light (440 and 630 nm)induced release and uptake of ACV, GCV, and TCV through chicken skin tissue by VSMIP (c). F


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ACS Applied Bio Materials Binding Specificity. GCV and TCV were used as competing materials to investigate the binding specificity of VSMIP to ACV. Figure 7 shows that VSMIP displayed higher binding capacities toward ACV than GCV and TCV. Namely, VSMIP displayed a good binding specificity to ACV. Visible-Light-Induced Release and Uptake of ACV by VSMIP/VSNIP. The visible-light-induced release and uptake of ACV, GCV, and TCV were studied in 3 mL of DMF and THF (1:9, v/v) by alternating irradiation at 440 and 630 nm, in which the initial concentrations of ACV, GCV, and TCV were 40 μmol L−1 (Figure 8a). When 15.0 mg of VSMIP was added into this solution, 77.2 nmol ACV was adsorbed on VSMIP via specific and nonspecific binding. Irradiation at 440 nm induced an azobenzene chromophore change from trans to cis isomer, resulting in the release of 20.7 nmol ACV from VSMIP. The solution was then irradiated with a 630 nm light, which caused 19.1 nmol ACV in the solution rebound by VSMIP. Nearly 92.3% of the released ACV was rebound by VSMIP. Similar results were obtained during repeating of the 440/630 nm irradiation. Namely, the visible-light-induced release and uptake of ACV was repeatable. Smaller amounts of GCV and TCV were taken up and released by VSMIP upon 440/630 nm irradiation. Compared with VSMIP, VSNIP had no significant effect on the visible-light-induced release and uptake of ACV. To evaluate the feasibility of visible-light (440 and 630 nm)induced release and uptake of a drug (ACV) by the VSMIP in deep tissue, a chicken skin tissue with a thickness of 1 mm was placed between the triggered light source and the cuvette. Both the blue (440 nm) and red (630 nm) lights penetrated the chicken skin tissue (Figure 8b). The photoisomerization of the VSMIP through the chicken skin was also effective (Figure S2). The photoisomerization of VSMIP material through the chicken skin required a longer photoresponse time; both ktrans→cis and kcis→trans were smaller when compared with those without the chicken skin tissue (Table S3), but there was no significant change in the photoisomerization of the VSMIP material. Figure 8c shows visible-light (440 and 630 nm)induced release and uptake of ACV, GCV, and TCV through chicken skin tissue by VSMIP. The results were similar to those without chicken skin except that the photoresponse time was slightly prolonged. In previous reports of photoresponsive molecularly imprinted polymers based on azobenzene, a UV light (365 nm in common) was adopted to trigger the release of the analyte.7−10 The Wu group34,35 recently reported a red-light-induced release of analyte using a tetra-ortho-methoxy-substituted azobenzene. In this work, the VSMIP can recognize, release, and uptake the analyte upon visible-light irradiation. The excellent visible-lightresponsive performance and weak phototoxicity of VSMIP may extend its application in the biomedical field and DDSs.37−40

combined with the molecular imprinting technique could be explored in the future.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsabm.8b00275. Detailed synthesis and characterization of these compounds, SEM and TEM analyses, photoisomerization analysis of ADDDM and VSNIP, and photoisomerization of VSMIP through chicken skin (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +86-23-6825-2360. Fax: +86-23-6825-4000. ORCID

Qian Tang: 0000-0002-5054-5557 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are thankful for the financial support from the Chongqing Science and Technology Commission (cstc2017shmsA0104), the Chongqing City Board of Education (CY170220 and CY170205), and the National Natural Science Foundation of China (20872121).

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CONCLUSIONS In summary, we successfully prepared a visible-light-responsive molecularly imprinted polymer (VSMIP) based on a visiblelight-responsive azobenzene functional monomer (ADDDM). VSMIP could release and uptake ACV specifically and repeatedly under irradiation with visible lights (440/630 nm). The ability of red and blue light to penetrate the chicken skin ensured that ACV could be released deep into the skin. The excellent visible-light-responsive performance extends the practicality of MIPs in DDSs. With the advantages of weak phototoxicity and specificity, red and blue light treatment G


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