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A Facile Strategy to Prepare Enzyme-Responsive Mussel Mimetic Coating for Drug Delivery Based on Mesoporous Silica Nanoparticles Chunlin Hu, Xinling Wang, Ping Huang, Zhen Zheng, and Zhibiao Yang Langmuir, Just Accepted Manuscript • Publication Date (Web): 09 May 2017 Downloaded from http://pubs.acs.org on May 11, 2017

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A Facile Strategy to Prepare Enzyme-Responsive Mussel Mimetic Coating for Drug Delivery Based on Mesoporous Silica Nanoparticles Chunlin Hu†, Ping Huang†, Zhen Zheng†, Zhibiao Yang*‡, Xinling Wang*† †

School of Chemistry and Chemical Technology, State Key Laboratory of Metal Matrix

Composites, Shanghai Jiao Tong University, Shanghai 200240 China ‡

Shanghai Key Laboratory of veterinary Biotechnology, School of Agriculture and Biology,

Shanghai Jiao Tong University, Shanghai 200240 China *Correspondence to: [email protected], [email protected] KEYWORDS: enzyme-responsive; mussel mimetic coating; drug delivery; mesoporous silica nanoparticles; lysine-dopamine ABSTRACT: Surface functional mesoporous silica nanoparticles (MSNs) have been widely used as promosing materials for drug delivery. Herein, we reported a facile strategy to construct MSNs coated by enzyme-resposive polylysine-dopamine (PLDA) films through selfpolymerization of dopamine derivative lysine-dopamine, in which the drug could be loaded and delivered efficiently. In details, RhB or DOX was used as a drug model and loaded in functional MSNs via one-pot procedure among MSNs, drug and lysine-dopamine (LDA) under basic

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condition. Owing to the peptide bonds between lysine and dopamine can be cleaved under triggering by pepsin, the resulting RhB/DOX@PLDA-MSNs exibit enzyme-responsive characterization. After the DOX@PLDA-MSNs entering into the cancer cells, the drug can be released effectively through degradation of peptide bonds under the influence of enzyme in cancer cells, which shows marked anticancer activity in vitro. This facile strategy may provide a new platform to construct enzyme-responsive controlled drug delivery system. INTRODUCTION Over the past few decades, mesoporous silica nanoparticles (MSNs) have attracted considerable interest owing to their excellent chemical and thermal stability, large surface area, high pore volume, adjustable morphology/pore size and well biocompatibility, resulting in the corresponding application potentials in drug storage and delivery for biomedical therapy.1-5 However, the conventional MSNs used as drug carriers still faces many barriers, such as the spontaneous leakage of cargo molecules during the material preparation process and the premature release in the course of cargo delivery. To address these issues, many reports on design of capped MSNs have been developed and shown a great potentional application in controlled drug delivery systems. At present, gold nanoparticles,6-9 inorganic iron oxide nanoparticles,10-17 dendrimers18 and cyclodextrin 7-amino-coumarin derivative19-22 have been employed as “gatekeepers” to cap the channels of MSNs to realize the drugs controlled release. Thereafter, these systems based on various gatekeepers are developed in responsive to external or internal stimuli, such as redox,10,13 photoirradiation,23-29 temperature,30,31 pH,9,12,14,20-23 and enzymes,32-34 thereby regulating the release of loaded drug molecules. Among those various stimuli, controlled release systems based on enzyme-responsive have garnered much attention because of the mild reaction conditions and low side effect to normal tissues. Unfortunately,


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aforementioned reports based on functionalized MSNs usually need to be modified via many complicated steps. More importantly, the residual chemical reagent after modification might be capped in the pore of MSNs and released to cause side effect to body tissues. Therefore, it is a challenge to construct a platform that could load and modify MSNs with the trigger through onepot. 3,4-dihydroxyphenylalanine (DOPA) has been proved to be the functional group for marine mussels to adhere to various surfaces. Messersmith and co-workers reported the selfpolymerization of dopamine to modify the surface of various materials under an alkaline environment35. Subsequently, they found some phenols and polyphenols derivatives including epigallocatechin gallate, epicatechin gallate, epigallocatechin and tannin, could self-polymerize to form colourless multifunctional coatings36 for reduction of Ag+, which were also used as antibacterial coatings. A polydopamine nano/microcapsules37 was produced by deposition of polydopamine on the template surface, followed by the removal of the template. The Rh6G could be uptake by polydopamine nano/microcapsules but couldn’t be released in an aqueous buﬀer solution, which is reversed in the ethanol. In our previous work, a dopamine derivative lysinedopamine could be self-polymerized to form a coating which has bioactive and show specific binding capacity of plasminogen38. Meanwhile, many peptide mimetic polymers were degradable materials which can be cleaved by some enzyme, polyurethanes containing pseudo tyrosine dipeptide segment can be degraded by chymotrypsin and hydrogen peroxide aqueous with cobaltous chloride39-42. We developed polyurethanes containing a tyrosine-fumaric acid-tyrosine segment which can be degraded by enzyme43. Therefore, a promising platform through the selfpolymerization of lysine-dopamine to form the nontoxicity coatings covered on MSNs which is in responsive to enzyme could be expected.


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Herein, we present a facile strategy to construct functionalized MSNs coated by enzymeresponsive PLDA films via one-pot for drug delivery (scheme 1). In details, RhB/DOX was encapsulated in MSNs through self-polymerization of LDA in tris 8.5 solution to obtain the RhB/DOX@PLDA-MSNs. After the RhB/DOX@PLDA-MSNs entering cancer cells, the RhB or DOX could be released due to the degradation of peptide bonds under the action of enzyme in cancer cells. The biocompatibility of PLDA-MSNs was evaluated by using Marc-145 cells. In vitro drug release under enzyme stimuli, anticancer activity in vitro, and cellular internalization behaviour of DOX@PLDA-MSNs were also investigated.

Scheme 1. Construction of enzyme-responsive MSNs-based drug delivery system

Experimental Section Materials.

All

reagents

used

were

available

from

commercial

sources.

N-

Cetyltrimethylammonium bromide (CTABr), tetraethoxysilane (TEOS), DOX, rhodamine B (RhB). lysine, N-hydroxysuccinimide (NHS), dopamine hydrochloride (DA·HCl) and 1-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) were purchased from Adamas


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and used without further purification. Anhydrous ether, tetrahydrofuran (THF), ethyl acetate (EA), methanol and triethylamine (TEA) was distilled under reduced pressure and dried before use. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were acquired from Invitrogen. HCl and NaHCO3 were purchased from Sinopharm Chemical Reagent Company. RPMI-1640, fetal bovine serum, penicillin and streptomycin were purchased from Gibco. Methods. Synthesis of Lysine-Dopamine LDA was synthesized using lysine and dopamine. The detailed synthesis procedures are shown in Scheme S1. Synthesis of (Boc)2-Lysine-OH (BL) In a flask, L-lysine (0.73 g, 5 mmol) was dissolved in the 100 mL deionized water and 30 mL TFH and 6.3 g NaHCO3 were added. Then di-t-butyl dicarbonate (Boc anhydride) (2.732 g, 75 mmol) was dissolved in THF and added dropwise into the flask. The reaction was carried out at 30 °C for 24 h under a nitrogen atmosphere. And then solvent was removed by using a rotary evaporator. The pH of mixture was adjusted to 3.0 through adding 1 mol L-1 HCl aqueous solution into the flask. Finally, the product was extracted by using EA and then the solvent was evaporated to obtain the product. The product was dried in an oven (60 °C) for 24 h to give BL (1.54 g, 89%). 1H NMR (400 MHz, DMSOd6) δ (ppm): 12.42 (br.s, 1H, COOH), 6.98 (d, 1H, –OCONH–CH–), 6.78 (t, 1H,– OCONH–CH2–), 3.78 (m, 1H, –OCONH–CH–), 2.85 (m, 2H,–OCONH–CH2–), 1.85– 1.05 (m, 24H, –CH2– and –CH3). Synthesis of (Boc)2-Lysine-NHS (BLN)


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To the solution of BL (1.54 g, 4.45 mmol) in CH2Cl2 (70 mL), NHS (0.75 g, 6.6 mmol) and EDC·HCl (1.2 g, 6.6 mmol) were added. The mixture was stirred at 0 °C for 30 min. Then the mixture was stirred at room temperature for 5.5 h under a nitrogen atmosphere. The resulting solution was washed with water (3 × 50 mL), dried over Na2SO4, and concentrated to dryness under reduced pressure. The product was dried in an oven (60 °C) to give BLN (1.67 g, 85%). 1

H NMR (400 MHz, DMSO-d6) δ (ppm): 7.55 (d, 1H, –OCONH–CH–), 6.78 (t, 1H, –

OCONH–CH2–), 4.27 (m, 1H, –OCONH–CH–), 2.96–2.65 (m, 6H, –N(CO–CH2)2 and – OCONH–CH2–), 1.85–1.05 (m, 24H, –CH2– and –CH3) Synthesis of (Boc)2-Lysine-Dopamine (BLDA) To the solution of BLN (1.67 g, 3.7 mmol) in CH3OH (100 mL), DA·HCl (1.07 g, 5.6 mmol) was added. After the DA·HCl was dissolved completely, TEA (0.8 mL) was added into the solution (mole ratio, DA·HCl:TEA, 1.5:1.3). The reaction mixture was stirred at room temperature for 12 h under a nitrogen atmosphere. After the solvent was removed, the crude product was dissolved in EA, washed with deionized water (3 × 100 mL ) The organic phase was collected, dries over Na2SO4, evaporated and dried in an oven (45 °C) for 24 h to obtain product BLDA (0.9 g, 71%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.60–8.90 (d, 2H, –Ar (OH)2), 7.76 (t, 1H, –CONH–CH2–), 6.85–6.65 (m, 3H, – OCONH–CH< and –OCONH–CH2–), 6.64–6.30 (m, 3H, –Ar), 3.78 (m, 1H, –OCONH– CHCH– NH2),7.79 (s, 2H, –CH2–NH2), 6.64–6.30 (m, 3H, –Ar), 3.64 (m, 1H, >CH–NH2), 3.42– 3.10 (m, 2H, –CONH–CH2–), 2.73 (m, 2H, –CH2–NH2), 2.53 (m, 2H, –CONH–CH2– CH2–), 1.85–1.05 (m, 6H, –CH2–). ES MS m/z 282.18 [M+H]+. One-Pot Synthesis of Drug-Loaded Polylysine-Dopamine Film Coated MSN MCM-41 was prepared using previously published methods10. Fluorescein dye RhB or DOX as a model drug (4 mg) was dissolved in 25 mL of tris 8.5. Then MCM-41 (200 mg) was added in the solution which was sonicated for 30 min, and stirred at 25 °C for 24 h. After that LDA 0.25 g was added into the flask, and stirred at 25 °C for 24 h. The precipitate was centrifuged, washed with PBS 7.4 to remove the redundant dye and LDA on the surface of RhB@PLDAMSNs. The drug loading efficiency (DLE) and drug loading content (DLC) were calculated according to the following formula. The DLE and DLC of RhB is about 84% and 1.67%, DLE and DLC of DOX is about 89% and 1.75%, respectively. % =

( ) − ( ) × 100% ( )

(!")% =

( ) − ( ) × 100% ( ) + ($%&)

In Vitro Drug Release Typically, 50 mg of DOX@PLDA-MSNs was added into a dialysis bag, then 2 mL PBS (pH = 7.4) was added. Then the dialysis bag was sealed and put into the brown bottle with 100 mL of PBS with different concentration of pepsin. The brown bottle was placed in a constant


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temperature shock chamber at 37 °C and shook at the speed of 100 rpm. At predetermined time intervals, 3 mL of the external buffer solution was withdraw and replaced with 3 mL of fresh PBS buffer solution. The amount of released DOX was analyzed by UV/vis spectrometer at 559 nm. Cells Culture Human cervix carcinoma cell line (HeLa) was cultured in RPMI-1640. The culture mediums contain 10% FBS heat-inactivated fetal bovine serum (FBS) (56 °C, 30 min) and antibiotics (50 units per mL penicillin and 50 units per mL streptomycin). Cells were cultured under a humidified atmosphere at 37 °C containing 5% CO2. Cytotoxicity Assay The relative cytotoxicity of MSNs and PLDA-MSNs was estimated by MTT viability assay against Marc-145 cells. Marc-145 cells were seeded into a 96-well plate at the concentration of 5 × 105 cells mL-1 in 200 µL of RPMI-1640 and allowed to attach for 24 h. The culture medium was removed and replaced with 200 µL of RPMI-1640 containing serial dilutions of MSNs and PLDA-MSNs. The cells were incubated for another 24 h at 37 °C. Then, 20 µL of 5 mg mL-1 MTT assay stock solution in PBS was added to each well. After the cells were incubated for 4 h, the medium containing unreacted MTT was carefully removed. Then, the obtained blue formazan crystals were dissolved in 200 µL well-1 DMSO, and the absorbance was measured in a BioTek Synergy H4 hybrid reader at a wavelength of 490 nm. The blank was subtracted to the measured optical density (OD) values, and the cell viability was expressed as % of the values obtained for the untreated control cells. Cellular uptake of DOX@PLDA-MSNs by HeLa cells


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HeLa cells were seeded in 6-well plates at 2 × 105 cells per well in 2 mL of complete DMEM and incubated for 24 h. The original medium was replaced with DMEM containing with pepsin of pH 2.0. After incubation for 2 h, cells were washed by cold PBS and incubated with DOX@PLDA-MSNs at a final DOX concentration of 20 µg mL-1 in complete DMEM for an additional 2 h. The cellular uptake of free DOX by HeLa cells was used as a control. After incubation at 37 °C for 2 h, culture medium was removed, and cells were washed with PBS for two times. Subsequently, the cells were fixed with 4% formaldehyde for 30 min at room temperature, and the slides were rinsed with PBS three times. Finally, the cells were stained with 2-(4-amidinophenyl)-6-indolecarbamidine dihydrochloride (DAPI) for 15 min, and the slides were rinsed with PBS three times. The resulting slides were mounted and observed with a LEICA TCS SP8 fluorescence microscopy. In Vitro Activity Analysis HeLa cells were used to evaluate the in vitro cytotoxicity of DOX-loaded PLDA-MSNs by MTT assay. MSNs, PLDA-MSNs, and free DOX were used as a control. HeLa cells were seeded into 96-well plates at 1 × 104 cells per well in 200 µL of culture medium. After 12 h incubation, the medium was removed and replaced with 200 µL of a medium containing serial dilutions of MSNs, PLDA-MSNAS, DOX or DOX@PLDA-MSNs. The cells without the treatment were used as control. The cells were grown for another 24 h. After the incubation, the culture medium was removed and washed with PBS for twice. Then, 200 µL of RPMI-1640 and 20 µL of 5 mg mL-1 MTT stock solution in PBS were added. After the cells were incubated for 4 h, the medium containing unreacted MTT was carefully removed. Then, the obtained blue formazan crystals were dissolved in 200 µL well-1 DMSO, and the absorbance was measured in a BioTek Synergy H4 hybrid reader at a wavelength of 490 nm. The blank was subtracted to the measured optical


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density (OD) values, and the cell viability was expressed as % of the values obtained for the untreated control cells. Measurements. 1HNMR and

13

CNMR spectra were obtained with a Varian a (Mercury plus-

400) NMR spectrometer at room temperature in Methanol-d and chemical shifts were reported in ppm relative. Elemental analysis was performed on Elementar (Vario EL Cube). The surface area was calculated by the BrunauerEmmettTeller (BET) method and the pore size was obtained from the maxima of the pore size distribution curve calculated by the BarrettJoynerHalenda (BJH) method using the adsorption branch of the isotherm. The surface chemical composition was analyzed using a Shimadzu-Kratos (AXIS Ultra). The X-ray photoelectron spectroscopy (XPS) measurements were carried out at a base pressure of about 5 ×10-10 mbar using an Mg Xray (1253.6 eV) source. The UV-vis spectrum was recorded on a Perkin Elmer (Lambda 35) UVvis spectrometer. All measurements were performed in quartz cuvettes. PBS pH 7.4 and pH 1.7 was used as a blank. Powder XRD patterns were recorded on a X-ray diffractometer (D/MAX2200/PC, Rigaku) equipped with Cu Kα radiation (40 kV, 20 mA) at a rate of 1.0 °/min over the range of 6 (2θ). The morphology of the materials was investigated by transmission electron microscopy (TEM) on a JEOL 2010F Analytical Electron Microscope at 200kV. The confocal laser scan microscopy images were performed by LSM510 META, ZEISS. RESULTS AND DISCUSSION Synthesis and characterization of PLDA-MSNs The functionalized PLDA-MSNs were prepared via the self-polymerization of lysine-dopamine (LDA) on the surface of MSNs. The detailed procedure to synthesize LDA was shown in Scheme S1. The chemical structure of BL, BLN, BLDA, and LDA were confirmed by 1H NMR (Figure S1). The molecular weight of LDA product was verified by TOF-MS techniques (Figure


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S2). These results demonstrated that the LDA was synthesized successfully. In order to verify the successful self-polymerization of LDA on the surface of MSNs, TEM and EDX were used to testify the structure of the samples. From Figure 1 a, MSNs shows a typical structure with wellordered hexagonal and uniform pore sizes. Compared with the TEM image of MSNs, the image of PLDA-MSNs (Figure 1b) shows an obvious layer around MSNs due to the selfpolymerization of LDA to form a coating on surface of MSNs under alkaline environment (tris 8.5)44,45. After covering by PLDA coating, the diameter of PLDA-MSNs is 150 ± 20 nm, which is larger than that of MSNs (130 ± 20 nm). The same results were obtained by using DLS measurement. Figure 2 gives the DLS curve of pure MSNs and LDA-MSNs, indicating a narrow unimodal size distribution and an average diameter of approximate 146.8 nm for pure MSNs, while about 183.2 nm for LDA-MSNs. The surface modification of MSNs was also evaluated by measuring the zeta potential. The results shows that zeta potential of pure MSNs was -33.2 mV owing to the presence of negatively charged silanol groups. After MSNs covered with the PLDA coating, the zeta potential increased from -33.2 mV to -20.4 mV, suggesting a decrease in the density of free silanol groups.

Figure 1. TEM images of MSNs (a) and PLDA-MSNs (b)


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20

MSNs PLDA-MSNs

15 Intensity (%)

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10 5 0 10

100 Diameter (nm)

1000

Figure 2. Size distributions of MSNs and PLDA-MSNs

Figure 3. (a) EDX spectrum of PLDA-MSNs. Mapping results of Si (b), C (c), O (d), N (e).


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Moreover, EDX was employed to trace the element N of LDA-MSNs. The results are shown in Figure 3 and Table 1. From Table 1, the weight and atomic percentage of elements of N of PLDA coating on MSN are 1.12%, 1.34%, respectively. While no element N is traced on pure MSNs. The mapping results of Si (Figure 3b), C (Figure 3c), O (Figure 3d) and N (Figure 3e) indicate that MSNs are uniform covered by PLDA coating46. Table 1. Summary of the EDX results of MSNs and PLDA-MSNs MSNs

PLDA-MSNs

Element

Weight percentage %

Atomic Percentage %

Element

Weight percentage%

Atomic percentage%

CK

23.53

34.64

CK

27.37

38.24

Si K

40.27

25.35

Si K

32.31

19.30

OK

36.19

40.00

OK

39.20

41.12

NK

1.12

1.34

MSNs LDA-MSNs

b

O1s

N1s O1s

1200

C1s Si 2p

C1s

900 600 300 Binding energy (eV)

Si 2p

MSNs C1s

0 292

c LDA-MSNs C 1s

284.9 284.8 C-C

286.7 C-O 288.1 C=O

Intensity (a.u)

a

Intensity(a.u)

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288 284 280 295 Binding energy (eV)

284.6 284.6 C-C

286.1 C-O 286.2 C-N 288.5 C=O

290 285 Binding energy (eV)

280

Figure 4. (a) XPS spectra of MSNs and PLDA-MSNs. (b,c) C1s peak-fitting curves of MSNs (b) and PLDA-MSNs (c). The chemical compositions of LDA coating on MSNs were investigated by XPS technique. The results were shown in Figure 4 and surface atom percentages were listed in Table 2. As shown in the Figure 4a, the content of Si and O decreases from 30.29% to 17.81% and 65.08% to 45.94% after coating with LDA, while the percentage of C and N increases from 4.6 to 32.73%


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and 0% to 3.52%, respectively. As shown in Figure 4b, the peaks at 284.8, 286.7, and 288.1 eV belong to carbon species of C-C, C-O, and C=O, respectively. After coating with LDA, the peaks corresponding to carbon species of C-C, C-O and C=O shift to 284.6, 286.1, and 288.5 eV, respectively. Furthermore, the new peak appears at 286.2 eV corresponding to carbon species of C-N in the C1s peak-fitting curves of PLDA-MSNs (Figure 4c). All the results demonstrate that PLDA-MSNs were synthesized successfully. Table 2. Surface atom percentages of MSNs and PLDA-MSNs Sample

Atom percenctage（100%） C 1s

O 1s

N 1s

Si 2p

MSNs

4.63

65.08

-

30.29

PLDA-MSNs

32.73

45.94

3.52

17.81

Figure 5 shows XRD patterns of the MSNs and RhB@PLDA-MSNs. From Figure 5, the intensity of RhB@PLDA-MSNs powder X-ray diffraction d100, d110, d200 peaks decrease because of MSN filled with Rh B and covered by PLDA coating47. 6000 MSNs RhB@LDA-MSNs

5000 Intensity (a.u)

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4000 3000 2000 1000 0 0

1

2 3 4 5 2 Theta (degree)

6

Figure 5. X-ray diffraction (XRD) patterns of MSN and RhB@PLDA-MSNs.


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The N2 adsorption−desorption of pure MSNs and RhB@PLDA-MSNs was analyzed to reveal the porous information. The adsorption−desorption isotherms and the pore size distribution curves are shown in Figure 6. From Figure 6a, pure MSNs and RhB@PLDA-MSNs indicate type IV with H3-type hysteresis loops in accord with the isotherms of nitrogen adsorption/desorption. After drug loading, the BET surface, pore size and pore volume decrease from 833.5 m2 g-1, 3.80 nm, 0.82 cm3 g-1 for MSNs to 160.4 m2 g-1, 2.21 nm, 0.26 cm3 g-1 for RhB@PLDA-MSNs, respectively48-50. The adsorption−desorption data illustrate drug is effectively blocked in the pores of PLDA-MSNs successfully. And LE (%) of RhB and DOX is about 84% and 89%, respectively.

a 600 3

Quantity adsorbed (cm /g STP)

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

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500

b

MSNs RhB@PLDA-MSNs

MSNs RhB@PLDA-MSNs

400 300 200 100 0 0.0

0.2 0.4 0.6 0.8 Relative pressure(P/P ) 0

1.0

0

2

4 6 Pore size (nm)

8

10

Figure 6. Nitrogen adsorption−desorption isotherms for MSNs and RhB@PLDA-MSNs (a) BET, (b) Pore size distribution. The surface functionalization extent of MSNs was estimated by TGA analysis. As shown in Figure 7, no obvious weight loss is observed during the heating process of pristine MSNs, indicating the excellent thermal stability of MSNs. In contrast, around 6.0 wt % weight loss of PLDA-MSNs is observed, demonstrating the successful self-polymerization of LDA on MSNs surface. In addition, the weight loss of RhB@PLDA-MSNs is about 4.0% when the temperature


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is heated from ca. 25 to 300 °C, which is attributed to the desorption of physically adsorbed water. Substantial weight loss is obtained after heating it from ca. 300 to 800 °C, which may be ascribed to the decomposition of RhB and PLDA coating on MSNs surface heating with the N2. The results of TGA suggest that PLDA-MSNs were fabricated and RhB was loaded in the PLDA-MSNs successfully51,52.

100 Mass fraction (%)

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95 90 85 80

MSNs PLDA-MSNs RhB@PLDA-MSNs

200

400 600 o Temperature ( C)

800

Figure 7. TGA curves of MSNs, PLDA-MSNs and RhB@PLDA-MSNs. In Vitro Release The PLDA coating is peptide mimetic polymer, which is self-polymerized by a pseudo dipeptide LDA synthesize by using lysine and dopamine. The peptide mimetic polymer could be degraded by pepsin. To verify whether PLDA can be degraded through triggering by pepsin, in vitro release experiments were measured at different concentration of pepsin at pH 1.7. The cumulative release curve of DOX under different condition is shown in Figure 8. At the pH value of 7.4 and 1.7 without pepsin, only about 10% drug is released within 114 h, which suggested that peptide bonds with high stability at these conditions. However, at pH 1.7 with 5 U of pepsin, approximate 30% of DOX is released within 114 h. when the concentration of pepsin increases


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to 40 U, the amount of released DOX is up to 56% at pH 1.7 within the same period. It reveals that the pepsin can accelerate the release of DOX with the concentration of pepsin increasing under low pH value.

80 Cumulative release (%)

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pH 1.7 + 40 U pH 1.7 + 5 U pH 1.7 pH 7.4

60 40 20 0

0

40

80 Time (h)

120

160

Figure 8. In vitro release curves of DOX from DOX@PLDA-MSNs at different pH value (7.4 and 1.7) and different concentration of pepsin at pH 1.7. Cytotoxicity assay In vitro cell cytotoxicity of MSNs and PLDA-MSNs to Marc-145 cells was investigated by MTT. It can be seen from Figure 9a that both of MSNs and PLDA-MSNs show no obvious cytotoxic effect against Marc-145 cells at 0.5 µg mL-1 after incubation for 24 h. Even the concentration of PLDA-MSNs is as high as 50 µg mL-1, the cell viability was about 96% after incubation for 24 h. These results demonstrated that both MSN and PLDA-MSNs are nontoxic. Therefore, PLDA-MSNs are highly biocompatible and suitable to use as the drug delivery carriers. The proliferation inhibition of DOX@PLDA-MSNs was evaluated against HeLa cancer cells, comparing with MSNs, PLDA-MSNs, and DOX. The cells without any treatment were used as


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the control. As displayed in Figure 9b, no obvious HeLa cells proliferation inhibition is induced by MSNs and PLDA-MSNs in test concentration range after incubation for 48 h, indicating the nontoxic against HeLa cells. The cell viability of HeLa cells incubating with DOX@PLDAMSNs decreased with an increasing concentration of DOX but much lower than that of free DOX. Compared with free DOX, the lower cytotoxicity of DOX@PLDA-MSNs may be mainly a result of the sustained drug release from the PLDA-MSNs.

a 150

b 100

MSNs PLDA-MSNs

120

Cell viability (%)

Cell viability (%)

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90 60 30 0

0

0.5 1 2.5 5 10 25 50 Concentration (µg/mL)

80 60 40 MSNs PLDA-MSNs DOX@PLDA-MSNs DOX

20 0

0.1

1 10 Concentration (µg/mL)

Figure 9. (a) cell viabilities of Marc-145 cells incubated with different concentrations of MSNs and PLDA-MSNs for 24 h, (b) cell viabilities of Hela cells incubated with different concentrations of MSNs, PLDA-MSNs, DOX and DOX@PLDA-MSNs for 24 h (Data are presented as the average ± standard deviation (n=3)). The cellular uptake of DOX@PLDA-MSNs by Hela cells was further investigated by CLSM. Firstly, Hela cells were cultured at 37 °C for 24 h, and pretreated with pepsin and PBS (pH 2.0). Then the cells were incubated with DOX@PLDA-MSNs at a DOX concentration of 20 µg mL-1 for 2 h. The nucleus was stained with DAPI and the resulted cells were observed with a fluorescence microscopy (Figure 10). As shown in Figure 10a, the red fluorescence of DOX@PLDA-MSNs is in both cytoplasm and nuclei according to the merged image. The results


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confirm that DOX@PLDA-MSNs could be internalized by the cells and DOX can be released efficiently. Meanwhile, the DOX also can enter into cell nucleus. Compared with DOX@PLDAMSNs, the CLSM image of free DOX shows that the fluorescence of DOX is mainly observed in the cells nucleus when the cells were incubated with free DOX for 12 h. The CLSM results shown that DOX@PLDA-MSNs could enter into the cells by endocytosis mechanism and the DOX could be released efficiently in endocytic compartments with pepsin and low pH value.

Figure 10. CLSM images of HeLa cells incubation with DOX@PLDA-MSNs (a) and free DOX (b) for 12 h (DOX concentration: 20 µg mL-1). Cell nuclei were stained with DAPI. CONCLUSION In summary, we have demonstrated LDA can self-polymerized to form a coating covered on MSNs to obtain an enzyme-responsive drug delivery system for cancer therapy. The RhB/DOX can be loaded effectively into the pore channel of MSNs. And the drug was released effectively from PLDA-MSNs through the degradation of PLDA films triggered by pepsin at low pH value. In vitro cellular cytotoxicity demonstrated that PLDA-MSNs are highly biocompatible and nontoxic as drug carriers. Furthermore, CLSM results shown that DOX@PLDA-MSNs could


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enter into cancer cells efficiently and released DOX can kill cancer cell, resulted the highly in vitro anticancer activity. In conclusion, we believe that this facile strategy may have a potential application for the treatment of varieties of stomach diseases. ASSOCIATED CONTENT Supporting Information The synthesis road of LDA, 1H NMR spectra of BL, BLN, BLDA and LDA, MS of LDA. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected], [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENT The authors are grateful for project support from The Dow Chemical Company, the National Science Fund of China (21274085) and the Shanghai Leading Academic Discipline Project (No. B202). REFERENCES (1) Slowing, I. I.; Trewyn, B. G.; Giri, S.; Lin, V. Y. Mesoporous Silica Nanoparticles for Drug Delivery and Biosensing Applications. Adv. Funct. Mater. 2007, 17, 1225−1236. (2) Trewyn, B. G.; Slowing, I. I.; Giri, S.; Chen, H.-T.; Lin, V. Y. Synthesis and Functionalization of a Mesoporous Silica Nanoparticle Based on the Sol-Gel Process and Applications in Controlled Release. Acc. Chem. Res. 2007, 40, 846−853.


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A Facile Strategy to Prepare Enzyme-Responsive Mussel Mimetic Coating for Drug Delivery Based on Mesoporous Silica Nanoparticles Chunlin Hu, Ping Huang, Zhen Zheng, Zhibiao Yang, Xinling Wang


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