Multifunctional Yolk-Shell Mesoporous Silica Obtained via Selectively

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Biological and Medical Applications of Materials and Interfaces

Multifunctional Yolk-Shell Mesoporous Silica Obtained via Selectively Etching the Shell: a Therapeutic Nanoplatform for Cancer Therapy Jing Xu, Xiaoxiao Wang, Zhaogang Teng, Guangming Lu, Nongyue He, and Zhi-Fei Wang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b08574 • Publication Date (Web): 02 Jul 2018 Downloaded from http://pubs.acs.org on July 2, 2018

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ACS Applied Materials & Interfaces

Multifunctional Yolk-Shell Mesoporous Silica Obtained via Selectively Etching the Shell: a Therapeutic Nanoplatform for Cancer Therapy Jing Xu a, Xiaoxiao Wang a, Zhaogang Tengc, Guangming Luc*, Nongyue Heb, and Zhifei Wang a *

a

Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, China

b

School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China c

Department of Medical Imaging, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu, P.R. China

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ABSTRACT: Herein, we fabricated a new yolk-shell structured mesoporous silica nanoparticle (YMSN) with multifunctionalities of fluorescence imaging, photothermal therapy (PTT) and drug delivery by using fluorescein Isothiocyanate (FITC)-doped silica nanoparticle partially covered by patchy gold as the core. Different from the conventional selective etching procedure, the multifunctional silica core is left intact, and the alkali etching mainly occurs in CTAB/silica hybrid layer, which leads to the formation of the void space in YMSNs. And the utilization of patchy gold as the PTT agent can avoid the shield against the outer irradiation on the core. Results show that as-prepared YMSNs have the good biocompatibility in the concentration of 0-1000 µg·mL-1 and the high DOX loading capability (8.04 wt.%). In vitro and in vivo antitumor experiments reveal that resulting YMSNs can be utilized for chemo- and photothermic combination therapy as well as the optical imaging.

KEYWORDS: yolk-shell, mesoporous silica, multifunctional, photothermal therapy, drug delivery, optical imaging

1. INTRODUCTION The achievement in the synthesis of nanomaterials provides the breakthrough in the fight against cancer considering their potential applications as drug delivery,1 imaging contrast agent,2 and therapy agent3,4 in cancer diagnosis and treatment. Among various nanomaterials, mesoporous silica based materials have been in particular studied as “nanocarrier” for the delivery of drugs and also used as the ideal platform for building up multifunctional nanocomposites since the pioneering work on utilizing MCM-41 as the drug carrier in 2001.5-7


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In comparison with other materials, silica-based materials possess the acceptable biosafety, the versatile structure character, and easily chemical surface

functionalization.

Recently,

as

a

kind

of

mesoporous

silica

nanomaterials, hollow or yolk-shell structured mesoporous silica nanoparticles (YMSNs) have also been paid much attention because of loading more drugs in comparison with conventional porous silica materials , resulting from the large void space inside the shell.8-10 Considering the increasing demand on the multifunctional medical nanoplatform for simultaneous imaging and therapy, how

to

construct

yolk-shell

mesoporous

silica

based multifunctional

nanoplatform will be thus interesting and of significance. At present, many strategies, including post-calcination,11 surface-protected etching12,13 and selectively etching,14,15 have been employed for fabricating yolk-shell mesoporous silica nanoparticles, and the resulting approaches can be categorized into template-assisted methods16,17 and template-free methods.18,19 In comparison to the template-free methods, template-assisted methods can endow new functionalities to mesoporous silica nanoparticles (NPs) by embedding various functional cores inside the hollow NPs, which specially caters to a desire for the fabrication of YMSNs based multifunctional nanoplatform.20-22 However, uncontrollable etching of core and tedious synthesis procedure associated with the generation of interior void always hinder their development of such strategy. To date, only a few functional cores, including gold NPs/quantum dots for bioimaging,23,24 and iron oxide NPs for



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targeting,25,26 have been reported to be encapsulated inside the mesoporous silica shell. To further enrich such multifunctional nanoplatform, the design of new multifunctional core and study of corresponding synthesis procedure will be necessary. Meanwhile, as one of medical imaging techniques, the fluorescence imaging has been extensively adopted in clinic because of its high sensitivity and the convenience in real time monitoring. The luminescent labels usually involve organic dyes, such as FITC,27 and quantum dot.28 However, the photobleaching and quenching associated with dye molecules and the toxicity brought by quantum dot always hinder their clinical application. A promising alternative candidate is to form dye-doped silica composite, which highly enhances the fluorescence intensity while possesses the good biocompatibility.29 For example, fluorescence silica NPs in form of Cornell dots have already been approved for stage I human clinical trial by FDA. Moreover, as one of complementary

therapy

approaches

to

the

traditional

chemotherapy,

photothermal therapy, which is referred to as a way to kill cancer with heat generated by absorbing radiation in the near-infrared region (NIR), has demonstrated great potential for tumor therapy in recent years.30-32 The obvious improvement in the cell-killing efficiency resulting from synergistic effect brought by chemo-photothermal therapy has been observed in many reports.33-35


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Inspired by the above background, herein we design and fabricate a new YMSN with multifunctionalities of fluorescence imaging, photothermal therapy (PTT) and drug delivery by encapsulating fluorescence silica NPs and patchy gold inside mesoporous silica (also called PAFS-YMSNs later). Different from the traditional gold nanoshell, patchy gold just partially covers the surface of core but still keeps the similar plasm resonances as gold nanoshell. So, the utilization of patchy gold as the PTT agent can avoid the shield against the outer irradiation on the core, which often occurs in the case of gold nanoshell.36 In addition, different from the reported selective etching procedure occurred in the removal of the interior silica core, we find that the combination of embedded FITC in silica cores and the attachment of polyethylenimine (PEI) to their surfaces could prevent the etching of interior silica, which deepens the understanding of the synthesis strategy of YMSNs. The in vitro and in vivo studies show that as-prepared PAFS-YMSNs can be utilized as the chemo- and photothermic combination therapy agent for tumour treatment as well as the optical imaging probe.

2. EXPERIMENTAL SECTION 2.1. Materials. Chloroauric acid (HAuCl4·3H2O), (Hexadecyl trimethyl ammonium bromide

(CTAB),

tetraethyl

orthosilicate

(TEOS,

99%),

and

3-aminopropyl)triethoxysilane (APTS) were purchased from Sigma-Aldrich. Ethanol (CH3CH2OH), ammonia solution (NH3·H2O), and ascorbic Acid (AA) were obtained



from Sinopharm Chemical Reagent Limited Corporation (China). Polyethylenimine (PEI, 30% water solution, average MW~800), α-mPEG-ω-COOH (MW =5 kDa), 1-ethyl-3-(3-dimethylamino-propyl) carbodimide (EDC), and N-hydroxysuccinimide (NHS) were from Aladdin. 2.2. Synthesis of FITC-doped SiO2 NPs. Fluorescein-Isothiocyanate isomer I (FITC, Alfa Aesar)-doped SiO2 NPs were prepared, and further dispersed in ethanol (1 mg·mL-1) according to the literature.37 2.3. Surface modification of FITC-doped SiO2 NPs with PEI. For the linkage of PEI to the surface of FITC doped SiO2 NPs, NPs’ surface was successively modified with APTS and glutaraldehyde in advance. First, 300 µL of APTS was added into 8 mL of ethanol solution containing FITC doped SiO2 NPs, and the resulting mixture was stirred for 24 h at room temperature. Then, APTS modified NPs were purified by centrifugation and further dispersed in 10 mL of carbonate buffer solution (pH = 8) with the concentration of 1 mg·mL-1. After that, 100 µL of glutaraldehyde was added, and resulting mixture solution was kept under stirring for 3 h at 37 oC. After the reaction, resulting NPs were washed with water and carbonate buffer solution for two times, separately, and then re-dispersed in 8 mL of carbonate buffer solution (pH = 8). Next, 300 µL of PEI (30% water solution) was added. And the resulting solution was kept under stirring for another 3 h at 37 oC. Finally, obtained PEI-grafted NPs were washed, and further dispersed in water with the concentration of 1 mg·mL-1.


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2.4. Preparation of Patchy Au on FITC-doped SiO2 NPs. Patchy Au on FITC doped SiO2 NPs were synthesized according to the literature.36 1 mL of HAuCl4 solution (1%) was first added into 8 mL of aqueous solution containing PEI/FITC doped SiO2 NPs. After 5 min incubation, NPs were washed with water to remove free HAuCl4, and then dispersed in 8 mL of water again. Next, 3 mL of ascorbic acid (AA) solution (0.1 mol/L) was added under stirring to reduce AuCl4- ions. After the reaction for 1 min, as-prepared patchy Au/FITC doped SiO2 NPs was washed, and dispersed in water with the concentration of 1 mg·mL-1. 2.5. Preparation of PAFS-YMSNs. To further deposit CTAB/silica hybrid layer on the surface of NPs prepared above, 25 mg of patchy Au/FITC doped SiO2 NPs were first dispersed in ethanol/water mixture solution (70 mL/30 mL) at 37 o

C, followed by adding 2 mL of ammonia (28% w/w) and 1.6 g of CTAB.

Before adding 0.2 mL of TEOS, the resulting solution was stirred for 40 min. After 24 h reaction, patchy Au/FITC doped silica@CTAB/silica NPs were obtained. To selectively etch CTAB/silica layer, resulting NPs were further added into 50 mL of Na2CO3 solution (0.3 mol/L) at 65 oC. After 15 min incubation, as-prepared PAFS-YMSNs were centrifuged, further washed with water and ethanol for two times, and finally dispersed in water. 2.6. Surface modification of PAFS-YMSNs with mPEG-COOH. The PEGylation of PAFS-YMSNs was carried out in two steps: (1) the surface of PAFS-YMSNs was first modified with APTS by adding 400 µL of APTS into 8



mL of ethanol solution containing PAFS-YMSNs, and resulting mixture solution was stirred for 24 h at room temperature. APTS-functionalized PAFS-YMSNs was obtained by the centrifugation, then washed with ethanol, and finally dispersed in 5 mL of PBS solution. (2) mPEG-COOH was covalently linked to APTS-functionalized PAFS-YMSNs in the presence of EDC/NHS. To 1 mL of mPEG-COOH aqueous solution (50 mg/mL), 1 mg of EDC and 1 mg of NHS were separately added. After activating reaction for 30 min, the aqueous solution containing APTS-functionalized PAFS-YMSNs was further added. The resulting solution was incubated for 24 h. Finally, PEG functionalized PAFS-YMSNs were separated by the centrifugation, and washed with water for 2 times, and then dispersed in 10 mL of water. 2.7. Determination of photothermal effect. 2 mL of PAFS-YMSNs aqueous solution with different concentrations (0.05, 0.1, 0.2 mg/mL) was irradiated by a 808 nm laser (MW-GX-808/0-5 W·cm-2) for 8 min. The temperature of the solution was measured by infrared imager (FLUKE) and recorded every 30 seconds. 2.8. Loading and in vitro release of DOX. The loading and in vitro release of DOX were conducted according to the literature38 with the slight modification. To load DOX, 30 mg of PEG functionalized PAFS-YMSNs was first added into 12 mL of PBS solution containing 3 mg of DOX. After incubation for 24 h in darkness, excess DOX was removed through centrifugation. The change in the concentration of DOX was monitored by UV-visible spectrophotometric.


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The release of DOX from the DOX-loaded PAFS-YMSNs under the stimuli of pH alternation or the 808 nm laser irradiation was similarly measured. 2.9. Cytotoxicity Assay. In vitro cytotoxicity of PAFS-YMSNs (0-1000 µg/mL), DOX-loaded PAFS-YMSNs (0-20 µg/mL), or free DOX (with the equal amount of DOX in DOX-loaded PAFS-YMSNs) to MCF-7 cells (the Chinese Academy of Sciences Cells Bank) were analysed by a MTT colorimetric assay.36 And the detail procedure can be found in Supporting Information. 2.10. Fluorescence imaging. In vitro and in vivo fluorescence imaging of PAFS-YMSNs were respectively studied by using MCF-7 cells and mice as the model according to the literature,37 and the detail procedure can be found in Supporting Information. 2.11. In Vitro/in Vivo Photothermal Therapy of PAFS-YMSNs. The experimental procedure for evaluating in vitro/in vivo photothermal therapy of PAFS-YMSNs (50 µg/mL) or DOX-loaded PAFS-YMSNs (1 µg/mL) is similar to the literature,36 and can be found in Supporting Information. 2.12. Characterization. The transmission electron microscopy (TEM, JEM 2100) was used to observe the morphology of NPs. The UV-Vis-NIR absorbance spectra were obtained with Helios Gamma spectrophotometer. Maestro all-optical imaging system (Caliper Life Science, Hopkinton, MA) was employed to obtain in vivo fluorescence imaging. The absorption and fluorescence emission were obtained on a Fluoromax-4 (Horiba, Japan). Temperature monitoring and thermal images were recorded by an IR thermal



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imaging (FLUKE). The images of MCF-7 cells were taken by confocal laser scanning microscopy (CLSM) (TCS SP8, Leica, Germany). Nitrogen adsorption/desorption isotherms were acquired at -196

o

C on a nitrogen

adsorption apparatus (Micromeritics ASAP 2010 volumetric adsorption apparatus) after degassing of the sample at 300 oC for 3 h.

3. Results and discussion 3.1. Preparation and characterization of PAFS-YMSNs. The synthesis procedure of PAFS-YMSNs is illustrated in Scheme 1. As the fluorescence interior silica, FITC doped SiO2 NPs are prepared by modified Stöber process according to the literature,37 and FITC is covalently incorporated inside silica matrix via the reaction of FITC and APTS. To facilitate the subsequent growth of patchy gold on their surfaces, the resulting FITC doped SiO2 NPs are further modified with polycationic PEI. With the help of the electrostatic interaction between amine groups in PEI and AuCl4- ions, AuCl4- ions are then adsorbed onto the surface of FITC doped SiO2 NP. Under the controlled reaction condition, adsorbed AuCl4- ions are next reduced into Au0 and form the cup-like patches on the surface of FITC doped SiO2 NP in the growth mode of Frank-van der Merwe.36 The mechanism involved in this procedure has been reported in our previous work.36 After the formation of functionalized interior silica, the outer mesostructured silica layer further grows on their surface via the co-assembly of CTAB and oligomers from hydrolyzed TEOS in the Stöber solution. Finally, PAFS-YMSNs are obtained by treating resulting NPs in 0.5 M Na2CO3 solution at 65 oC for 15 min. In this procedure, the selective etching of outer


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mesostructured silica layer occurs, and a void space appears between the outer mesostructured silica and functionalized interior silica, which provides a space for subsequent drug loading.

Scheme 1. Schematic illustration for the synthesis of PAFS-YMSNs.

Figure 1 gives TEM images of various NPs involved in above procedure. It can be found that FITC doped SiO2 NPs are the uniform spheres with the diameter of about 150 nm (Figure 1a). After the adsorption/reduction of AuCl4ions, there are several gold patches with the size of 30-50 nm on most of FITC doped SiO2 NPs’ surfaces (Figure 1b). High-resolution TEM image in Figure S1 (SI) further indicates that the spacing of lattice fringe in the patches is about 0.24 nm, which corresponds to (111) planes of fcc Au.39 Obvious core-shell structure with dark functionalized interior silica encapsulated in gray outer layer is observed in Figure 1c after the deposition of CTAB and silica hybrid composites. The thickness of outer mesostructured silica layer is about 30 nm. When further treated in 0.5 M Na2CO3 solution at 65 oC for 15 min, we can find that the outer silica layer turns thin (Figure 1d-1f) and the whole particle has the character of YMSNs. Meanwhile, it can also be found that during the Na2CO3



etching the functionalized interior silica is nearly left intact and the selective etching just occurs in the outer silica layer, which causes their thickness to decrease from previous 30 nm to about 5 nm. This phenomenon is different from reported etching procedure40 but provides the way for the fabrication of new YMSNs based therapeutic nanoplatform in our work. After the etching, the Au content of the as-prepared PAFS-YMSNs is about 40 % on the basis of the ICP analysis.

Figure 1. TEM images of (a) FITC doped SiO2 NPs, (b) patchy gold on FITC doped SiO2 NPs, (c) NPs with the deposition of CTAB and silica hybrid composites, and PAFS-YMSNs obtained after etching with Na2CO3 at 65 oC for (d) 5, (e) 10 or (f) 15 min.

It should be noted that the resistance of CTAB/silica hybrid composites to alkali etching is reported to be higher than that of the unique solid silica (sSiO2).41,42 So the core-shell structured sSiO2@CTAB/silica has always been adopted in formation of YMSNs via selective etching. However, herein, we find that when compared with another kind of solid silica (patchy gold on FITC


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doped SiO2 NPs), the CTAB/silica hybrid layer is relatively easily etched. To verify this speculation, we further test the fluorescence of the supernatant and corresponding PAFS-YMSNs after etching with Na2CO3 at 65 oC for various time. As shown in Figure 2a, before etching, as-prepared patchy Au-FITC doped SiO2@CTAB/SiO2 NPs emit the strong fluorescence centered at 520 nm upon the excitation of 490 nm resulting from the incorporation of FITC, which is similar to that of FITC doped SiO2 NPs.37 After etching with Na2CO3, the fluorescence intensity of resulting PAFS-YMSNs just slightly decreases with the increase in etching time from 5 to 15 min. Meanwhile, the fluorescence of the corresponding supernatant only increases from 1.01×105 to 2.1×105, but still keeps weak, demonstrating that only a very small quantity of FITC exists in the supernatant and the patchy Au-FITC doped SiO2 is scarcely etched by Na2CO3. To probe the possible cause for this selective etching, three control experiments were also conducted under the guidance of the compositional difference-based selective etching strategy.14 In the first experiment, pure sSiO2@CTAB/silica NPs obtained with the similar synthetic condition to that of PAFS-YMSNs was used instead. As illustrated in Figure S2 (SI), after 5 min etching, the hollow sphere with the mesoporous shell is observed, demonstrating that pure sSiO2 is more easily etched away than CTAB/silica layer as reported.15 According to the silica-etching chemistry,43 OH- ions can coordinate with Si atoms from amorphous silica framework under alkali condition, thus leading to the breakage of Si-O-Si bonds and further release of



negatively charged soluble silicate species from silica. If there are CTA+ surfactants in the silica framework, the dissolved silicate species will deposit again and be re-condensed to form silica due to the electrostatic interaction between them. On the contrary, in the absence of CTA+ surfactants like pure sSiO2 core, under the attack of OH- ions, the dissolution of silicate species will keep going until the whole sSiO2 core is consumed. That is why the alkali resistance of CTAB/silica shell is higher than that of sSiO2 core. In the second control experiment, FITC doped SiO2@CTAB/silica NPs, in which the surface of interior FITC doped SiO2 wasn’t modified with PEI, was also etched in 0.5 M Na2CO3 solution at 65 oC. From Figure S3 (SI), it is found that the whole NP is simultaneously etched and there is no obvious interface between outer CTAB/silica layer and the core FITC doped SiO2, indicating that both of them are equal in ability to resist to the alkali etching. As mentioned above, FITC was doped into sSiO2 core via the covalent conjugation with APTS and subsequent co-condensation with TEOS, which is similar to the combined use of octadecyltrimethoxysilane (C18TMS, one of organosilanes) and TEOS in the structural difference-based selective etching strategy reported by Shi and co-worker.14 So it can be deduced by analogy that the incorporation of FITC might improve the condensation degree of Si-O-Si network, making FITC doped SiO2 more resist to alkali etching. In the third control experiment, pure sSiO2@CTAB/silica NPs, in which the surface of sSiO2 core was modified with PEI in advance, were also etched as above. From Figure S4 (SI), it can be found


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that after the linkage of PEI the resistance of sSiO2 core to alkali etching is greatly improved and both outer CTAB/silica layer and sSiO2 core are simultaneously etched. As we know, PEI, which contains a lot of amino groups, can strongly adsorb on the surface of sSiO2 through the electrostatic interaction and even some hydrogen bonding between amino group and the hydroxyl groups from sSiO2 surface. And such a strong interaction can improve the resistance of the sSiO2 surface to alkali etching, as reported by Su and co-worker.44 On the basis of above results, herein, we presented the mechanism of “multi protection-based selective etching” to explain the formation of multifunctional yolk-shell mesoporous silica. In comparison with CTAB/silica shell, the stability of multifunctional sSiO2 core under alkali condition can be attributed to the combination of the incorporation of organosilanes and the protection of surface. So the alkali etching just selectively occurs inside the shell under this condition. To further examine the porous nature of as-prepared PAFS-YMSNs, Figure 2b gives their nitrogen adsorption-desorption isotherm. The isotherm shows a type IV curve and a large hysteresis loop in the P/P0 range of 0.5-1.0, which results from the capillary condensation of the void space between mesoporous silica layer and patchy Au-FITC doped SiO2 core. The surface area of the PAFS-YMSNs is calculated to be as high as 875 m2 g−1. The pore sizes of PAFS-YMSNs calculated according to the nonlocal density functional theory are about 2.2 nm and 4 nm (Figure 2c). All above results indicate that obtained



PAFS-YMSNs possess the character of conventional hollow mesoporous silica spheres. In addition, we further characterized PAFS-YMSNs with UV-Vis-NIR absorption spectrum. As shown in Figure 2d, there are two broad absorption peaks centered at 490 nm and 720 nm, which correspond to the absorption of FITC and that of patchy gold, respectively. Therefore, it is concluded that obtained PAFS-YMSNs can be used as the multifunctional therapeutic nanoplatform.

Figure 2. (a) Fluorescence emission spectra (Ex. 490 nm) (a-g: PAFS-YMSNs etched by Na2CO3 for 0, 5, 10 or 15 min at 65 oC, the corresponding supernatant for 15, 10,or 5 min); (b) nitrogen adsorption-desorption isotherm of PAFS-YMSNs; (c) the corresponding pore size distribution curve; (d) UV-Vis-NIR absorption spectrum of PAFS-YMSNs.

3.2. Surface modification with mPEG-COOH. In order to improve the dispersion of PAFS-YMSNs in aqueous solution, we further modified their surface with APTS and mPEG-COOH in the presence of EDC/NHS successively. As shown in Figure S5, the zeta potential of PAFS-YMSNs changes from -41.13 mV to 22.18 mV after the covalent linkage of APTS, demonstrating that the negatively charged surface of PAFS-YMSNs, resulting from the dissociation of silanol groups, has been changed to


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positively charged surface due to the exist of amine group from APTS. After the attachment of mPEG-COOH via an amide bond, the zeta potential of resulting PAFS-YMSNs decreases to -18 mV. The changes in the zeta potential clearly demonstrate that the surface of PAFS-YMSNs is grafted with mPEG-COOH successfully. And the hydrodynamic diameter of the PEG-grafted PAFS-YMSNs determined by Dynamic Light Scattering is about 324 nm (Figure S6 in SI). 3.3. Photothermal Conversion Ability. The photothermal conversion ability of PAFS-YMSNs was measured upon the 808 nm laser irradiation (0.8-5 W·cm-2), and recorded via an IR thermal camera. As shown in Figure 3a and 3b, the temperature of aqueous solution containing PAFS-YMSNs increase rapidly as the irradiation time increases, and reaches the maximum in 8 min. On the other hand, for the solution containing FITC doped SiO2@mSiO2, its temperature just increases from the initial 19.2 oC to 21.8 oC under the similar irradiation, clearly demonstrating that the photothermal conversion ability of PAFS-YMSNs comes from patchy gold. The photothermal heating rate is greatly affected by the content of PAFS-YMSNs in the solution, and the maximum temperature changes from 35.2 oC for 0.05 mg/mL to 50.2 o

C for 0.2 mg/mL after 8 min irradiation with 0.8 W·cm-2. From Figure 3b, it can also

be found that the maximum temperature increases from 50.2 oC to 78 oC as the power densities change from 0.8 W·cm-2 to 5 W·cm-2. From Figure 3c and 3d, the photothermal conversion efficiency (η) of PAFS-YMSNs can be determined to be 21.27% (the detail calculation can be seen in SI, Figure S7), which is nearly equivalent to 21.77% of conventional hollow Au nanoshell.45 However, different from



the gold shell, the gold patches here don’t affect the utilization of FITC doped SiO2 core as the optical imaging agent.

Figure 3. (a) Temperature changes of the aqueous dispersion of PAFS-YMSNs with different concentrations under 808 nm irradiation with a power density of 0.8 W·cm-2; (b) the irradiation with various power densities (0.2 mg·mL-1); (c) Photothermal effect of the aqueous solution of PAFS-YMSNs, in which the laser was turned off after 9 min irradiation; (d) The cooling period versus negative natural logarithm of driving force temperature (τs=291.12 s).

3.4. In Vitro DOX Loading and Release. To evaluate the potential of PAFS-YMSNs in drug delivery system (DSS), we loaded the anticancer drug doxorunicin (DOX) in PAFS-YMSNs by physically mixing DOX and NPs together, in which DOX molecules can store in the void space and mesoporous silica shell. The loading efficiency of DOX is about 88.5% (namely, 8.04 wt.%) according to the absorbance change of DOX at 482 nm before and after the loading (Figure S8, SI). The cumulative DOX release from PAFS-YMSNs at different pH values as a function of time is also illustrated in Figure 4a. For the DOX release at pH 7.4, it is found that


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the release rate of DOX is relatively fast in the initial 10 h but becomes very slow in the subsequent 50 h, which is due to the primary release of weakly adsorbed DOX on PAFS-YMSNs’ surface. However, when the pH value reaches 5, the DOX release is obviously accelerated, and almost 80% of trapped DOX is released in 60 h. As is known, DOX molecules are generally positively charged, whereas the inner surface of silica matrix is negatively charged, thus resulting in the strong electrostatic interaction between them. With the increase in proton concentration, this electrostatic interaction will be weakened, and therefore more DOX is released. Additionally, under the irradiation of laser, patchy gold will convert the absorbed energy to heat, which is thus expected to stimulate the DOX release. Figure 4b further gives the 808 nm laser-responsive cumulative DOX release from PAFS-YMSNs at different pH values. It can be found that the release of DOX is obviously accelerated by the 808 nm laser irradiation when compared with the negative control group. For example, at pH 7.4, 25.3% of DOX has been released in 15 min. So, it can be concluded that the laser irradiation can also be used to stimulate the DOX release from PAFS-YMSNs, which will favour the chemo-/photothermal combination therapy in cancer treatment. It should be pointed out that during investigating the potential of PAFS-YMSNs in drug delivery system we also studied the stability of FITC-doped SiO2 NPs under various conditions with the pH value ranging from 7.4 to 5 (the temperature of 37 oC) or the temperature ranging from 30 oC to 55 oC (pH 7.4) for 24 h. After the incubation, FITC-doped SiO2 NPs were separated by the centrifugation, and re-dispersed in fresh water. As shown in Figure S9 (SI), there is no obvious change in



both the fluorescence intensity and UV absorption of FITC-doped SiO2 NPs before and after the incubation. In addition, no fluorescence from FITC is detected in the supernatant. So, it can be concluded that as-prepared FITC-doped SiO2 NPs have the good stability and themselves will not release the doped FITC under the external stimulus.

Figure 4. DOX-release profiles of DOX loaded PAFS-YMSNs measured (a) at various pH value and (b) when exposed to 808 nm laser irradiation.

Figure 5. MCF-7 cells viability obtained with MTT assay after 24 h incubation with (a) PAFS-YMSNs, (b) free DOX or DOX loaded PAFS-YMSNs.

3.5. Toxicity Evaluation. Before investigating in vitro or in vivo application of PAFS-YMSNs, we first examined their cytotoxicity with MTT assay on MCF-7 cells. Free DOX and DOX loaded PAFS-YMSNs were also studied as the control. As shown in Figure 5a, PAFS-YMSNs have no obvious toxicity on MCF-7 cell, and the cell survival rates still remain above 95% in the concentration range of 0-1000 µg·mL-1, demonstrating the good biocompatibility of as-prepared PAFS-YMSNs. By


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control, from Figure 5b, we can see that the viability of MCF-7 cell greatly rely on the dosage of DOX loaded PAFS-YMSNs. When it just reaches 20 µg·mL-1, the corresponding cell viability decreases to 20%. As we know, DOX is a highly potent chemotherapeutic agent. So the high toxicity of DOX loaded PAFS-YMSNs is the result of the DOX release, indicating that DOX loaded PAFS-YMSNs can be used for chemotherapy. Meanwhile, we can see that the viability of cells incubated with DOX loaded PAFS-YMSNs is still higher than that of cells incubated with the equal amount of free DOX. It is likely that the embedded DOX is not fully released from PAFS-YMSNs.

Figure 6. (a) CLSM images of MCF-7 cells cultured without PAFS-YMSNs (Control Group) or with PAFS-YMSNs (Experimental Group) for 24 h; (b) Fluorescence images of tumor and the corresponding fluorescence intensity change as the function of time.



3.6. In vivo and ex vivo fluorescence imaging of PAFS-YMSNs. As mentioned above, as-prepared PAFS-YMSNs emit the strong fluorescence centered at 520 nm upon the excitation of 490 nm, which can be used for the fluorescence imaging. The fluorescence spectrum in Figure S10 (SI)) indicates that the corresponding fluorescence intensity reach 5.8×106 when their concentration is 0.12 mg/mL. Herein, we first studied their application in cellular imaging using MCF-7 cells. In the experiment, MCF-7 cells were cultured with PAFS-YMSNs for 24 h, followed by the nuclei staining with Hoechst 33342. The CLSM images were obtained under the excitation at 488 and 340 nm, respectively. As shown in Figure 6a, after being cultured with PAFS-YMSNs for 24 h, the cells maintain the normal morphology, and the green fluorescence of FITC can be observed inside the cells. The merged images further illustrate that PAFS-YMSNs are internalized into the cytoplasm of MCF-7 cells via the endocytosis, indicating that PAFS-YMSNs can be employed for cellular imaging. To further investigate the potential of PAFS-YMSNs in in vivo fluorescence imaging, we examine the change in real time in the fluorescence intensity of FITC around the tumor in the mouse via the optical imaging system. PAFS-YMSNs were injected into the mouse through the tail vain, and the fluorescence images were acquired 1 h later. Figure 6b gives the fluorescence images of tumor and the corresponding fluorescence intensity change as the function of time. It can be found that the fluorescence from PAFS-YMSNs around tumor is obviously observed at 2 h after the administration and turns stronger and stronger with the increase in the time. As is well known, nanosized material tends to accumulate in tumor tissue through the


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permeable tumor vasculature by prolonging the circulation time (namely, enhanced permeability and retention effect (EPR)). Therefore, the enhanced fluorescence intensity in tumor can be attributed to EPR-based accumulation of PAFS-YMSNs in tumour tissue. By measuring the content of Au in the tumor site after sacrificing the mouse, we further deduced that about 0.5% of PAFS-YMSNs were trapped in tumor site, which is slightly lower than mesoporous silica-based delivery system with the size of 100 nm (1%) reported in the literature.46 On the basis of the above results, it can be induced that PAFS-YMSNs can work for the optical imaging.



Figure 7. (a) Fluorescence images of MCF-7 cells in the control (Group I), with PAFS-YMSNs (Group II), or with DOX loaded PAFS-YMSNs (Group III) for 24 h, then irradiated by an 808 nm laser for 0, 2, 6 min, and finally stained by calcein-AM/PI; (b) Corresponding MCF-7 cell viability obtained by MTT assay.

3.7. In Vitro Chemo-Photothermal Effect of PAFS-YMSNs. The chemo- and photothermic synergistic therapy efficiency of DOX loaded PAFS-YMSNs on MCF-7 cells was first visually evaluated by using the calcein-AM/PI double staining. As shown in Figure 7a, for MCF-7 cells without any treatment, the 808 nm laser irradiation alone doesn’t harm MCF-7 cells even after 6 min irradiation and all cells keep alive (the green fluorescence), indicating that the irradiation with the power density of 0.8 W/cm-2 is safe to cells. However, for MCF-7 cells treated with PAFS-YMSNs or DOX loaded PAFS-YMSNs, most of them are dead (the red fluorescence) resulting from the good photothermic effect of NPs. Figure 7b further quantitatively gives the results obtained by MTT assay, and the irradiation time-dependent cell viability is obviously observed for the cells treated with PAFS-YMSNs or DOX loaded PAFS-YMSNs. It can be found that after 6 min irradiation only 38.4% of MCF-7 cells are still alive for PAFS-YMSNs and 27.6% of the cells are alive for DOX loaded PAFS-YMSNs. Such cell viability difference between PAFS-YMSNs and DOX loaded PAFS-YMSNs can be attributed to the chemotherapy effect brought by entrapped DOX. In the second group, we also investigated the effect of equal amount of free DOX on the viability of MCF-7 cells, and found that the corresponding cell viability just decreases to 51%. Therefore, it is expected that as-prepared DOX loaded PAFS-YMSNs can be utilized for chemo-and photothermic combination therapy in cancer treatment.


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3.8. In vivo photothermal effect of PAFS-YMSNs. Three groups of MDA-MB-231 breast cancer-bearing mice were utilized as the animal model to study the in vivo photothermal effect of PAFS-YMSNs. In the control group I, the mice were intratumorally injected with the saline. In another group II and III, the mice were injected with free DOX and DOX loaded PAFS-YMSNs, respectively. At 1 h after the administration, the 808 nm laser was used to irradiate tumors for 6 min, and the intratumoral temperature was monitored by an infrared camera. As shown in Figure 8a, the intratumoral temperature of the mice treated with DOX loaded PAFS-YMSNs increases from 17.5 oC to 50.4 oC, which is high enough to induce the tissue damage. On the contrary, no obvious temperature change is observed in group I and II. This is consistent with the above results that the increase in temperature mainly stems from the photothermic effect of PAFS-YMSNs. The anticancer effects of the saline, free DOX or DOX loaded PAFS-YMSNs were continuously investigated by irradiating tumors once a day for 4 min until the 7th day. Figure 8b gives the photos of mice taken after treatment for various time. It can be found that the tumor injected with the saline grows rapidly, indicating that the laser irradiation itself can’t inhibit the growth of tumor. In contrast, for the tumor treated with DOX loaded PAFS-YMSNs, the necrosis begins to appear after 1 day owing to thermal damage. On the 7th day, the tumor obviously shrinks, and the black scar is left on the tumor sites after two weeks. As for the mice injected with equal amount of free DOX, the tumor still grows but the growth rate of tumor is slower than that of mice injected with the saline. As we know, to achieve the good anticancer effect, the dosage of DOX is usually as high as 500



mg/m2 in clinic. In our experiment, the dosage of DOX is too low to suppress the tumor growth. That is why the tumor still grows for mice injected with equal amount of free DOX. These results further prove that DOX loaded YMSNs can serve as effective photothermal agent for cancer treatment.

Figure 8. (a) Photothermal images of mice injected with saline (Group I), free DOX (Group II), or DOX loaded PAFS-YMSNs (Group III) under 808 nm laser irradiation for 6 min, respectively; (b) Photos of mice taken after treatment for various time: saline (group A), free DOX (group B), and DOX loaded PAFS-YMSNs (group C) during 4 min irradiation of 0.8 W·cm-2 NIR every day.


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4. Conclusions In summary, this work presents the fabrication of the yolk-shell mesoporous silica based therapeutic nanoplatform by the combination of the selectively etching and the construction of multifunctional silica core. Different from the reported selective etching procedure, the multifunctional silica core was left intact, and the etching mainly occurred in CTAB/silica hybrid layer. We find that the incorporation of FITC and surface modification of PEI makes silica more resist to the alkali etching, which sheds light on the synthesis of functionalized YMSN in future. The results show that the surface area of as-prepared PAFS-YMSNs reaches 875 m2g-1 and the pore size in shell is about 2.2 and 4 nm, which endows PAFS-YMSNs with the high DOX loading (8.04 wt.%). In vitro and in vivo studies further reveal that obtained PAFS-YMSNs have the good biocompatibility in the range of 0-1000 µg·mL-1 and can be utilized as chemo- and photothermic combination therapy agent as well as the optical imaging probe. In addition, as the comparison and contrast, the DOX loading efficiency and photothermal conversion efficiency of other YMSNs with the similar structure as PAFS-YMSNs are comparatively listed in Table 1 (SI). It can be found that our system has the good balance between the DOX loading efficiency and photothermal conversion efficiency while processing the functionality of fluorescence imaging, which provides an alternative for the construction of the therapeutic nanoplatform for cancer therapy.



ASSOCIATED CONTENT Supporting Information This material is available free of charge via the Internet at http://pubs.acs.org. The detail experimental procedure, HR-TEM of patchy Au on FITC doped SiO2, TEM of sSiO2@CTAB/SiO2 NPs and FITC doped SiO2@CTAB/SiO2 NPs after etching.

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected]. *E-mail: [email protected].

Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS This study was financially supported by the State key Basic Research Program of the PRC (2014CB744501), the NSF of China (81771976), Fundamental Research Funds for the Central Universities, and the joint fund of Southeast University and Nanjing Medical University.

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Table of Contents Graphic:


Multifunctional Yolk-Shell Mesoporous Silica Obtained via Selectively

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