Nano Res

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Hollow mesoporous Ia3d silica nanospheres with single-unit-cell-thick shell: Spontaneous formation and drugdelivery application

Nien C. Lai1, Chih Y. Lin1, Pei H. Ku1, Li L. Chang1, Kai W. Liao1, Wun T. Lin1, and Chia M. Yang1,2 (), Nano Res., Just Accepted Manuscript • DOI: 10.1007/s12274-014-0503-2

http://www.thenanoresearch.com on May 27 2014

© Tsinghua University Press 2014

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Nano Research

DOI 10.1007/s12274-014-0503-2

1

TABLE OF CONTENTS (TOC)

Hollow Mesoporous Ia3d Silica Nanospheres with

Single-Unit-Cell-Thick Shell: Spontaneous Formation

and Drug Delivery Application

Nien-Chu Lai,¶ Chih-Yu Lin,¶ Pei-Hsin Ku,¶ Li-Lin

Chang,¶ Kai-Wei Liao,¶ Wun-Ting Lin¶ and Chia-Min

Yang¶§*

¶ Department of Chemistry, Tsinghua

University, Taiwan, China

§ Frontier Research Center on Fundamental and Applied

Sciences of Matters, Tsinghua University,

Taiwan, China

Page Numbers. The font is

ArialMT 16 (automatically

inserted by the publisher)

A direct synthesis of uniform hollow nanospheres composed of

thin mesoporous silica shell with cubic Ia3d structure has been

discovered. The material exhibits high loading capacity and fast

biodegradation through fragmentation and is promising for drug

delivery and other biomedical applications.

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Hollow Mesoporous Ia3d Silica Nanospheres with Single-Unit-Cell-Thick Shell: Spontaneous Formation and Drug Delivery Application

Nien C. Lai1, Chih Y. Lin1, Pei H. Ku1, Li L. Chang1, Kai W. Liao1, Wun T. Lin1, and Chia M. Yang1,2() 1 Department of Chemistry, Tsinghua University, Hsinchu 30013, Taiwan, China 2 Frontier Research Center on Fundamental and Applied Sciences of Matters, Tsinghua University, Hsinchu 30013, Taiwan, China

Received: day month year / Revised: day month year / Accepted: day month year (automatically inserted by the publisher) © Tsinghua University Press and Springer-Verlag Berlin Heidelberg 2011

 

ABSTRACT   Mesoporous silica nanoparticles (MSNs) are promising for drug delivery and other biomedical applications

owing to excellent chemical stability and biocompatibility. For these applications, a hollow morphology with

thin shell and open mesopores is preferred for MSNs to maximize loading capacity of drugs. Herein we report

a novel and direct synthesis of such an ideal drug delivery system in the dilute and alkaline solution of

benzylcetyldimethylammonium chloride and diethylene glycol hexadecyl ether. The mixed surfactants can

guide the formation of MSNs with cubic Ia3d mesostructure, and at a concentration of sodium hydroxide

between 9.8 and 13.5 mM, hollow MSNs with uniform sizes of 90-120 nm and single-unit-cell-thick shell are

formed. A formation mechanism of the hollow Ia3d MSNs, designated as MMT-2, is proposed based on in-situ

small-angle X-ray scattering measurements and other analyses. MMT-2 exhibits much higher loading capacity

of ibuprofen and degrades faster in simulated body fluid and phosphate buffer saline than non-hollow MSNs

do. The degradation of MMT-2 can be significantly retarded by modification with polyethylene glycol. More

interestingly, the degradation of MMT-2 involves fragmentation instead of void formation, a phenomenon

beneficial for their elimination. The results demonstrate the uniqueness of the hollow Ia3d MSNs and the great

potential of the material for drug delivery and biomedical applications.

KEYWORDS hollow mesoporous silica nanospheres, cubic Ia3d mesostructure, drug delivery, silica degradation

Instructions for using the template

1. Introduction

Mesoporous silica nanoparticles (MSNs) have

recently attracted great interest as drug delivery

systems (DDSs) due to their biocompatibility,

Nano Res DOI (automatically inserted by the publisher) Research Article

———————————— Address correspondence to First A. Firstauthor, email1; Third C. Thirdauthor, email2

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chemical stability and dispersibility [1-9]. They can

be prepared with controlled size, morphology,

structural and textural properties (e.g. pore size,

surface area and porosity) for therapeutic uses [1-9],

and versatile chemistry for encapsulation and

surface modification further renders MSNs

additional functions of gate-keeping [10,11],

targeting [12-14], and bio-imaging [15-17]. As DDSs,

MSNs must be able to carry and transport large

amount of drug molecules and, to avoid the

problems of accumulation in organisms after

releasing the cargo, they should be cleared from the

body by biodegradation [18-21], renal excretion or

other pathways [2,5,22,23]. The loading capacity of

MSNs is mainly determined by their pore volume,

and ideally a silica-based DDS should have suitable

particle size, hollow morphology and thin silica

shell with open and uniform mesopores to

maximize the specific loading capacity (the loading

capacity per gram of silica) and allow further

functionalization.

Hollow MSNs (HMSNs) are typically

fabricated by dual-templating methods, with

mesopore-generating surfactant attached onto soft

(e.g. emulsified liquid droplets [24-27] or polymeric

micelles [28-30]) or hard (e.g. polymer beads [31])

templates for the formation of hollow core. The

soft-soft templating methods often suffer from

broad particle size distribution, difficulty to control

the shell thickness and the co-existence of mixed

mesostructures and forms, whereas the soft-hard

templating routes involve complex surface

modification for the deposition of mesoporous

silica layer and the removal of hard template and

therefore are usually uneconomic and complicated

[32-34]. Alternatively, selective etching [35] and

“dissolution-regrowth” processes [36] have also

been developed to form HMSNs, but the

generation of mesoporous silica shell with

controlled and uniform thickness and regular

mesopores is challenging for these processes.

Besides, it is extremely difficult for the

abovementioned methods to prepare HMSNs with

uniform and fully open mesopores. Obviously,

there is still strong need to prepare silica-based

DDSs with desired morphological and textural

properties.

Herein we report a novel and direct synthesis

of hollow silica nanospheres with nearly ideal

morphology and textural properties for DDS. The

discovery was originated from the synthesis

systems of a variety of MSNs with mesostructures

in between 2D-hexagonal and lamellar phases

[37-41] in the dilute solutions of mixed

cetyltrimethylammonium bromide (CTAB) and

tetraethylene glycol dodecyl ether (C12E4). By using

structure-directing cationic/nonionic surfactants

with larger packing parameter, for the first time we

observed spontaneous formation of rather uniform

(90-120 nm) hollow nanospheres composed of

mesoporous silica shell with cubic Ia3d structure

and unit cell thickness. The hollow nanospheres

with 3D-interconnected mesopores displayed more

than twice the loading capacities of MCM-41- and

MCM-48-type MSNs while exhibiting nearly

identical rate of drug release. More interestingly,

they not only dissolved faster than the solid

(non-hollow) MSNs in simulated body fluid (SBF)

and phosphate buffer saline (PBS) but also

fragmented into even smaller pieces, a

phenomenon beneficial for the elimination of the

DDS. The results demonstrate the uniqueness and

great potential of the hollow mesoporous

nanospheres for drug delivery and other

biomedical applications.

2. Results and Discussion

The synthesis was conducted in the dilute solution

of benzylcetyldimethylammonium chloride

(BCDAC) and diethylene glycol hexadecyl ether

(C16E2) using tetraethoxysilane (TEOS) as silica

source and sodium hydroxide as base catalyst.

Detailed synthesis procedures are given in the

Experimental section. Compared to CTAB with

nearly identical length (l) and volume (V) of

hydrocarbon chain, BCDAC has smaller effective

head group area (a0) due to - interactions

between the benzyl groups of adjacent molecules

and therefore has slightly larger packing parameter

g (defined as g = V/a0l) [42] that may allow it to

4

direct the formation of mesostructures with mean

interfacial curvature lower than that of

2D-hexagonal mesophase synthesized with CTAB.

Indeed, we found that BCDAC alone could direct

the formation of MSNs (0.25-1.0 m in size,

scanning electron microscopy (SEM) in Figure S1

and transmission electron microscopy (TEM)

images in Figure S2 in the Electronic

Supplementary Material (ESM)) with cubic Ia3d

structure at [NaOH] = 16.3 mM (cf. Figure 1A). We

then replaced 25-35 % of BCDAC with C12E4 to see

if any structural transformation similar to that

observed in the CTAB/C12E4 systems [37-39] (Figure

1A) would take place. However, the replacement

resulted in particles (200-700 nm, Figure S1) with

decreased structural order and/or mixed phases

(Figure 1A). We then changed the nonionic

surfactant to C16E2 with larger g and found that the

structural order was markedly improved without

causing any transformation. The sample

synthesized with BCDAC:C16E2 = 7:3 contained

100~200 nm-sized nanospheres (Figure S1) and

showed sharp X-ray diffraction (XRD) peaks of Ia3d

structure with unit cell constant (a) of 9.5 nm

(Figure 1A). After calcination, the sample had a of

9.0 nm and exhibited type IV nitrogen (N2)

physisorption isotherm (Figure 1B) with a steep

step at relative pressure (p/p0) of 0.29, referring to a

mesopore diameter of 2.6 nm (cf. Table S1).

In short, it is necessary to consider the

matching of packing parameters of cationic and

nonionic surfactants for forming highly ordered

MSNs, and the systems of CTAB/C12E4 and

BCDAC/C16E2 are favored for the formation of

2D-rectangular and cubic Ia3d structures,

respectively.

We further modulated the cubic Ia3d

mesoporous materials by varying the concentration

of NaOH. With fixed BCDAC/ C16E2 ratio of 7:3, the

cubic Ia3d materials could be prepared at relatively

wide range (9.8-20.0 mM) of [NaOH] (Figure S3),

again suggesting excellent capability of the mixed

surfactants for directing the mesophase formation.

However, the materials synthesized at lower

[NaOH] (< 14.5 mM) had distinct textural

properties, suggested by broader XRD peaks and

additional H4-type hysteresis loop at higher p/p0 in

N2 physisorption isotherm (e.g. the sample

synthesized at [NaOH] = 12.7 mM, cf Figure 1A and

1B). Figure 2 further compares the electron

microscopic images of this sample and the one

synthesized at [NaOH] = 16.3 mM. As revealed by

SEM images, the nanospheres synthesized at

[NaOH] = 12.7 mM are smaller and more uniform

in size (90-120 nm). Surprisingly, some fragments

and nanospheres (indicated by the arrows in Figure

2a) hinted at the possibility of the formation of

hollow morphology. Indeed, the SEM images of the

crushed sample revealed that the nanospheres are

hollow with very thin shell (Figure 2b). In line with

the observations, all the nanospheres show

noticeable contrast in TEM images between the

hollow core and mesoporous shell with a thickness

of ~10 nm (Figure 2c), a value consistent with single

unit cell dimension of the cubic mesostructure.

Notably, most nanospheres had “cube-like” shape,

and projections along [100] and [311] directions of

Ia3d structure were observed throughout

individual nanospheres (Figure 2d and Figure S4).

To our best knowledge, such a spontaneous

formation of HMSNs with single-unit-cell-thick

shell and excellent structural order has never been

discovered before. For the sample synthesized at

[NaOH] = 16.3 mM, TEM images again revealed

excellent structural order of the nanospheres with

darker contrast at the center, typical for solid

(non-hollow) MSNs (Figure 2e-f). With extensive

and careful examinations, we found that purely

hollow and non-hollow MSNs could be

synthesized at [NaOH] = 9.8-13.5 mM and 14.5-20.0

mM, respectively, and a mixture was formed at

[NaOH] = 13.5-14.5 mM (Figure 3 and Figure S5).

In order to gain more insights into the

formation of the hollow mesoporous Ia3d

nanospheres, we performed small-angle X-ray

scattering (SAXS) measurements on the synthesis

mixture (at [NaOH] = 12.7 mM) at different

reaction time t and characterized the solid products

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Figure 1 (A) XRD patterns of the materials synthesized with BCDAC, CTAB or mixed cationic/nonionic surfactants as indicated (with

molar ratio of 7:3) and [NaOH] = 16.3 mM. The sample labeled with asterisk was synthesized with [NaOH] = 12.7 mM. (B) Nitrogen

physisorption isotherms of the two samples synthesized with BCDAC/C12E6 after calcination.

Figure 2 Electron microscopic images of the samples synthesized with mixed BCDAC/C16E2 (molar ratio of 7:3) at [NaOH] = 12.7 mM

(a-d) and 16.3 mM (e and f). (b) SEM image of the crushed nanospheres.

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Figure 3 TEM image of the materials synthesized with

BCDAC/C16E2 (7:3) at [NaOH] = 13.5 mM.

obtained by quickly quenching the synthesis at t by

SEM. As shown in Figure 4, no peaks were

observed in the SAXS patterns until t = 18 min, at

which a strong peak at q = 0.139 Å-1 and a relatively

weak peak at q = 0.279 Å-1 appeared. The pattern

could be attributed to the formation of lamellar

mesophase with an interlamellar spacing of 4.5 nm,

and the solid collected at this stage was composed

of platelet-shaped particles. At t = 20 min, spherical

particles were already observed by SEM and the

Bragg peaks became slightly weaker. Within the

following six minutes, a structural transformation

took place and a SAXS pattern containing peaks

that could be indexed as 211, 220, 321, 400, 420 and

332 reflections of the Ia3d structure was recorded at

t = 26 min. Obviously, the spherical morphology

was developed prior to the formation of the Ia3d

mesostructure. Similar morphological and

structural evolution was observed for the synthesis

at [NaOH] = 16.3 mM.

Based on the observations of SAXS and SEM,

we proposed a formation mechanism for the cubic

Ia3d MSNs as schematically shown in Figure 5. The

anionic silicate species produced from

base-catalyzed hydrolysis of TEOS may interact

with the cationic BCDAC to induce the formation

of lamellar silicatropic liquid crystal (LSLC)

domains of mixed BCDAC/C16E2. The nascent LSLC

Figure 4 SAXS patterns of the synthesis mixture (at [NaOH] =

12.7 mM) and SEM images of the solid products taken at

different reaction times.

domains, small and comprising only a few

alternating inorganic/organic layers, may further

stack and grow into larger domains at higher

[NaOH] (14.5-20.0 mM) and finally become solid

particles. On the contrary, at lower [NaOH]

(9.8-13.5 mM), the LSLC domains could extend

preferentially in area to form sheet-like objects that

subsequently fold into multilamellar vesicle-like

particles. The hollow particles remain composed of

only a few layers (probably two surfactant layers

sandwiched within three silicate layers),

considering the single-unit-cell-thick shell in the

final HMSNs. The distinct morphology evolution

might be mainly associated with local

concentration of anionic silicate species: higher

7

Figure 5 Schematic representation of the formation of solid and hollow mesoporous Ia3d nanospheres at different range of [NaOH] with

mixed BCDAC/C16E2 (molar ratio of 7:3).

local concentration at higher [NaOH] may facilitate

stacking of LSLC domains to reduce the exposed

surface (thereby reducing total surface free energy),

whereas lower local silicate concentration at lower

[NaOH] would kinetically allow the cooperative

assembly to take place at the edge of LSLC

domains. After the spherical morphology is

developed, further condensation of silicate species

would impose stress and geometrical frustration

and provoke undulation in LSLC mesophase,

leading ultimately to the Ia3d structure. The

lamellar-to-Ia3d transformation should take place

coherently throughout each nanosphere to result in

excellent (even single-crystal-like) structural order.

The hollow mesoporous Ia3d silica

nanospheres, designated as MMT-2, are

promising for DDS and other biomedical

applications [1-9]. We further examined and

compared the loading capacity and

biodegradation of MMT-2 and MCM-48 and

MCM-41 nanospheres with similar mesopore

diameter (2.6 nm) and particle sizes (100-150 nm).

All the MSNs samples could be well dispersed in

aqueous solutions, and their particle sizes were

confirmed by SEM (Figure S6) and dynamic light

scattering (DLS, Figure S7). We chose ibuprofen

(IBU) for capacity and release studies because the

model drug has been frequently used for related

studies of MSNs and other DDSs [1,5,18]. The

samples loaded with IBU (using methanol

solution) were placed in cellulose dialysis

membrane tubes to separate the solid from PBS

solution, and the IBU concentration in the outer

solution was monitored. As shown in Figure 6A,

a complete release of IBU was achieved within

around 5 hours for the three samples and the

final IBU concentration decreases in the sequence:

MMT-2 >> MCM-48 > MCM-41. The results were

highly reproducible with the relative error

smaller than 5 %. As expected, the hollow interior

8

Figure 6 (A) Ibuprofen release profiles of different types

of MSNs and free IBU in PBS at 37 °C. (B) Degradation

profiles of different types of MSNs in SBF and PBS (inset)

at 37 °C.

in MMT-2 offers extra space for drug storage, and

the loading capacity of MMT-2 (124 ± 4.3 mg

gsilica-1) is more than twice higher than that of

MCM-48 (58 ± 2.5 mg gsilica-1). The capacity ratio of

MMT-2 and MCM-48 is close to that of their total

pore volumes (cf. Table S2 and Figure S8). The

lower capacity of MCM-41 (51 ± 2.3 mg gsilica-1) is

mainly due to its lower porosity than that of

MCM-48. The release profiles were further fitted

to the Higuchi model: [18,43]

Q = kH t1/2, where Q is the (normalized) amount of

released IBU, kH is the release rate constant, and t is

the release time. Good linear fits were obtained

(Figure S9), indicating that the release was mainly

governed by Fickian diffusion. For the

~100-nm-sized nanospheres, the release kinetics

seems to be correlated more strongly to pore

topology than to pore interconnectivity, as

suggested by the fact that the kH values for the three

samples, all with channel-type mesopores, do not

differ too much (kH = 48.2-48.6 h-1/2). It has to be

mentioned that methanol (instead of hexane) was

used for the studies because it minimizes

preferential IBU adsorption on silica [1,18,44], a

phenomenon not necessarily present for other

drugs, allowing fair comparison of volumetric

loading capacity of silica DDSs.

Finally, silica degradation in SBF and PBS was

investigated. As shown in Figure 6B, the

dissolution of silica was faster in SBF than in PBS

because the magnesium and calcium ions in SBF

may facilitate the reaction by preferentially

interacting with the deprotonated Q3 species

(Si(OSi)3(OH)1) [45-47]. Overall speaking, MMT-2

dissolved much faster than MCM-41 and MCM-48

MSNs owing to its thin-shell hollow morphology,

and a period of about 8 hours in SBF or 3 days in

PBS was sufficient to dissolve 90 % of silica in

MMT-2. The dissolution of MCM-41 is faster than

what was previously reported for the same type of

materials [18,19], which may be mainly due to the

small size of MSNs [48] and the differences in

detailed conditions for degradation studies.

Moreover, distinct ways of degradation were

observed for MMT-2 and MCM-48. Figure 7 shows

the TEM images of the two samples after 40 % or 80

% of silica dissolution in SBF. While extensive voids

were formed without significant change in particle

size for MCM-48, MMT-2 dissolved and broke into

small fragments. The fast degradation through

fragmentation is unique and beneficial for the

elimination after drug delivery. On the other hand,

the dissolution of MMT-2 could be significantly

retarded by modifying the surface with

polyethylene glycol (PEG) [3,4,20]. Around 85 % of

silica in the PEGylated MMT-2 (designated as

P-MMT-2, see Figure S10 for 29Si MAS NMR

spectrum) was dissolved after immersing in SBF for

63 hours or in PBS for 9 days (Figure 6B). It seems

that the solvated PEG may suppress silica Figure 7

9

TEM images of MSNs of MCM-48 (a and b), MMT-2 (c and

d), and P-MMT-2 (e and f) after 40% (a, c and e) or 80% (b, d

and f) of silica dissolution in SBF. Scale bars indicate 50 nm.

dissolution by preventing alkaline earth ions from

approaching silica surface [3,4,20]. Nevertheless,

similar to MMT-2, the degradation of P-MMT-2 was

through fragmentation instead of void formation

and the fragments observed after 80 % of silica

dissolution are slightly larger than those in MMT-2.

This may probably associated with the presence of

PEG groups that were covalently linked to silica

surface. Preliminary data of MTT assays showed

that all these MSNs showed negligible cytotoxicity

for HepG2 cells, and further studies on biomedical

applications of MMT-2 are in progress.

3. Conclusions

In summary, we discovered a direct synthesis

of uniform and hollow nanospheres composed of

single-unit-cell-thick mesoporous silica shell with

cubic Ia3d structure. With high loading capacity

and fast biodegradation through fragmentation, the

material is promising for drug delivery and other

biomedical applications.

4. Experimental Section

Materials synthesis: The synthesis of MSNs started

from the preparation of a solution containing

cationic surfactant (CS, CTAB or BCDAC),

nonionic surfactants (NS, C12E4 or C16E2), NaOH

and water. TEOS was injected (with an injection

rate of 7.5 mL h-1) into the solution using a

syringe pump to result in a synthesis mixture

with a molar composition of 1 TEOS : (0.1-fn) CS :

fn NS : x NaOH : 1200 H2O, with fn = 0 or 0.03

and x = 0.22-0.42. The mixture was stirred at 35 °C

for 2 h followed by aging at 90 C for 24 h, and

finally the solid product was collected by

filtration, washed by water then acetone, and

dried in ambient. The surfactants in the solid

products were removed by calcination at 540 C

for 6 h. For the preparation of P-MMT-2, the

calcined MMT-2 (0.2 g) was heated at 150 C in

vacuum for 12 h to remove the adsorbed water

and was then dispersed in a solution of

2-[methoxy(polyethyleneoxy)propyl]-trimethoxy

silane (PEG-silane, MW 596-725 g mol-1, 90 % in

methanol, 1 mL) and toluene (10 mL). The

mixture was stirred at 80 C for 24 h, and the

solid was collected by centrifugation (10,000 rpm),

washed repeatedly by ethanol, and finally dried

at 60 C for 12 h.

Materials characterization: X-ray diffraction (XRD)

patterns were recorded on a Mac Science 18MPX

diffractometer using Cu K radiation. Scanning

electron microscopy (SEM) images were obtained

with a field emission JEOL JSM-7000F microscope

operating at 10 kV. The samples were coated with

platinum before measurements. Transmission

electron microscopy (TEM) images were taken

from ultramicrotomed samples (thickness of

80–100 nm, supported on carbon-coated copper

grids) by using a JEOL JEM-2010 microscope

operated at 200 kV. N2 physisorption isotherms

were measured at 77 K using a Quantachrome

Autosorb-1MP instrument. The desorption

branches were analyzed by the

10

Barrett-Joyner-Halenda (BJH) method to evaluate

pore sizes, and the adsorption branches in the

relative pressure range of 0.05-0.30 were used to

calculate surface areas by the

Brunauer-Emmett-Teller (BET) method. Pore

volumes were evaluated at a relative pressure of

0.90. Small-angle X-ray scattering (SAXS) data

were acquired at the beamline 23A1 of

Synchrotron Radiation Research Center (NSRRC),

Taiwan, China. Detailed measurement conditions

were given in Ref. 40. Dynamic light scattering

(DLS) measurements were performed on a

particle size analyzer (Brookhaven Instruments

Corporation, Holtsville, NY). Solid-state 29Si MAS

NMR spectra were measured on a Bruker

DSX400WB spectrometer using a 7-mm probe.

IBU loading and release studies: MSN sample (50

mg) was dispersed in a methanol solution of IBU

(60 mg mL-1, 3 mL) at 37 C for 24 h. The solid

was filtered by anodic alumina membrane (pore

diameter: 20 nm, Whatman) and dried. The

IBU-loaded sample (40 mg) was added in a

cellulose dialysis membrane tube (Cellu·Sep T4,

nominal MWCO = 12000-14000). The tube was

placed in a polypropylene (PP) bottle, and PBS

(prepared from PBS tablets purchased from

Medicago AB, Uppsala, Sweden) was then

poured inside (10 mL) and outside (200 mL) the

tube. The outer solution was stirred (60 rpm) at

37 C, and 3.0 mL of the solution was removed

(and replaced by fresh PBS) at different times and

analyzed by a JASCO V-650 UV-visible

spectrophotometer to monitor the concentration

of IBU at 273 nm.

Silica degradation studies: MSN sample (40 mg)

was placed in a cellulose dialysis membrane tube

containing SBF [18,20] or PBS (40 mL). The tube

was put into PP bottle containing the same buffer

solution (360 mL), and the outer solution was

stirred (60 rpm) at 37 C. 5.0 mL of the outer

solution was removed (and replaced by fresh

buffer) at different times to determine the

concentration of silicate species dissolved in SBF

or in PBS by the molybdenum blue method [18,48]

or by inductively coupled plasma-mass

spectroscopy (Agilent 7500ce).

Acknowledgements

We thank the Frontier Research Center on

Fundamental and Applied Sciences of Matters and

the Ministry of Science and Technology of Taiwan,

China (under the contract no.

NSC101-2628-M-007-001-MY2) for financial

support.

Electronic Supplementary Material:

Supplementary material is available in the online

version of this article at

http://dx.doi.org/10.1007/s12274-***-****-*. References

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