Synthesis of pH-Responsive Biodegradable Mesoporous Silica

Subscriber access provided by READING UNIV

Article

Synthesis of pH-responsive biodegradable mesoporous silicacalcium phosphate hybrid nanoparticle as a high potential drug carrier Yongju He, Bowen Zeng, Shuquan Liang, Mengqiu Long, and Hui Xu ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b16787 • Publication Date (Web): 07 Dec 2017 Downloaded from http://pubs.acs.org on December 8, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

ACS Applied Materials & Interfaces is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 19 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

ACS Applied Materials & Interfaces

Synthesis of pH-responsive biodegradable mesoporous silica-calcium phosphate hybrid nanoparticles as a high potential drug carrier Yongju He 1, 2, Bowen Zeng1, Shuquan Liang2, Mengqiu Long1, 3*, Hui Xu1* 1

Lab of Nano-biology Technology, Institute of Super-microstructure and Ultrafast Process in Advanced Materials, School of Physics and Electronics, Central South University, Changsha, Hunan 410083, China 2 School of Material Science and Engineering, Central South University, Changsha, Hunan 410083, China 3. School of Physical Science and Technology, Xinjiang University, Wulumuqi, 830046, China

ABSTRACT: Biodegradability is one of the most critical issues for silica-based nanodrug delivery systems, since it is crucial prerequisites for the successful translation in clinics. In this work, a novel mesoporous silica-calcium phosphate (MS-CAP) hybrid nanocarrier with a fast pH-responsive biodegradation rate was developed by a one-step method, where CAP precursors (Ca2+ and PO43-) were incorporated into silica matrix during the growth process. The morphology and structure of MS-CAP were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), N2 adsorption-desorption isotherms, fourier transformed infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). Furthermore, the drug loading and release behavior of MS-CAP have been tested. TEM and inductively coupled plasma-optical emission spectrometer (ICP-OES) results indicated that the pH-responsive biodegradation of MS-CAP was so fast that could be almost finished within 24 h due to the easy dissolution of CAP embedded in the particle and the escape of Ca2+ from the structure of Si-O-Ca in acid environment. The MS-CAP exhibited a high doxorubicin (DOX) entrapment efficiency (EE) of 97.79 %, which was about 4-fold higher compared with that of pure mesoporous silica nanoparticles (MSN), and our density functional theory (DFT) calculational results suggested that the higher drug EE of MS-CAP would originate from the strong interaction between calcium in the particle and carboxylate group of DOX. The loaded DOX was effectively released, with a cumulative release as high as 98.06 % within 48 h at pH 4.5 in buffer solution, owing to the rapid degradation of MS-CAP. The obtained results indicated that the as-synthesized MS-CAP could act as a promising drug delivery system, and would have a hopeful prospect in the clinical translation. KEYWORDS: mesoporous silica, nanoparticle, calcium phosphate, biodegradability, 1

ACS Paragon Plus Environment

ACS Applied Materials & Interfaces 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

Page 2 of 19

pH-response, nanocarrier Mesoporous silica-based nanoparticles are being widely studied in drug delivery because of high delivery efficiency, excellent compatibility, controlled drug release and potential targeting property

1-8

. However, the clinical translation of silica-based

drug delivery still remains great challenge due to the low biodegradability of silica 4, 9, 10

. The condensed and inert Si-O-Si framework make silica difficult to biodegrade in

physiological environment 11, 12. It was reported that the whole degradation process of mesoporous silica nanoparticles (MSN) would last from one to two weeks the entire clearance of MSN from body could be over four weeks

13, 14

, and

15

. The reluctant

biodegradation of MSN could lead to great accumulation within the body, which may cause severe tissue damages and potential biosafety issues

16-20

. Therefore, the fast

biodegradation rate of silica-based nanocarriers is great necessary for their practical applications in vivo drug delivery and further clinical translation. To date, optimizing the biodegradation of silica nanoparticles has not been effectively realized. In order to shorten the degradation time in physiological environment, silica nanoparticles with less Si-O-Si condensed degree are much desired. Many scientists attempted to improve the biodegradability of silica by doping organic moieties (e.g., methylene-blue

21-23

, doxorubicin (DOX)

21, 24

, starch

25

) into

the particle to reduce the Si-O-Si degree. Although the biodegradability of silica was improved after organic moieties incorporation, these organic moieties-doped silica nanoparticles were non-mesoporous, slow biodegradation and biodegraded in neutral simulated body fluid (SBF), thus non-applicable for further in vivo drug delivery. Disulfide-cleavable

silsesquioxanes

21,

26-29

and

2


enzymatically

cleavable

Page 3 of 19 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


silsesquioxanes accelerate

the

30-32

were also employed to insert into silica nanoparticles to

biodegradation

of

silica.

The

as-synthesized

disulfide-

or

oxamide/ester-doped silica nanoparticles could be degraded by addition of reducer (e.g., glutathione (GSH) and dithiothreitol) 33-36 or enzyme (e.g., trypsin and esterase) 30, 36, 37

, and the degradation kinetics were proportional to the amount of incorporated

disulfide- or oxamide/ester-containing groups within a range. However, the synthesized disulfide- or oxamide/ester-doped silica nanoparticles were nonporous or low porosity, and long degradation time (e.g., 2 d, 5 d, 7 d) 4, which restricted their application in medical field, especially drug delivery (e.g., low drug payloads and bioaccumulation). In order to improve the mesoporosity of disulfide- or oxamide/ester-doped silica nanoparticles, a mixture of bridged organoalkoxysilanes was used: one dictated the formulation of porosity, and the other provided the biodegradability

26, 38

. For instance, Shi et al. reported a redox-triggered degradable

hollow MSN prepared from a combination of phenylene bridges for porosity and redox-sensitive bis (propyl) tetrasulfide bridges, and its degradation was monitored by transmission electron microscopy (TEM) and dynamic light scattering (DLS) analyses and observed after a few days 39. Khashab et al. used phenylene- and oxamide-bridged organoalkoxysilames to prepare enzymatic-triggered degradable MSN, the former directing the formation of mesoporosity and the latter providing the enzymatic responsive biodegradability 40. Recently, tuning the silica degradability via inorganic doping has attracted great attention. Zhang et al.

41

developed a MSN-hydroxyapatite hybrid carrier for DOX 3



delivery, which enhanced the biodegradability of silica by a one-step method. The nanoparticles could be degraded into small particles in acid buffer solution, accelerating drug release. However, drug release was also fast in neutral buffer solution, owing to the degradation of the particles, which was unfavorable for drug delivery system. Shi et al.

42

introduced manganese (Mn) doping into MSN to endow

MSN with tumor microenvironment-triggered biodegradability. The Mn-MSN could effectively degrade effectively under concurrent acid condition and reducing environment, but the framework had undergone change only in 6 h incubation within neutral SBF, and spherical morphology was cloudy after 48 h incubation within neutral SBF solution, which may lead to premature drug release in normal physiological environment before reaching the targeted site. Therefore, it still remains a challenge to develop a silica-based drug nanocarrier with fast biodegradability at acid condition but excellent stability in neutral physiological environment. In this study, a novel mesoporous silica-calcium phosphate (MS-CAP) hybrid drug nanocarrier with fast pH-responsive biodegradability was successfully developed by doping CAP into the framework of MSN during the growth process (Scheme 1). The incorporation of CAP, on one hand, could promote the pH-responsive disintegration and the pH-responsive biodegradation of MS-CAP due to the dissolution of CAP and release of Ca2+ from the structure of Si-O-Ca in acid environment, on the other hand, could endow the MS-CAP with high drug loading capacity and drug release efficiency.

4


Page 4 of 19

Page 5 of 19 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


Scheme 1 Schematic illustration of the synthesis and degradation process of MS-CAP.

The pH-responsive biodegradable MS-CAP was synthesized according to our previous report on the preparation of MSN with some modification n-octadecyltrimethoxysilane

(C18TMS),

tetraethylorthosilicate

43

. First,

(TEOS),

Na2HPO4.12H2O and CaCl2 were added into a mixture solution composed of ethanol, deionized water and ammonia. After reaction for 6 h at 30 ℃, the product was collected and dried for hours, and then calcined at 550 ℃ for 6 h to obtain MS-CAP (Figure 1). The scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images revealed that the MS-CAP were spherical nanoparticles with an average diameter of around 50 nm. Additionally, the pores were seen to be arranged over the MS-CAP particles in TEM image at high magnification (inset of Figure 1b).

5



Page 6 of 19

Figure 1 SEM (a) and TEM images (b) of MS-CAP.

The

texture

parameters

of

MS-CAP were

investigated

by

the

N2

adsorption-desorption technique. The surface area, pore size and pore volume were calculated

from

the

desorption

branch of

the

N2

isotherms

using

the

Brunauer-Emmett-Teller (BET) method and Barrett-Joyner-Halenda (BJH) model, respectively. It was shown that MS-CAP had a bimodal pore distribution with a mean value of 3.44 nm and 24.33 nm respectively (Figure 2b), a high surface area (378.96 m2/g) and a large pore volume (1.27 cm3/g). The large pore size and pore volume of the nanoparticles were demonstrations of potential for high drug loading efficiency 44.

Figure 2 N2 adsorption-desorption isotherm (a) and pore size distribution (b) of MS-CAP.

The fourier transform infrared (FTIR) spectroscopy was used to characterize the

6


Page 7 of 19 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


chemical bonds and existing inorganic substances within MS-CAP. As seen in Figure 3. There were two strong absorption peaks at 3000-3700 and 1635 cm-1 , which were due to O-H stretching resulting from hydroxyl ethyl orthosilicate and adsorbed water, respectively

41, 45, 46

. Additionally, the peaks at 1090, 803, and 463 cm-1 were

originated from Si-O-Si stretching vibration, O-Si-O bending vibration, and Si-O-Si rocking vibration, respectively

41

. It was notable that the characteristic asymmetric

stretching vibration of PO43- groups overlapped with Si-O-Si stretching vibration at 1090 cm-1 47, 48， and the adsorption peak of Si-O-Ca asymmetric bending vibration centered at 562 cm-1

49

. Furthermore, the XPS spectra (Figure S1) also indicated the

existence of Si-O-Ca within MS-CAP. These results suggested that the introduction of Ca2+ could substitute some Si within the Si-O-Si bonds, forming Si-O-Ca bonds 41.

Figure 3 FTIR spectra of MS-CAP and MSN.

In order to make the elemental component of MS-CAP intuitive, scanning TEM-energy dispersive X-ray elemental mapping of MS-CAP was conducted. As seen in Figure 4a, O, Si, Ca and P signals were detected to be distributed in the particles, indicating the infiltration of CAP precursors into the silica framework. The 7



O, Si, Ca and P were also investigated by X-ray photoelectron (XPS) (Figure 4b), the atomic percentages of O1s, Si2p, Ca2p and P2p within MS-CAP were calculated to be 66.68 %, 29.64 %, 2.21 % and 1.47 %, respectively.

Figure 4 Element distribution (a) and XPS analysis (b) of MS-CAP.

To investigate the in vitro degradation behaviors of MS-CAP, two typical approaches were employed: One was directly observing the time-dependent morphology changes of MS-CAP by TEM during the degradation process, and the other was detecting the accumulative release of Ca2+ from the silica framework by inductively coupled plasma-optical emission spectrometer (ICP-OES). For the first approach, the phosphate buffer solution (PBS) with a pH value of 4.5, which to some extent imitated the acidic intracellular environment, was adopted as a paradigm to investigate the pH-responsive biodegradability of the as-synthesized MS-CAP. The TEM images revealed that the MS-CAP nanoparticles were obviously eroded, resulting in cloudy morphology without spherical structure at pH 4.5 in PBS only after 4 h (Figure 5b). Moreover, the degradation was accelerated as the time increased. The structure of MS-CAP nanoparticles were completely destroyed and almost broken 8


Page 8 of 19

Page 9 of 19 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


into very small fragments of 10-20 nm after 8 h (Figure 5c). When the time was extended to 24 h, the fragments were almost completely dissolved (Figure 5d), and only some blurred residues could be observed (Figure 5e), indicating the degradation was almost completed. For the second approach, MS-CAP was immersed into PBS with different pH values (pH 7.4, 6.5, 5.5, 4.5). At certain time points, a small amount of degradation solution was extracted to calculate the amount of Ca2+ release by ICP-OES. As shown in Figure 5f, the release of Ca2+ from MS-CAP exhibited an obvious pH-dependent manner. The release rate increased as the pH value of buffer solution decreased. The release of Ca2+ in PBS at pH 4.5 for 48 h was 1.23, 5.34 and 7.89 folds higher than that at pH 5.5, pH 6.5 and pH 7.4, respectively. Additionally, the amount of Ca2+ release was also presented by percent compared to the initial calcium amount (Figure S2). As seen from Figure S2, at pH 7.4 and pH 6.5, only 12.53 % and 18.49 % of Ca2+ released in PBS after 48 h, respectively. However, the cumulative Ca2+ release reached to 80.23 % and 98.84 % at pH 5.5 and pH 4.5 after 48 h respectively, indicating that the calcium was almost completely released from MS-CAP in PBS with pH 4.5 after 48 h. These results suggested that MS-CAP had a good stability in neutral and mild acidic environment, while rapid degradability in strong acidic environment. It was explained that the acidity-triggered degradation of MS-CAP might be attribute to the easy dissolution of CAP component embedded in the particle and the removal of Ca2+ from the structure of Si-O-Ca

41

under acidic condition. It was

believed that the dissolution of CAP and the release of Ca2+ induced the collapse of 9



silica framework, resulting in small species 41. Additionally, the release of Ca2+ from Si-O-Ca could induce many non-bridge oxygens, which contained lots of local sites for the nucleophilic attack of OH-, leading to the leaching of silicic acid 4 and further the dissolution of MS-CAP.

Figure 5 TEM images of the MS-CAP degradation in PBS of pH 4.5 for 0 h (a), 4 h (b), 8 h (c), 12 (d), 24 h (e) and the release of Ca2+ in PBS with different pHs (f).

To explore the capability of the as-synthesized MS-CAP as drug carrier, DOX, a classic anticancer drug, was used as a model drug to load into MS-CAP. The drug loading efficiency (DL) and entrapment efficiency (EE) of MS-CAP were presented in Figure 6. It can be seen that the EE increased with the decrease of the DOX/MS-CAP ratio and could reach up to 97.93 %, while the DL decreased as the DOX/MS-CAP ratio decreased (Figure 6a and Table S1). It was reported that inorganic carriers such as MSN tended to have a high DL but a low EE 50, 51. However, in our case, MS-CAP held a high EE of 97.93 % when the DOX/MS-CAP ratio was 1:10, which was more 10


Page 10 of 19

Page 11 of 19 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


than 4 times higher compared with that of MSN (23.12 %). In particular, 94.37 % of DOX could be effectively loaded into MS-CAP within 30 min, and there was only a slight improvement for EE when the time was extended to 24 h (97.93 %) (Figure 6b and Table S2), demonstrating the rapid drug loading ability of MS-CAP. These results indicated that MS-CAP had remarkable drug loading capacity and was indeed an effective DOX loading vehicle. It was well-known that surface area, pore structure and surface property of MSN played important roles on their drug loading capacity 52. Generally, large surface and pore size, high pore volume and strong host-guest interaction would induce the high drug EE

52

. However, in our case, the as-synthesized MS-CAP possessed a relative

low surface area (409.14 m2/g) compared with that of MSN (980.14 m2/g), but presented over 4-fold higher EE than that of MSN. It was speculated that the fast and high drug loading capacity of MS-CAP was not only attributed to the electrostatic interaction and hydrogen bonds between negatively charged silanol groups on MS-CAP surface and positively charged DOX molecules

53-56

, but also owing to the

complexation interaction between carboxyl group of DOX and calcium in MS-CAP 57. Namely, both the physical adsorption (electrostatic interaction and hydrogen bonds) and the complexation interaction between carboxyl group of DOX and calcium in MS-CAP could effectively drive DOX molecules loading into MS-CAP, thus resulting in high drug loading capacity. Comparatively, the drugs loaded into MSN only depended on the manner of the physical adsorption, therefore, resulting in low drug loading efficiency. 11



Page 12 of 19

Figure 6 The drug EE and drug DL of MS-CAP at different DOX/MS-CAP weight ratios (a), and the drug EE of MS-CAP at drug loading durations (b).

To further explain that the complexation interaction between carboxyl group of DOX and calcium in MS-CAP could promote drug loading, we demonstrated the interactions between the carboxyl group of DOX and MSN or MS-CAP in a simplified model by density functional theory (DFT) calculations. We choose a silica nanoparticle with silicon atom as center point and 6.3 Å as radius to model MSN, which was putted into a 30 Å × 30 Å × 30 Å unit cell, as shown in Figure 7a, while the DOX could be represented by a acetic acid molecule (CH3COOH), and the H group and CH3 group could represent other part of DOX. There were four different Si atom positions (labeled by Si1, Si2, Si3, Si4 in Figure 7a) could be replaced by calcium atoms, those systems were represented by CaSi1O2, CaSi2O2, CaSi3O2 and CaSi4O2, respectively. After bringing the acid molecule on the surface of silica nanoparticle (Figure 7b), we calculated the adsorption energy ( Ea ) as shown in Figure 7c, which can be expressed as:

Ea = Enanoparticle + ECH 3COOH − Etotal Where

(4)

Etotal , Enanoparticle and ECH3COOH were the total free energy of CH3COOH

adsorbed nanoparticle and the energy of nanoparticle and CH3COOH, respectively. It 12


Page 13 of 19 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


was clearly seen that the introduction of calcium in silica nanoparticle could greatly improve the ability to adsorb carboxyl group, especially the case of calcium substituting the outer silicon atom. Thus, the incorporation of calcium in the particle could truly lead to high drug loading efficiency. Comparatively, the drugs loaded into MSN with low adsorption energy resulting in low drug loading efficiency.

Figure 7 Model of silica nanoparticle (a), CH3COOH adsorbed silica nanoparticle (b) and adsorption energy of CH3COOH adsorbed silica nanoparticle and calcium doped silica nanoparticle (c).

The release profiles of DOX from MS-CAP were tested at various pH values (pH 7.4, pH 6.5, pH 5.5, pH 4.5) in PBS over a 48 h period. As shown in Figure 8, DOX exhibited an excellent pH-responsive release behavior from MS-CAP, which could be assigned to the pH-responsive degradation of the MS-CAP. Additionally, DOX released from MS-CAP exhibited a two-step release pattern with an initial burst release in the first 10 h and an almost constant release during the next hours. At pH 7.4, the drug release was really limited within 48 h, and the cumulative release of DOX was as low as 22.42 %, suggesting that MS-CAP had a good stability in neutral physiological environment. At pH 6.5, the release of DOX was relatively fast, and the cumulative release reached to 30.82 % after 48 h due to the partial degradation of MS-CAP in mild acid environment. Further, the drug release showed much enhanced rate at pH 5.5 and pH 4.5, with a cumulative release as high as 61.28 % and 98.06 % 13



respectively after 48 h. It was noted that the almost complete release of the loaded DOX at pH 4.5 might be attributed to the almost complete dissolution of MS-CAP. These results indicated that the pH-responsive degradable MS-CAP could be effectively trigger the release of DOX in acidic environment, which was significantly important for drug delivery systems.

Figure 8 The drug release profiles of DOX@MS-CAP in PBS with different pHs.

In summary, a kind of novel MS-CAP hybrid nanocarrier with fast pH-responsive biodegradation rate, high drug loading and release efficiency was successfully synthesized. The biodegradation of MS-CAP could almost be finished within 24 h at pH 4.5 in buffer solution due to the easy dissolution of CAP and release of Ca2+ from the structure of Si-O-Ca. Additionally, 94.73 % of DOX was effectively loaded into MS-CAP within 30 min, and the EE increased to 97.93 % after 24 h, owing to the electrostatic interaction and hydrogen bonds between negatively charged silanol groups on MS-CAP surface and positively charged DOX molecules, as well as the complexation interaction between DOX and calcium in the particles. Furthermore, the loaded DOX was effectively triggered release with a high cumulative release of 98.06 % at pH 4.5 in buffer solution after 48 h due to the rapid degradation of MS-CAP. These results would suggest that the as-synthesized MS-CAP was a very 14


Page 14 of 19

Page 15 of 19 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


promising nanocarrier for drug delivery in medical application.

ASSOCIATED CONTENT Supporting Information Materials, synthesis, characterization details, detailed experiment/method of degradation behavior, drug loading, drug release and DFT calculations, figure for high-resolution XPS spectra, figure for the cumulative Ca2+ release, tables for drug entrapment efficiency and drug loading efficiency.

AUTHOR INFORMATION Corresponding Author *Email: [email protected], [email protected]

ORCID Hui Xu: 0000-0002-8269-870x

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS We gratefully acknowledge support by the National Natural Science Foundation of China (Grant No. 21673296) and the Chinese Postdoctoral Scientific Research Funding (Grant number 140050005).

REFERENCES (1) Hao, N.; Li, L.; Tang, F. Roles of particle size, shape and surface chemistry of mesoporous silica nanomaterials on biological systems. Mater. Rev. 2016, 62, 1-21. (2) Song, Y.; Li, Y.; Xu, Q.; Liu, Z. Mesoporous silica nanoparticles for stimuli-responsive controlled drug delivery: advances, challenges, and outlook. Int. J. Nanomed. 2017, 12, 87-110. 15



(3) Moreira, A. F.; Dias, D. R.; Correia, I. J. Stimuli-responsive mesoporous silica nanoparticles for cancer therapy: A review. Micropor. Mesopor. Mater. 2016, 236, 141-157. (4) Croissant, J. G.; Fatieiev, Y.; Khashab, N. M. Degradability and Clearance of Silicon, Organosilica, Silsesquioxane, Silica Mixed Oxide, and Mesoporous Silica Nanoparticles. Adv. Mater. 2017, 29, 1604634-1604685. (5) Singh, R. K.; Patel, K. D.; Leong, K. W.; Kim, H. W. Progress in Nanotheranostics Based on Mesoporous Silica Nanomaterial Platforms. Acs Appl. Mater. Inter. 2017, 9, 10309-10337. (6) Castillo, R. R.; Colilla, M.; Vallet-Regí, M. Advances in mesoporous silica-based nanocarriers for co-delivery and combination therapy against cancer. Expert. Opin. Drug Del. 2016, 14, 229-243. (7) Feng, Y.; Panwar, N.; Tng, D. J. H.; Tjin, S. C.; Wang, K.; Yong, K. T. The application of mesoporous silica nanoparticle family in cancer theranostics. Coordin. Chem. Rev. 2016, 319, 86-109. (8) Karimi, M.; Mirshekari, H.; Aliakbari, M.; Sahandizangabad, P.; Hamblin, M. R. Smart mesoporous silica nanoparticles for controlled-release drug delivery. Nanotechnol. Rev. 2016, 5, 195-207. (9) Alexis, F.; Pridgen, E.; Molnar, L. K.; Farokhzad, O. C. Factors Affecting the Clearance and Biodistribution of Polymeric Nanoparticles. Mol. Pharm. 2008, 5, 505-515. (10) Kempen, P. J.; Greasley, S.; Parker, K. A.; Campbell, J. L.; Chang, H. Y.; Jones, J. R.; Sinclair, R.; Gambhir, S. S.; Jokerst, J. V. Theranostic mesoporous silica nanoparticles biodegrade after pro-survival drug delivery and ultrasound/magnetic resonance imaging of stem cells. Theranostics 2015, 5, 631-642. (11) Pohaku Mitchell, K. K.; Liberman, A.; Kummel, A. C.; Trogler, W. C. Iron(III)-doped, silica nanoshells: a biodegradable form of silica. J. Am. Chem. Soc. 2012, 134, 13997-4003. (12) Peng, Y. K.; Tseng, Y. J.; Liu, C. L.; Chou, S. W.; Chen, Y. W.; Tsang, S. C.; Chou, P. T. One-step synthesis of degradable T(1)-FeOOH functionalized hollow mesoporous silica nanocomposites from mesoporous silica spheres. Nanoscale 2015, 7, 2676-2687. (13) Chen, H.; Hu, T.; Zhang, X.; Huo, K.; Chu, P. K.; He, J. One-Step Synthesis of Monodisperse and Hierarchically Mesostructured Silica Particles with a Thin Shell. Langmuir 2010, 26, 13556-13563. (14) Yamada, H.; Urata, C.; Aoyama, Y.; Osada, S.; Yamauchi, Y.; Kuroda, K. Preparation of Colloidal Mesoporous Silica Nanoparticles with Different Diameters and Their Unique Degradation Behavior in Static Aqueous Systems. Chem. Mater. 2012, 24, 1462-1471. (15) Liu, T.; Li, L.; Teng, X.; Huang, X.; Liu, H.; Chen, D.; Ren, J.; He, J.; Tang, F. Single and repeated dose toxicity of mesoporous hollow silica nanoparticles in intravenously exposed mice. Biomaterials 2011, 32, 1657-1668. (16) He, Q.; Shi, J. Mesoporous Silica Nanoparticle Based Nano Drug Delivery Systems: Synthesis, Controlled Drug Release and Delivery, Pharmacokinetics and Biocompatibility. J. Mater. Chem. 2011, 21, 5845-5855. (17) Huang, X.; Li, L.; Liu, T.; Hao, N.; Liu, H.; Chen, D.; Tang, F. The shape effect of mesoporous silica nanoparticles on biodistribution, clearance, and biocompatibility in vivo. Acs Nano 2011, 5, 5390-5399. (18) Huo, S.; Ma, H.; Huang, K.; Liu, J.; Wei, T.; Jin, S.; Zhang, J.; He, S.; Liang, X. J. Superior penetration and retention behavior of 50 nm gold nanoparticles in tumors. Cancer Res. 2013, 73, 16


Page 16 of 19

Page 17 of 19 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


319-330. (19) Parveen, S.; Misra, R.; Sahoo, S. K. Nanoparticles: a boon to drug delivery, therapeutics, diagnostics and imaging. Nanomed. Nanotechnol. Biol. Med. 2012, 8, 147-166. (20) Ferlay, J. Global cancer statistics, 2002. Ca A Cancer J. Clinic. 2015, 55, 74-108. (21) Zhang, S.; Chu, Z.; Yin, C.; Zhang, C.; Lin, G.; Li, Q. Controllable Drug Release and Simultaneously Carrier Decomposition of SiO2-Drug Composite Nanoparticles. J. Am. Chem. Soc. 2013, 135, 5709-5716. (22) Chu, Z.; Zhang, S.; Yin, C.; Lin, G.; Li, Q. Designing nanoparticle carriers for enhanced drug efficacy in photodynamic therapy. Biomater. Sci-Uk 2014, 2, 827-832. (23) Zhao, S.; Zhang, S.; Ma, J.; Fan, L.; Yin, C.; Lin, G.; Li, Q. Double loaded self-decomposable SiO2 nanoparticles for sustained drug release. Nanoscale 2015, 7, 16389-16398. (24) Zhou, X.; Chen, L.; Wang, W.; Jia, Y.; Chang, A.; Mo, X.; Wang, H.; He, C. Electrospun nanofibers incorporating self-decomposable silica nanoparticles as carriers for controlled delivery of anticancer drug. Rsc Adv. 2015, 5, 65897-65904. (25) Wang, A.; Yang, Y.; Qi, Y.; Qi, W.; Fei, J.; Ma, H.; Zhao, J.; Cui, W.; Li, J. Fabrication of Mesoporous Silica Nanoparticle with Well-defined Multicompartment Structure as Efficient Drug Carrier for Cancer Therapy in vitro and in vivo. Acs Appl. Mater. Interf. 2016, 8, 8900-8907. (26) Croissant, J.; Cattoën, X.; Man, M. W. C.; Gallud, A.; Raehm, L.; Trens, P.; Maynadier, M.; Durand, J. O. Biodegradable Ethylene-Bis(Propyl)Disulfide-Based Periodic Mesoporous Organosilica Nanorods and Nanospheres for Efficient In-Vitro Drug Delivery. Adv. Mater. 2014, 26, 6174-6181. (27) Yang, Y.; Lei, Z.; Gao, C.; Liang, X.; Bai, S.; Liu, X. Pyrene-based BODIPY: synthesis, photophysics and lasing properties under UV-pumping radiation. Rsc Adv. 2014, 4, 38119-38123. (28) Croissant, J. G.; Mauriellojimenez, C.; Maynadier, M.; Cattoën, X.; Wong, C. M. M.; Raehm, L.; Mongin, O.; Blancharddesce, M.; Garcia, M.; Garybobo, M. Synthesis of disulfide-based biodegradable bridged silsesquioxane nanoparticles for two-photon imaging and therapy of cancer cells. Chem. Commun. 2015, 51, 12324-12327. (29) Hu, L. C.; Shea, K. J. ChemInform Abstract: Organo-Silica Hybrid Functional Nanomaterials: How Do Organic Bridging Groups and Silsesquioxane Moieties Work Hand-in-Hand? Chem. Soc. Rev. 2011, 42, 688-695. (30) Fatieiev, Y.; Croissant, J. G.; Julfakyan, K.; Deng, L.; Anjum, D. H.; Gurinov, A.; Khashab, N. M. Enzymatically degradable hybrid organic-inorganic bridged silsesquioxane nanoparticles for in vitro imaging. Nanoscale 2015, 7, 15046-15050. (31) Maggini, L.; Travaglini, L.; Cabrera, I.; Castro-Hartmann, P.; De, C. L. Biodegradable Peptide-Silica Nanodonuts. Chemistry 2016, 22, 3697-3703. (32) Tsao, N. H.; Hall, E. A. H. Enzyme-Degradable Hybrid Polymer/Silica Microbubbles as Ultrasound Contrast Agents. Langmuir 2016, 32, 6534-6543. (33) Wang, D.; Xu, Z.; Chen, Z.; Liu, X.; Hou, C.; Zhang, X.; Zhang, H. Fabrication of single-hole glutathione-responsive degradable hollow silica nanoparticles for drug delivery. Acs Appl. Mater. Interf. 2014, 6, 12600-12608. (34) Zhang, Z.; Pang, S.; Xu, H.; Yang, Z.; Zhang, X.; Liu, Z.; Wang, X.; Zhou, X.; Dong, S.; Chen, X. Electrodeposition of nanostructured cobalt selenide films towards high performance counter electrodes in dye-sensitized solar cells. Rsc Adv. 2013, 3, 16528-16533. (35) Quignard, S.; Masse, S.; Laurent, G.; Coradin, T. Introduction of disulfide bridges within 17



silica nanoparticles to control their intra-cellular degradation. Chem. Commun. 2013, 49, 3410-3412. (36) Maggini, L.; Cabrera, I.; Ruiz-Carretero, A.; Prasetyanto, E. A.; Robinet, E.; De, C. L. Breakable mesoporous silica nanoparticles for targeted drug delivery. Nanoscale 2016, 8, 7240-7247. (37) Prof, A. C.; Dr, U. D.; Dr, M. A.; Dr, E. F.; Dr, I.; Ortega, L. Organic–Inorganic Nanospheres with Responsive Molecular Gates for Drug Storage and Release &dagger. Angew. Chem. 2009, 48, 6247-6250. (38) Teng, Z.; Zhang, J.; Li, W.; Zheng, Y.; Su, X.; Tang, Y.; Dang, M.; Tian, Y.; Yuwen, L.; Weng, L. Mesoporous Nanoparticles: Facile Synthesis of Yolk–Shell-Structured Triple-Hybridized Periodic Mesoporous Organosilica Nanoparticles for Biomedicine. Small 2016, 12, 3550-3558. (39) Wu, M.; Meng, Q.; Chen, Y.; Xu, P.; Zhang, S.; Li, Y.; Zhang, L.; Wang, M.; Yao, H.; Shi, J. Ultrasmall Confined Iron Oxide Nanoparticle MSNs as a pH‐Responsive Theranostic Platform. Adv. Funct. Mater. 2014, 24, 4273-4283. (40) Croissant, J. G.; Fatieiev, Y.; Julfakyan, K.; Lu, J.; Emwas, A. H.; Anjum, D. H.; Omar, H.; Tamanoi, F.; Zink, J. I.; Khashab, N. M. Biodegradable Oxamide-Phenylene-Based Mesoporous Organosilica Nanoparticles with Unprecedented Drug Payloads for Delivery in Cells. Chemistry 2016, 22, 14806-14811. (41) Hao, X.; Hu, X.; Zhang, C.; Chen, S.; Li, Z.; Yang, X.; Liu, H.; Jia, G.; Liu, D.; Ge, K. Hybrid Mesoporous Silica-Based Drug Carrier Nanostructures with Improved Degradability by Hydroxyapatite. Acs Nano 2015, 9, 9614-9625. (42) Yu, L.; Yu, C.; Wu, M.; Cai, X.; Yao, H.; Zhang, L.; Chen, H.; Shi, J. “Manganese Extraction” Strategy Enables Tumor-Sensitive Biodegradability and Theranostics of Nanoparticles. J. Am. Chem. Soc. 2016, 138, 9881-9894. (43) He, Y.; Xu, H.; Ma, S.; Zhang, P.; Huang, W.; Kong, M. Fabrication of mesoporous spherical silica nanoparticles and effects of synthesis conditions on particle mesostructure. Mater. Lett. 2014, 131, 361-365. (44) Argyo, C.; Weiss, V.; Braeuchle, C.; Bein, T., ChemInform Abstract: Multifunctional Mesoporous Silica Nanoparticles as a Universal Platform for Drug Delivery. Cheminform 2014, 45, 435-451. (45) Min, J.; Park, J. K.; Shin, E. W. Lanthanum functionalized highly ordered mesoporous media: implications of arsenate removal. Micropor. Mesopor. Mater. 2004, 75, 159-168. (46) Karin Moller, †; Thomas Bein, A.; Fischer‡, R. X., Entrapment of PMMA Polymer Strands in Micro- and Mesoporous Materials. Chem. Mater. 1998, 10, 1841-1852. (47) Zhang, C.; Yang, J.; Quan, Z.; Yang, P.; Li, C.; Hou, Z.; Lin, J. Hydroxyapatite Nano- and Microcrystals with Multiform Morphologies: Controllable Synthesis and Luminescence Properties. Phys. Rev. B 1999, 59, 1758-1775. (48) Zhang, C.; Li, C.; Huang, S.; Hou, Z.; Cheng, Z.; Yang, P.; Peng, C.; Lin, J. Self-activated luminescent and mesoporous strontium hydroxyapatite nanorods for drug delivery. Biomaterials 2010, 31, 3374-3383. (49) Ahsan, M. R.; Mortuza, M. G. Infrared spectra of x CaO(1- x- z )SiO 2 z P 2 O 5 glasses. J. Non-Cryst. Solids 2005, 351, 2333-2340. (50) Liu, F.; Eisenberg, A. Preparation and pH triggered inversion of vesicles from poly(acrylic acid)-block-polystyrene-block-poly(4-vinyl pyridine). J. Am. Chem. Soc. 2003, 125, 15059-15064. 18


Page 18 of 19

Page 19 of 19 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


(51) Matsumura, Y.; Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986, 46, 6387-6392. (52) Horcajada, P.; Rámila, A.; Pérez-Pariente, J.; Vallet-Regı, M. Influence of pore size of MCM-41 matrices on drug delivery rate. Micropor. Mesopor. Mate. 2004, 68, 105-109. (53) Zhu, Y.; Toshiyuki, I.; Nobutaka, H.; Stefan, K., Rattle-Type Fe3O4@SiO2 Hollow Mesoporous Spheres as Carriers for Drug Delivery. Small 2010, 6, 471-478. (54) Ma, M.; Huang, Y.; Chen, H.; Jia, X.; Wang, S.; Wang, Z.; Shi, J., Bi2S3-embedded mesoporous silica nanoparticles for efficient drug delivery and interstitial radiotherapy sensitization. Biomaterials 2015, 37, 447-455. (55) Huang, S.; Cheng, Z.; Ma, P.; Kang, X.; Dai, Y.; Lin, J., Luminescent GdVO4:Eu3+ functionalized mesoporous silica nanoparticles for magnetic resonance imaging and drug delivery. Dalton T. 2013, 42, 6523-30. (56) Ma, M.; Chen, H. R.; Chen, Y.; Wang, X.; Chen, F.; Cui, X. Z.; Shi, J. L., Au capped magnetic core/mesoporous silica shell nanoparticles for combined photothermo-/chemo-therapy and multimodal imaging. Biomaterials 2012, 33, 989-998. (57) Yu, M.; Xue, Y.; Ma, P. X.; Mao, C.; Lei, B. Intrinsic Ultrahigh Drug/miRNA Loading Capacity of Biodegradable Bioactive Glass Nanoparticles toward Highly Efficient Pharmaceutical Delivery. Acs Appl. Mater. Interf. 2017, 9, 8460-8470.

Table of Contents graphic

19


Synthesis of pH-Responsive Biodegradable Mesoporous Silica

Recommend Documents