bioinspired diselenide‐bridged mesoporous silica

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Bioinspired Diselenide-Bridged Mesoporous Silica Nanoparticles for Dual-Responsive Protein Delivery

Dan Shao, Mingqiang Li, Zheng Wang, Xiao Zheng, Yeh-Hsing Lao, Zhimin Chang, Fan Zhang, Mengmeng Lu, Juan Yue, Hanze Hu, Huize Yan, Li Chen, Wen-fei Dong,* and Kam W. Leong*

Dr. D. Shao, Dr. M. Li, Y.-H. Lao, Dr. M. Lu, H. Hu, H. Yan, Prof. K. W. LeongDepartment of Biomedical EngineeringColumbia UniversityNew York, NY 10027, USADr. D. Shao, Dr. Z. Wang, Z. M. Chang, J. Yue, Prof. W.-f. DongCAS Key Laboratory of Bio Medical DiagnosticsSuzhou Institute of BiomedicalEngineering and TechnologyChinese Academy of SciencesSuzhou 215163, ChinaE-mail: [email protected]. D. Shao, X. Zheng, F. Zhang, Prof. L. ChenDepartment of PharmacologyNanomedicine Engineering Laboratory of Jilin ProvinceCollege of Basic Medical SciencesJilin UniversityChangchun 130021, ChinaProf. K. W. LeongDepartment of Systems BiologyColumbia UniversityNew York, NY 10032, USAE-mail: [email protected]

The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adma.201801198.

DOI: 10.1002/adma.201801198

Although mesoporous silica nanoparticles (MSNs) have received considerable atten-tion in drug delivery due to their tunable pore size, morphology, and surface-func-tionalization, the slow biodegradability of a pure inorganic framework limits their applications, particularly where a matrix-degradation controlled release mechanism is preferred.[1] Organo-bridged MSNs can address this drawback by incorporating functional organosilica moieties into the mesoporous silica framework at the molecular level.[2] Disulfide-bond-bridged MSNs, which can exhibit redox-respon-sive biodegradability for controlled drug release is such an example.[3] In this study, we propose to expand their environmental responsiveness by further incorporating other elements into the mesoporous silica framework for protein delivery.

Protein therapeutics is one of the most potent drugs to intervene at the molecular level due to its high target speci-ficity.[4] Unlike gene therapy, it can produce therapeutic effects without causing permanent genetic alterations and adverse effects. However, controlled release of protein is challenging because of its vulnerability to protease degradation and dena-turation.[5] To minimize denaturation in the encapsulation pro-cess, an aqueous formulation would be advantageous, which then requires a charge complexation between the protein and the carrier. Release of the protein would in turn mostly rely on the degradation of the carrier. Several elegant nanosys-tems have been reported to achieve “on-demand” release at the target site with promising therapeutic efficacy.[6] Disulfide-bond-bridged and large-pored MSN is one example capable of intracellular protein delivery because of the degradation of MSN in the bioreductive cellular environment.[7] To enhance biodegradation and to improve on-demand protein release of organo-bridged MSNs, it would be highly advantageous to incorporate other organosilica moieties that can undergo multiple self-destructive pathways in response to different stimuli, such as reactive oxygen species (ROS) and pH.[8]

Selenium (Se) is an essential element in the human body with a wide range of biological functions because of its

Controlled delivery of protein therapeutics remains a challenge. Here, the inclusion of diselenide-bond-containing organosilica moieties into the framework of silica to fabricate biodegradable mesoporous silica nano-particles (MSNs) with oxidative and redox dual-responsiveness is reported. These diselenide-bridged MSNs can encapsulate cytotoxic RNase A into the 8–10 nm internal pores via electrostatic interaction and release the payload via a matrix-degradation controlled mechanism upon exposure to oxidative or redox conditions. After surface cloaking with cancer-cell-derived membrane fragments, these bioinspired RNase A-loaded MSNs exhibit homologous targeting and immune-invasion characteristics inherited from the source cancer cells. The efficient in vitro and in vivo anti-cancer performance, which includes increased blood circulation time and enhanced tumor accumulation along with low toxicity, suggests that these cell-membrane-coated, dual-responsive degradable MSNs represent a promising platform for the delivery of bio-macromolecules such as protein and nucleic acid therapeutics.

Protein Delivery

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Dedicated to the memory of Professor Helmuth Möhwald, deceased March 27, 2018, in recognition of his inspiration and friendship

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antioxidant properties.[9] Compared with sulfur, selenium pos-sesses a larger atomic radius and weaker electronegativity, leading to a lower bond energy (172 kJ mol−1 for a diselenide bond; 240 kJ mol−1 for a disulfide bond). The diselenide bond can be more easily cleaved either by oxidation to form selen-inic acid or reduction to form selenol in different redox con-ditions.[10] Thus, diselenide bonds have been incorporated into polymer-based “on-demand” drug delivery systems.[11] However, this bioresponsive diselenide bond has not been applied in any organo-bridged MSNs-based delivery system, mostly because of the difficulty in synthesizing such nanocarriers.

Herein, we introduced diselenide-bond-containing orga-nosilica moieties into the framework of mesoporous silica to fabricate large-pore MSNs to deliver protein therapeu-tics for cancer therapy (Scheme 1). Cytotoxic ribonuclease A (RNase A)[12] was chosen as a model protein to evaluate the loading capability and matrix-degradation controlled release behavior in response to the oxidative/redox tumor microenvi-ronment. Furthermore, we coated the RNase A-loaded MSNs with cancer cell membrane (CM) to construct a bioinspired nanoplatform (MSN@RNase A@CM) exhibiting homologous targeting and immune-evading properties inherited from the source cancer cells. The in vitro and in vivo studies validated the hypothesized advantages of this cancer-cell-biomimetic, dual-responsive degradable MSN: sustained release of bioac-tive protein, increased blood circulation time, enhanced tumor accumulation, tissue biocompatibility, and anti-cancer thera-peutic efficacy.

A diselenide-bond-containing organosilica precursor namely bis[3-(triethoxysilyl)propyl]diselenide (BTESePD) was first

designed (Scheme S1, Supporting Information), synthesized and characterized by 1H, 13C, and mass spectrometry (MS) spectra (Figure 1a,b, Figures S1 and S2, Supporting Informa-tion). Organo-bridged MSNs were then fabricated by a modi-fied sol–gel method by mixing ethyltrimethylammonium tosylate as a structure-directing agent, and tetraethyl orthosili-cate (TEOS) and BTESePD as co-precursors in the presence of triethanolamine (TEAH3) (Scheme S2, Supporting Informa-tion). In the present study, two diselenide-bond-bridged MSNs with different selenium contents were prepared by tuning the mass ratio of TEOS to BTESePD (MSN1 = 4:1 and MSN2 = 3:2, respectively). In addition, the disulfide-bond-bridged MSN, termed MSN0, with the same TEOS/organosilica ratio of MSN1, was also synthesized in parallel for comparison to demonstrate the advantages of the diselenide-bond-bridged MSNs for protein delivery. Three types of uniform spherical nanoparticles with comparable diameters of ≈50 nm were observed under trans-mission electron microscopy (TEM) (Figure 1c–e) and scanning electron microscopy (SEM) (Figure S3, Supporting Informa-tion). Energy-dispersive X-ray spectroscopy analysis indicated the presence of selenium with the coexistence of silicon and oxygen (Figure S4, Supporting Information), while inductively coupled plasma optical emission spectrometry showed a higher selenium density in MSN2 (7.3%) than that in MSN1 (5.1%), corresponding to the higher amount of diselenide silicon pre-cursor during formation of the MSN2 framework. The classic absorptions of SeSe and SeC bonds (550–750 cm−1) in the Fourier transform infrared (FTIR) spectrum of MSNs also con-firmed the formation of diselenide bonds in the silica frame-work (Figure S5, Supporting Information). Furthermore, the

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Scheme 1. Schematic illustration of the synthesis procedure of biodegradable diselenide-bridged MSNs and applications for dual-responsive, cancer-cell-membrane-mimetic protein delivery.



nitrogen adsorption–desorption plots of the three types of MSNs exhibited similar type-IV isotherms (Figure S6, Sup-porting Information). The Brunauer–Emmett–Teller (BET) surface area, total pore volume and average pore size of MSN1 were determined to be 523.3 m2 g−1, 1.11 cm3 g−1, and 8.5 nm, respectively, which were higher than the corre-sponding values of 450.6 m2 g−1, 0.65 cm3 g−1, and 7.6 nm in the sulfur-based counterpart (MSN0). Notably, the BET sur-face area (641.3 m2 g−1), total pore volume (1.81 cm3 g−1), and average pore size (11.3 nm) of MSN2 increased with the ratio of diselenide precursor.

Hela cells cultured in the presence of the three types of fab-ricated MSNs with similar particle sizes and zeta potentials (Figure S7, Supporting Information) had more than 90% via-bility at concentrations below 100 µg mL−1 (Figure S8a, Sup-porting Information). While sulfur-based MSNs exhibited dose-dependent toxicity, the selenium-based MSNs showed higher toxicity at high concentrations (>400 µg mL−1). The IC50 values of MSN1 (368.7 µg mL−1) and MSN2 (263.0 µg mL−1) were lower than that of MSN0 (750.4 µg mL−1), which might be attributed to the cancer cell killing of selenium.[9b,13] However, the IC50 values of selenium-based MSNs on the normal mouse

embryonic fibroblast cell line (MEF) were higher than those on HeLa cells, indicating their tumor-specific killing capa-bility (Figure S8b, Supporting Information).[13b] Co-localization of FITC-labeled MSNs with lysosomes was observed in HeLa cells (Figure S9, Supporting Information), indicating their effi-cient cellular uptake through a lysosome-dependent pathway. To generate large pore size for protein delivery, the previously reported modification[14] of the carboxylate group on the surface of MSNs was used and confirmed by the change in zeta poten-tial (Figure S7, Supporting Information).

After incubation with RNase A (Mw 13.7 kDa, PI = 9.6, dimen-sions = 3.8 nm × 2.8 nm × 2.2 nm), MSN2 exhibited a higher loading capacity of 270.6 µg mg−1 than MSN1’s (212.0 µg mg−1) and MSN0’s (177.6 µg mg−1), which is consistent with the expectation that large pores in MSNs allow higher RNase A loading for intracellular delivery, compared with the small-pore MSNs.[15] The degradation behavior of MSNs was investigated in the media mimicking intracellular ROS conditions (H2O2, 100 × 10−6 m) or redox conditions (glutathione (GSH), 5 × 10−3 m) in tumor micro-environment.[8a,b] TEM images (Figure 2a) showed that after 1 d of incubation, the selenium-based MSNs underwent rapid degradation, including surface and bulk

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Figure 1. a) 1H NMR and b) mass spectrometry (MS) spectra of BTESePD. c,d) TEM images and reconstructed 3D models of MSN0 (SS, 4:1) (c), MSN1 (SeSe, 4:1) (d), and MSN2 (SeSe, 3:2) (e).



erosion, in both oxidative and reduced conditions. After 3 d exposure, the structure of MSNs disintegrated into small frag-ments, which might facilitate the renal clearance of selenium-based MSNs in vivo.[1c,16] In contrast, the sulfur-based MSNs only showed structural breakdown in the reducing condition but not in the oxidative condition. The structural degradation of these three types of MSNs was not observed in the absence of H2O2 and GSH (Figure S10, Supporting Information). Quanti-tative measurement revealed a faster degradation rate of MSN2 than MSN1 in both H2O2- and GSH-containing media, while MSN0 exhibited a slower degradation rate than MSN1 in GSH-containing media (Figure S11, Supporting Information). These phenomena are likely caused by the diselenide bond cleavage under both oxidative and reducing conditions. We further con-firmed one of these mechanisms by determining the Se 3d binding energy of seleninic acid, which increased from 56 to 60 eV after oxidation in H2O2 medium (Figure S12, Supporting Information).[10b]

After confirming the simultaneous ROS- and redox-responsiveness of the diselenide-bond-bridged MSN frame-work, we measured the corresponding release of RNase A under the same conditions (Figure 2b). Consistent with their degradable behavior, the three types of RNase A-loaded MSNs exhibited rapid protein release in GSH-containing media. However, although the release profiles of the selenium-based

MSNs and the sulfur-based MSNs were similar in the GSH-containing medium, only the selenium-based group showed a higher release trend in the H2O2-containing medium. All RNase A-loaded MSNs showed faster protein release in the first 24 h under the degradable conditions compared with the control, which is consistent with the degradation behavior of the MSNs and suggests a degradation-mediated release mecha-nism (Figure S11, Supporting Information).

To realize homologous targeting and shielding from the immune system for in vivo protein delivery, we used CM[17] from HeLa cells to coat the RNase A-loaded MSNs. All CM-cloaked MSNs possessed a spherical structure, enclosing MSNs in a thin and smooth shell (Figure 3a–c). MSNs@RNase A@CM displayed a slightly larger hydrodynamic size than the parental MSNs (Figure 3d), while the surface charge was more negative and similar to the CM vesicles (Figure 3e). The MSNs@RNase A@CM exhibited good colloidal stability and dispersibility after 7 d incubation in 10% fetal bovine serum-containing medium, while the bare MSNs@RNase showed strong aggregation right after mixing in the same solution (Figure S13, Supporting Information). Protein electrophoresis indicated that the membrane proteins from the source cell membrane could be well retained on the MSNs@RNase A@CM after coating (Figure 3f). The high degree of intracellular co-localization between the MSNs and CMs after 1 h of uptake

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Figure 2. Dual-responsive degradation and protein release behavior of diselenide-bridged MSNs. a) TEM images of MSNs under 5 × 10−3 m GSH or 100 × 10−6 m H2O2 at different degradation interval, scale bars represent 50 nm. b) Drug release profiles of MSNs@RNase A under 5 × 10−3 m GSH, 100 × 10−6 m H2O2 or water for 48 h.



further verified the structural integrity of the CM-cloaked MSNs (Figure 3g and Figure S14, Supporting Information). The over-lapping fluorescent signals were partly separated after 6 h of cellular uptake (Figure 3g and Figure S15, Supporting Informa-tion), suggesting the separation of the cell membrane from the MSNs after endocytosis.

After coating of the RNase A-loaded MSNs with the cancer cell membrane, we investigated their homologous targeting ability in HeLa cells and RAW264.7 murine macrophages (Figure 4a). With HeLa cells, MSNs@FITC-RNase A@CM showed a higher fluorescence intensity compared with FITC-RNase A@CM, suggesting that the enhanced internaliza-tion was caused by the cancer cell membrane coating.[18] Of note, there was no difference in internalization among the three types of MSNs@FITC-RNase A with or without cancer cell membrane coating due to their similar size and surface zeta potential. Fluorescent microscopy measurement further

confirmed that the targeting effects and the protein release behavior through endo/lysosome escape remained the same after the MSNs were coated with CMs (Figure S16–19, Sup-porting Information). Importantly, significantly higher fluo-rescence intensity was observed in HeLa cells compared with MCF-7 cells in the MSNs@FITC-RNase A@CM group, but not in the MSNs@FITC-RNase A group (Figure S20, Sup-porting Information). This targeting ability is likely attributed to the specific recognition conferred by the residual proteins from the source cell membrane, as demonstrated by previous reports.[18,19] Moreover, the cellular uptake of the MSNs@FITC-RNase A@CM group was also evaluated in macrophages to confirm their immune-invasion ability. A large amount of MSNs@FITC-RNase A was internalized by the RAW264.7 cells, resulting in a strong fluorescence, while a significantly weaker fluorescence was observed after cell-membrane coating (Figure 4a and Figures S21–24, Supporting Information). The

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Figure 3. Fabrication of cancer-cell-membrane-cloaked MSNs@RNase A. TEM images of a) MSN0@RNase A@CM, b) MSN1@RNase A@CM, and c) MSN2@RNase A@CM. d) particle size, e) zeta potential, and f) SDS-PAGE protein analysis of MSNs@RNase A@CM. g) Intracellular co-localization of DiD-labeled cancer cell membrane modifications (red) and FITC-labeled MSNs (green) in HeLa cells for 1 and 6 h. Scale bars represent 5 µm.



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immune-invasion mechanism may be based on two factors: 1) high expression of cell membrane protein CD47 present on the NPs, related to homotypic cell adhesion, therefore inhibiting the phagocytic uptake;[20] 2) reduced particle size compared to bare NPs in culture media due to the cell membrane coating (Figure S13, Supporting Information), a size less favorable than the micrometer-sized NPs for phagocytic uptake by macro-phages.[21] Given the selective cellular uptake behavior, the cytotoxicity of homologous-targeting RNase A-loaded MSNs to HeLa cells was subsequently evaluated. MSNs@RNase A with or without the cell-membrane coating showed increased cyto-toxicity compared with free RNase A (Figure 4b). As expected, the IC50 of the cell membrane-cloaked MSNs@RNase A was threefold lower than that of bare MSNs@RNase A. Importantly,

MSN2@RNase A@CM and MSN1@RNase A@CM showed significantly enhanced cytotoxicity compared with MSN0@RNase A@CM, which might be due to the faster MSN degradation and drug release in response to the dual-stimuli in cancer cells.

To investigate the role of cancer cell camouflaging on blood retention of RNase A-loaded MSNs, we investigated and com-pared their pharmacokinetic profiles. MSNs@RNase A@CM consistently exhibited remarkably improved blood retention com-pared with MSNs@RNase A without the cell-membrane coating (Figure 4c). The elimination half-times (T1/2) of MSN0@RNase A@CM (16.9 h), MSN2@RNase A@CM (20.1 h), and MSN3@RNase A@CM (15.2 h) were 1.8-, 2.1-, and 2.0 times higher than those of MSN0@RNase A (9.4 h), MSN2@RNase A (9.7 h), and

Figure 4. Homologous targeting, immune escape and anti-cancer properties of MSNs@RNase A@CM. a) Relative fluorescence intensity of HeLa cells or RAW264.7 cells after incubation of MSNs@FITC-RNase A@CM for 6 h. * p < 0.05 compared with the MSNs@FITC-RNase A group. b) The cytotoxicity of MSNs@RNase A or MSNs@RNase A@CM against HeLa cells at different concentrations for 48 h. These data represent three separate experiments. Data represent ± SD. The IC50 values of MSN0@RNase A, MSN1@RNase A, MSN2@RNase A, MSN0@RNase A@CM, MSN1@RNase A@CM, and MSN2@RNase A@CM were 7.5, 11.7, 18.8, 2.6, 3.5, and 5.9 µg mL−1, respectively. c) Circulation time of cy5.5-labeled MSNs@RNase A@CM in mice (n = 6). d) Biodistribution of cy5.5-labeled MSNs@RNase A@CM after 24 h of intravenous administration to HeLa-tumor-bearing nude mice (n = 5; mean ± SD, #p < 0.05 vs all MSNs@RNase A groups). e) Tumor photographs and f) tumor volume of MSNs@RNase A@CM-treated HeLa-tumor-bearing nude mice over 28 days. Data represent mean ± SD (n = 5; mean ± SD, * p < 0.05 vs MSN0@RNase A@CM group, #p < 0.05 vs MSN0@RNase A group).



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MSN3@RNase A (7.5 h), respectively. The extended blood cir-culation time was probably caused by the aforementioned col-loidal stability and the immune-evasive ability of the cancer cell membrane.[18] We further studied the biodistribution of Cy5.5-labeled MSNs@RNase A@CM in HeLa-tumor-bearing nude mice (Figure 4d). After 24 h, the vast majority of the intrave-nously injected MSNs were trapped in the reticuloendothelial system, including the liver and spleen.[22] Cancer-cell-membrane camouflaging of MSNs@RNase dramatically enhanced tumor accumulation, reduced spleen retention, and prolonged circu-lation time, consistent with observation in other CM-cloaked nanocarriers.[17d,22]

Encouraged by these results, we then examined the thera-peutic efficacy on the female nude mice bearing orthotopic HeLa tumors (Figure 4e,f). All mice treated with RNase A-loaded MSNs with or without cancer-cell-membrane cloaking showed reduced tumor volumes and tumor weights compared with the control group or the free RNase A group (Figure S25, Supporting Information). As expected, cell-membrane cloaking significantly enhanced the anti-cancer effect of RNase A-loaded MSNs due to homotypic tumor-targeting. Importantly, MSN2@RNase A@CM exhibited the highest therapeutic effi-cacy on tumor inhibition, and MSN1@RNase A@CM showed better anti-cancer performance rather than MSN0@RNase A@CM, indicating the advantages of the dual-responsiveness of selenium-containing MSNs. However, the selenium-based MSNs did not exhibit significant anti-cancer effect in vivo (Figure S26, Supporting Information). This phenomenon could be explained by the dose of these nanocarriers, which was not high enough to achieve anti-cancer effects in vivo. Regarding safety, none of the mice subjected to the full course of any treat-ment experienced weight loss (Figures S25 and 26, Supporting Information). For all the treated mice, no obvious changes were observed in serum biochemical parameters, including aspartate aminotransferase, alanine aminotransferase, alkaline phos-phatase, blood urea nitrogen, creatinine, total bilirubin, cho-lesterol, and triglyceride (Figure S27, Supporting Information). Furthermore, hematoxylin–eosin staining demonstrated no sig-nificant pathological changes in liver, spleen, kidney, heart, and lung tissue samples from all the groups (Figures S28–30, Sup-porting Information). Overall, consistent with our in vitro find-ings, the cancer-cell-membrane-cloaked MSNs@RNase A with dual-responsive degradable properties displayed efficient pro-tein therapeutic performance in vivo with negligible systemic toxicity.

In summary, we presented the development of new diselenide-bridged MSNs with large internal pores for matrix degradation-controlled protein delivery. The RNase A-loaded MSNs possessed oxidative/redox dual-responsive protein release behavior. After surface-cloaking with cancer-cell-membrane-derived fragments, MSNs@RNase A@CM showed homolo-gous targeting and immune-invasion characteristics, resulting in improved in vitro and in vivo anti-cancer efficacy along with lower systemic toxicity. Although both disulfide and diselenide-based MSNs held similar redox-responsive biodegradability, the diselenide-based MSNs were also sensitive to ROS in the micro-environment, adding to the versatility of this delivery system. The presented work suggests a design for multi-responsive degradable nanocarriers for the controlled delivery of bio-mac-

romolecules such as protein and nucleic acid therapeutics, with a possibility of on-demand release and low toxicity.

Supporting InformationSupporting Information is available from the Wiley Online Library or from the author.

AcknowledgementsProf. Jing Han, Prof. Du Cheng, Prof. Ming Zhang, Dr. Zaozao Chen, Dr. Timothy Cheung, Dr. Colleen Ngai, Dr. Tzu-Chieh Ho, Dr. Lianzhi Cui, Dantong Huang, Xing Meng, and Ya-wei Zhao are acknowledged for their help in preparing the paper. This work was supported by the National Natural Science Foundation of China (81601609, 81771982, 61535010, 81371681, and 8160071152), the NIH (HL109442, AI096305, 1UG3TR002142, and GM110494), the Guangdong Innovative and Entrepreneurial Research Team Program (2013S086), the Global Research Laboratory Program (Korean NSF GRL; 2015032163), and the National Key Research and Development Program of China (2017YFF0108600 and 2016YFF0103800). All animal experimental protocols were approved by the Ethics Committee for the Use of Experimental Animals of Jilin University.

Conflict of InterestThe authors declare no conflict of interest.

Keywordsbiodegradable mesoporous silica nanoparticles, cancer-cell-membrane cloaking, diselenide, dual-responsive, protein delivery

Received: February 20, 2018Revised: April 6, 2018

Published online: May 28, 2018

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