General and facile syntheses of hybridized deformable hollow mesoporous organosilica nanocapsules for drug delivery

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Abstract

Deformable materials have garnered widespread attention in biomedical applications. Herein, a controllable, general, and simple alkaline etching strategy was used to synthesize deformable hollow mesoporous organosilica nanocapsules (DMONs), in which multiple organic moieties were homogeneously incorporated into the framework. DMONs with double-, triple-, and even quadruple-hybridized frameworks were prepared by the selective introduction of organosilica precursors in accordance with the chemical homology principle through a surfactant-directed sol–gel procedure and a subsequent etching process in alkaline solution. The triple-hybridized DMONs possessed uniform and controllable diameters (100–330 nm), and large hollow cavities (50–270 nm). Liquid cell electron microscopy images demonstrated that the DMONs were deformable in solution. Elemental mapping images suggested that the organic components were homogeneous distribution within the entire DMONs framework. Statistical analysis of cell proliferation assays showed that breast cancer MCF-7 viability exceeded 85% when the cells are incubated with the triple-hybridized DMONs (800 μg mL−1) for 24 h. Histological assessments of main organs indicated no tissue injury or necrosis after intravenous injection of the DMONs 7 days (5 mg kg−1 body weight). Quantitative analysis indicated that the cellular uptake of the DMONs was 6-fold higher than that of their hard counterparts when the number of nanoparticles added was 1.25 × 104, and similar results were found for 4 T1 cells. Furthermore, doxorubicin (DOX) loaded triple-hybridized DMONs with a loading efficiency of 16.9 wt%, produced a strong killing effect on tumor cells. Overall, DMONs with various incorporated organic functional groups could serve as novel nanoplatforms for drug delivery in biomedical applications.

Graphical abstract

A controllable, general, and simple alkaline etching strategy was used to synthesize deformable hollow mesoporous organosilica nanocapsules (DMONs), in which multiple organic moieties were homogeneously incorporated into the framework.

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Introduction

Elastic or deformable nanoparticles with a low Young's modulus can affect the cellular uptake behaviors, showing a broad application prospect in biomedical field [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. For instance, Decuzzi et al. revealed that soft polymeric nanodiscoidals featured enhanced tumor accumulation compared with rigid nanodiscoidals [2]. Guo et al. demonstrated that decreasing the elastic modulus of nanomaterials enhanced their cellular internalization and tumor accumulation [3]. However, in general, the materials used to construct soft and deformable nanoparticles are polymers and liposomes [1], [8], [13], [14], [15], [16], [17], [18], [19], [20], [21]. Thus, broadening the range of traditional rigid particles to flexible frameworks is necessary. The frameworks of mesoporous silica are highly crosslinked that restricts their deformation. Recently, Teng et al. successfully prepared novel deformable hollow mesoporous organosilica nanocapsules (DMONs) containing one type of organic component in the frameworks by preferentially etching the inorganic silica in the surface composition and the interiors of the mesoporous organosilica nanospheres [22], [23]. The deformable organosilica nanocapsules possessed a low Young's modulus and exhibited a significant enhancement in cellular uptake relative to that of solid nanoparticles.

Integration of functional components into silica-based nanoparticles can endow them with excellent biomedical properties, thereby enhancing their performance [23], [24], [25], [26], [27], [28], [29], [30]. For example, ethynylene fragments in the framework endowed the mesoporous organosilica nanoparticles (MONs) with a low biodegradation rate and a low hemolytic effect [31]. Thioether groups could endow hollow MONs with reducing/acidic-responsive drug release properties, allowing a synergistic effect between high intensity focused ultrasound ablation therapy and chemotherapy for efficient treatment of tumors [32]. Phenyl-bridged MONs possessed a high hydrophobic drug loading ability due to an π-π effect [26]. However, to the best of our knowledge, only one kind of organic moiety has been incorporated into the reported DMONs. Therefore, it is very meaningful to synthesize DMONs with hybridized frameworks containing diverse organic components.

Herein, triple-hybridized DMONs containing three different multiple organic moieties were prepared through a surfactant-directed sol–gel process, which was followed by an etching in alkaline solution. Double- and quadruple-hybridized DMONs were successfully produced according to the chemical homology principle by selectively introducing organosilica precursors. The triple-hybridized DMONs possessed uniform and controllable diameters (100–330 nm), thin shells (10–30 nm), high surface areas (521–1000 m2 g−1), large hollow cavities (50–270 nm), and good biocompatibility. The uptake of DMONs by MCF-7 cells was six times as high as that of hard MONs. The triple-hybridized DMONs incorporated with benzene groups possessed a high paclitaxel (PTX) loading capacity (11.4 wt%) because of the π–π interactions. In addition, the doxorubicin (DOX) release behavior from triple-hybridized DMONs/DOX was responsive to the glutathione (GSH) due to the incorporated thioether groups, which led to a high tumor cell killing effect.

Section snippets

Materials

Bis-(triethoxysilyl)ethylene (BTEE), bis-(triethoxysilyl) ethane (BTSE), 1,4-bis(triethoxysilyl)benzene (BTSB), and bis[3-(triethoxysilyl)propyl]tetrasulfide (TESPTS) were supplied from Sigma-Aldrich (shanghai, China). Tetraethoxysilane (TEOS), N, N-dimethylformamide, triphenylphosphine, cetyltrimethylammonium bromide (CTAB), dimethyl sulfoxide (DMSO), anhydrous ethanol, dioxane, and NH3·H2O (25 wt%) were obtained from Sinopharm Chemical Reagent Co., Ltd. (China). PTX and DOX were obtained from

Results and discussion

As shown in Scheme 1, ethane-, benzene-, and thioether-hybridized DMONs were prepared through a surfactant-directed sol–gel procedure and followed by an etching in alkaline solution. In the reaction, the precursors (BTSE, TEOS, BTSB and TESPTS) were hydrolyzed in base solution and co-assemble with CTAB cations (CTA+) via electrostatic interaction to form organosilica/CTAB nanospheres (step 1). The inner layer and structurally stable Si−(O)4 tetrahedrons of the nanospheres were etched away when

Conclusion

In summary, we synthesized DMONs with multiple organic group-incorporated frameworks. Different kinds of organic groups (thioether-, ethylene-, phenyl-, and ethane-groups) could be evenly distributed in the framework of the DMONs. DMONs with various diameters can be conveniently achieved by adjusting the CTAB concentration or ethanol/water ratio. The triple-hybridized DMONs possess uniform diameters (100–330 nm) and large surface areas (521–1000 m2 g−1). Cell cytotoxicity assays and

CRediT authorship contribution statement

Junjie Zhang: Investigation, Methodology, Software, Writing - original draft. Nan Lu: Investigation, Methodology, Data curation, Software. Lixing Weng: Investigation, Methodology, Data curation, Software. Zhihao Feng: Investigation, Methodology, Data curation, Software. Jun Tao: Investigation, Methodology, Data curation, Software. Xiaodan Su: Investigation, Methodology, Data curation, Software. Ruifa Yu: Methodology, Data curation, Software. Wenhui Shi: Methodology, Data curation, Software. Qiu

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The authors appreciate the National Key Research and Development Program of China (2017YFA0205302), National Natural Science Foundation of China (21603106, 81971675, and 81901877), the Natural Science Foundation of Jiangsu Province (BK20160017), and the State Key Laboratory of Analytical Chemistry for Life Science (5431ZZXM1717).

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