Yuxia Tang

Facile Synthesis of Yolk–Shell Structured Inorganic–Organic Hybrid Spheres with Ordered Radial Mesochannels

Dr. Z. Teng, Dr. S. Wang, G. Chen, Dr. Y. Liu, Y. Tang, Prof. G. Lu Department of Medical Imaging Jinling Hospital School of Medicine Nanjing University Nanjing 210002 , P. R. China E-mail: cjr.luguangming@vip.163.com Dr. Z. Teng, Prof. H. Ju, Prof. G. Lu State Key Laboratory of Analytical Chemistry for Life Science School of Chemistry and Chemical Engineering Nanjing University Nanjing 210093 , P. R. China Dr. W. Luo, Prof. D. Y. Zhao Department of Chemistry Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials Laboratory of Advanced Materials Fudan University Shanghai 200433 , P. R. China Dr. X. Su, Dr. Z. Luo Key Laboratory for Organic Electronics and Information Displays and Institute of Advanced Materials Nanjing University of Posts and Telecommunications Nanjing 210046 , P. R. China

Facile Synthesis of Yolk–Shell-Structured Triple-Hybridized Periodic Mesoporous Organosilica Nanoparticles for Biomedicine

The synthesis of mesoporous nanoparticles with controllable structure and organic groups is important for their applications. In this work, yolk-shell-structured periodic mesoporous organosilica (PMO) nanoparticles simultaneously incorporated with ethane-, thioether-, and benzene-bridged moieties are successfully synthesized. The preparation of the triple-hybridized PMOs is via a cetyltrimethylammonium bromide-directed sol-gel process using mixed bridged silsesquioxanes as precursors and a following hydrothermal treatment. The yolk-shell-structured triple-hybridized PMO nanoparticles have large surface area (320 m(2) g(-1) ), ordered mesochannels (2.5 nm), large pore volume (0.59 cm(3) g(-1) ), uniform and controllable diameter (88-380 nm), core size (22-110 nm), and shell thickness (13-45 nm). In vitro cytotoxicity, hemolysis assay, and histological studies demonstrate that the yolk-shell-structured triple-hybridized PMO nanoparticles have excellent biocompatibility. Moreover, the organic groups in the triple-hybridized PMOs endow them with an ability for covalent connection of near-infrared fluorescence dyes, a high hydrophobic drug loading capacity, and a glutathione-responsive drug release property, which make them promising candidates for applications in bioimaging and drug delivery.

Smart Cancer Cell Targeting Imaging and Drug Delivery System by Systematically Engineering Periodic Mesoporous Organosilica Nanoparticles

The integration of diagnosis and therapy into one nanoplatform, known as theranostics, has attracted increasing attention in the biomedical areas. Herein, we first present a cancer cell targeting imaging and drug delivery system based on engineered thioether-bridged periodic mesoporous organosilica nanoparticles (PMOs). The PMOs are stably and selectively conjugated with near-infrared fluorescence (NIRF) dye Cyanine 5.5 (Cy5.5) and anti-Her2 affibody on the outer surfaces to endow them with excellent NIRF imaging and cancer targeting properties. Also, taking the advantage of the thioether-group-incorporated mesopores, the release of chemotherapy drug doxorubicin (DOX) loaded in the PMOs is responsive to the tumor-related molecule glutathione (GSH). The drug release percentage reaches 84.8% in 10 mM of GSH solution within 24 h, which is more than 2-fold higher than that without GSH. In addition, the drug release also exhibits pH-responsive, which reaches 53.6% at pH 5 and 31.7% at pH 7.4 within 24 h. Confocal laser scanning microscopy and flow cytometry analysis demonstrate that the PMOs-based theranostic platforms can efficiently target to and enter Her2 positive tumor cells. Thus, the smart imaging and drug delivery nanoplatforms induce high tumor cell growth inhibition. Meanwhile, the Cy5.5 conjugated PMOs perform great NIRF imaging ability, which could monitor the intracellular distribution, delivery and release of the chemotherapy drug. In addition, cell viability and histological assessments show the engineered PMOs have good biocompatibility, further encouraging the following biomedical applications. Over all, the systemically engineered PMOs can serve as a novel cancer cell targeting imaging and drug delivery platform with NIRF imaging, GSH and pH dual-responsive drug release, and high tumor cell targeting ability.

Superparamagnetic high-magnetization composite spheres with highly aminated ordered mesoporous silica shell for biomedical applications

Control of the morphology, mesostructure, and surface chemistry of multifunctional materials is important for their applications. We report here the fabrication of multifunctional spheres which possess a silica-coated magnetite core and a highly aminated mesoporous silica shell with radially aligned ordered pore channels. The well-designed core-shell structured spheres have superparamagnetism, high magnetization (32 emu g-1), large surface area (133 m2 g-1), uniform accessible mesopores (3.4 nm), and abundant amino groups on the mesoporous shell. Owing to the presence of the amino groups, the composite spheres exhibit high capacity for convenient connection of fluorescent dyes, which make them promising candidates for applications in various biomedical fields, such as cell imaging and cell sorting. Furthermore, a fibrin-specific magnetic resonance imaging (MRI) contrast agent was successfully prepared by connecting the composite spheres with pentapeptide Gly-Pro-Arg-Pro-Pro, which can significantly increase the MRI signal of thrombus.

Synergistic Chemo–Photothermal Therapy of Breast Cancer by Mesenchymal Stem Cell-Encapsulated Yolk–Shell GNR@HPMO-PTX Nanospheres

Mesenchymal stem cells (MSCs) have attracted increasing attention as vehicles for cancer treatment. Herein, MSC-based synergistic oncotherapy strategy is presented for the first time. To achieve this goal, yolk-shell structured gold nanorod embedded hollow periodic mesoporous organosilica nanospheres (GNR@HPMOs) with high paclitaxel (PTX) loading capability and excellent photothermal transfer ability upon near-infrared (NIR) light irradiation are first prepared. Cytotoxicity and migration assays show that the viability and tumor-homing capability of MSCs are well-retained after internalization of high content of PTX loaded GNR@HPMOs (denoted as GNR@HPMOs-PTX). In vitro experiments show the GNR@HPMOs-PTX loaded MSCs (GNR@HPMOs-PTX@MSCs) possess synergistic chemo-photothermal killing effects for breast cancer cells. Also, photoacoustic imaging shows that the MSCs can improve dispersion and distribution in tumor tissue for GNR@HPMOs-PTX after intratumoral injection. In vivo experiments in breast cancer model of nude mice further demonstrate that the GNR@HPMOs-PTX@MSCs significantly inhibit tumor growth, suggesting their great potential for synergistic therapy of cancer.

Cytochrome C capped mesoporous silica nanocarriers for pH-sensitive and sustained drug release

In this paper, pH-responsive drug nanocarriers based on mesoporous silica nanoparticles (MSNs) capped with a natural, nontoxic protein cytochrome C (CytC) are designed and demonstrated for cancer therapy. At neutral pH the positively charged CytC can prevent the premature release of a preloaded anti-cancer drug. The results show that the CytC capped nanocarriers have excellent doxorubicin (DOX) loading efficiency (414 μg mg-1 MSN) and the leakage of the drug is only 16% at pH 7.4 phosphate-buffered saline for 72 h. Simultaneously, the DOX release percentage can reach 54% by decreasing the pH to 5.5. In contrast, unsealed MSNs show a fast DOX release rate at pH 7.4 and a slight pH-response. Confocal laser scanning microscopy demonstrates that the nanocarriers can enter human breast cancer MCF-7 cells and the DOX is sustained released from the drug carriers. Cytotoxicity tests and histological assays confirm that the constructed CytC capped nanocarriers possess lower toxicity than free DOX and unsealed drug carriers. Furthermore, intratumoral administration of the nanocarriers is significantly more efficacious in tumor reduction than free DOX and unsealed drug carriers in the xenograft models of MCF-7 cancer. Overall, this study demonstrates new drug nanocarriers with pH-sensitive and sustained drug release properties by using natural and nontoxic proteins as pore blockers to achieve highly efficient cancer treatment.

Periodic Mesoporous Organosilica Coated Prussian Blue for MR/PA Dual‐Modal Imaging‐Guided Photothermal‐Chemotherapy of Triple Negative Breast Cancer

Complete eradication of highly aggressive triple negative breast cancer (TNBC) remains a notable challenge today. In this work, an imaging‐guided photothermal‐chemotherapy strategy for TNBC is developed for the first time based on a periodic mesoporous organosilica (PMO) coated Prussian blue (PB@PMO) nanoplatform. The PB@PMOs have organic‐inorganic hybrid frameworks, uniform diameter (125 nm), high surface area (866 m2 g−1), large pore size (3.2 nm), excellent photothermal conversion capability, high drug loading capacity (260 µg mg−1), and magnetic resonance (MR) and photoacoustic (PA) imaging abilities. The MR and PA properties of the PB@PMOs are helpful for imaging the tumor and showing the accumulation of the nanoplatform in the tumor region. The bioluminescence intensity and tumor volume of the MDA‐MB‐231‐Luc tumor‐bearing mouse model demonstrate that TNBC can be effectively inhibited by the combined photothermal‐chemotherapy than monotherapy strategy. Histopathological analysis further reveals that the combination therapy results in most extensive apoptotic and necrotic cells in the tumor without inducing obvious side effect to major organs.

pH-Dependent Transmembrane Activity of Peptide-Functionalized Gold Nanostars for Computed Tomography/Photoacoustic Imaging and Photothermal Therapy

Progress in multifunctional nanomaterials for tumor therapy mostly depends on the development of tumor-targeting delivery strategies. One approach is to explore a pH-responsive strategy to target the slightly acidic solid tumor microenvironment. A novel class of pH (low) insertion peptides (pHLIPs) with pH-dependent transmembrane activity can fold and rapidly insert into the lipid bilayer of tumor cells triggered by acidity, facilitating the cellular internalization of nanomaterials synchronously. Here, we innovatively decorated gold nanostars (GNSs) with pHLIPs (GNS-pHLIP) to improve their targeting ability and photothermal therapeutic (PTT) efficiency. The obtained GNS-pHLIP exhibited the excellent characteristics of uniform size and good biocompatibility. As compared to GNS-mPEG, the cellular internalization of GNS-pHLIP was 1-fold higher after a 2 h incubation with cells in media at pH 6.4 than at pH 7.4. Moreover, the tumor accumulation of the GNS-pHLIP was 3-fold higher than that of GNS-mPEG after intravenous injection into MCF-7 breast tumor animal models for 24 h. Furthermore, GNS-pHLIP exhibited stronger signals than the GNS-mPEG through computed tomography (CT) and photoacoustic (PA) imaging. Simultaneously, the desirable targeting efficiency significantly improved the PTT efficacy to tumors, with low side effects on normal tissues. The results clearly demonstrate that the GNS-pHLIP successfully took advantage of the tumor-targeting ability of pHLIPs and the good characteristics of GNSs, which may contribute to the study of tumor imaging and therapy.

Deformable Hollow Periodic Mesoporous Organosilica Nanocapsules for Significantly Improved Cellular Uptake

Mesoporous solids have been widely used in various biomedical areas such as drug delivery and tumor therapy. Although deformability has been recognized as a prime important characteristic influencing cellular uptake, the synthesis of deformable mesoporous solids is still a great challenge. Herein, deformable thioether-, benzene-, and ethane-bridged hollow periodic mesoporous organosilica (HPMO) nanocapsules have successfully been synthesized for the first time by a preferential etching approach. The prepared HPMO nanocapsules possess uniform diameters (240-310 nm), high surface areas (up to 878 m2·g-1), well-defined mesopores (2.6-3.2 nm), and large pore volumes (0.33-0.75 m3·g-1). Most importantly, the HPMO nanocapsules simultaneously have large hollow cavities (164-270 nm), thin shell thicknesses (20-38 nm), and abundant organic moiety in the shells, which endow a lower Youngs modulus (EY) of 3.95 MPa than that of solid PMO nanoparticles (251 MPa). The HPMOs with low EY are intrinsically flexible and deformable in the solution, which has been well-characterized by liquid cell electron microscopy. More interestingly, it is found that the deformable HPMOs can easily enter into human breast cancer MCF-7 cells via a spherical-to-oval morphology change, resulting in a 26-fold enhancement in cellular uptake (43.1% cells internalized with nanocapsules versus 1.65% cells with solid counterparts). The deformable HPMO nanocapsules were further loaded with anticancer drug doxorubicin (DOX), which shows high killing effects for MCF-7 cells, demonstrating the promise for biomedical applications.

Cisplatin and doxorubicin high-loaded nanodrug based on biocompatible thioether- and ethane-bridged hollow mesoporous organosilica nanoparticles

Herein, a mesoporous organosilica nanoparticle (MON) based nanodrug highly loaded with cisplatin (CDDP) and doxorubicin (DOX) (denoted as MONs/CDDP/DOX) has been successfully prepared for the first time. The MONs are characterized with core-contained double hollow shells, thioether and ethane groups separately incorporated frameworks, uniform diameter (420 nm), large surface area (592 m2/g), and ordered pore size (2.5 nm). The safety evaluation of the MONs based on cell viability, haemolytic activity, histological change, and serum biochemical index demonstrates that they have excellent biological compatibility. The efficient uptake of the MONs by human breast cancer MCF-7 cells is further confirmed via confocal laser scanning imaging and flow cytometry. Importantly, the contents of CDDP and DOX in the MONs/CDDP/DOX nanodrug are as high as 120 mg/g and 85 mg/g, respectively. Therefore, the MONs/CDDP/DOX shows a significant improved killing effect against human breast cancer MCF-7 cells compared with sole DOX or CDDP loaded MONs, demonstating the promise of the nanodrug for cancer treatment.