Zhaogang Teng

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

Selectively Sensitizing Malignant Cells to Photothermal Therapy Using a CD44-Targeting Heat Shock Protein 72 Depletion Nanosystem

Selectively enhance the therapeutic efficacy to malignancy is one of the most important issues for photothermal therapy (PTT). However, most solid tumors, such as triple negative breast cancer (TNBC), do not have identifiable surface markers to distinguish themselves from normal cells, thus it is challenging to selectively identify and eliminate those malignances by PTT. In this report, we hypothesized that, by targeting CD44 (one TNBC-overexpressed surface molecule) and depleting heat shock protein 72 (HSP72, one malignancy-specific-overexpressed thermotolerance-related chaperone) subsequently, the TNBC could be selectively sensitized to PTT and improve the accuracy of treatment. To this end, a rationally designed nanosystem gold nanostar (GNS)/siRNA against HSP72 (siHSP72)/hyaluronic acid (HA) was successfully constructed using a layer-by-layer method. Hydrodynamic diameter and zeta potential analysis demonstrated the formation of GNS/siHSP72/HA having a particle size of 73.2 ± 3.8 nm and a negative surface charge of -18.3 ± 1.6 mV. The CD44-targeting ability of GNS/siHSP72/HA was confirmed by the flow cytometer, confocal microscopic imaging, and competitive binding analysis. The HSP72 silencing efficacy of GNS/siHSP72/HA was ∼95% in complete culture medium. By targeting CD44 and depleting HSP72 sequentially, GNS/siHSP72/HA could selectively sensitize TNBC cells to hyperthermia and enhance the therapeutic efficacy to TNBC with minimal side effect both in vitro and in vivo. Other advantages of GNS/siHSP72/HA included easy synthesis, robust siRNA loading capacity, endosome/lysosome escaping ability, high photothermal conversion efficacy and superior hemo- and biocompatibility.

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.

A Multifunctional PB@mSiO2–PEG/DOX Nanoplatform for Combined Photothermal–Chemotherapy of Tumor

In this work, we design mesoporous silica-coated Prussian blue nanocubes with PEGyltation to construct multifunctional PB@mSiO2-PEG nanocubes. The PB@mSiO2-PEG nanocubes have good biocompatibility, excellent photothermal transformation capacity, in vivo magnetic resonance and photoacoustic imaging ability. After loading antitumor drug doxorubicin (DOX) in the PB@mSiO2-PEG nanocubes, the constructured PB@mSiO2-PEG/DOX nanoplatforms show an excellent pH-responsive drug release character within 48 h, namely, an ultralow cumulative drug release amount of 3.1% at pH 7.4 and a high release amount of 46.6% at pH 5.0. Upon near-infrared laser irradiation, the PB@mSiO2-PEG/DOX nanoplatforms show an enhanced synergistic photothermal and chemical therapeutic efficacy for breast cancer than solo photothermal therapy or chemotherapy.

Gold nanostars functionalized with amine-terminated PEG for X-ray/CT imaging and photothermal therapy

Multifunctional gold nanostructures effective at photothermal therapy (PTT) and high-quality X-ray/computed tomography (CT) imaging have drawn much attention in recent research. In particular, the development of improved PTT against cancer has been a particularly focused area of research for which the clinical need is great. Since the intracellular concentration of gold nanostructures is critical for their therapeutic photothermal efficacy, we decorated gold nanostructures with positively charged polyethylene glycol (PEG) to boost their degree of uptake by the cell. Herein gold nanostars (GNSs) were decorated with amine-terminated PEG (GNS-PEG-NH2) and methoxy-terminated PEG (GNS-mPEG). PEGylated GNSs showed good dispersivity, high stability and low cytotoxicity. Moreover, compared with GNS-mPEG, GNS-PEG-NH2 exhibited superior thermal therapeutic efficacy against breast tumor cells due to their higher cellular uptake. Measurement of the X-ray absorption coefficient revealed that the attenuation of GNS-PEG-NH2 was about 3.6-fold higher than that of the commercial CT contrast agent iodixanol at the concentration of 25 mg L-1. Importantly, GNS-PEG-NH2 also exhibited effective tumor therapeutic efficacy in vivo, and the tumor sites injected with GNS-PEG-NH2 showed high contrast X-ray/CT imaging. And most of the injected GNS-PEG-NH2 was cleared from tumors 15 days post-injection, indicating rapid clearance and minimal toxicity of GNS-PEG-NH2. Such PEGylated GNSs, when used for producing high-contrast images to guide enhanced PTT therapy, may thus provide new opportunities for the development of cancer theranostics.

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.

Hollow periodic mesoporous organosilica nanospheres by a facile emulsion approach.

Periodic mesoporous organosilicas (PMOs) with homogeneously incorporated organic groups, highly ordered mesopores, and controllable morphology have attracted increasing attention. In this work, one-step emulsion approach for preparation of hollow periodic mesoporous organosilica (HPMO) nanospheres has been established. The method is intrinsically simple and does not require any sacrificial templates, corrosive and toxic etching agents. The obtained HPMO nanospheres have high surface area (∼950m(2)g(-1)), accessible ordered mesochannels (∼3.4nm), large pore volume (∼3.96cm(3)g(-1)), high condensation degree (77%), and diameter (∼560nm), hollow chamber size (∼400nm), and shell thickness (∼80nm). Furthermore, cytotoxicity show the cell viability is higher than 86% after incubating with the HPMO nanospheres at a concentration of up to 1200μgmL(-1) for 24h. The hemolysis of HPMO nanospheres is lower than 1.1% at concentrations ranging from 10 to 2000μgmL(-1). The lower hemolysis and cytotoxicity make the HPMO nanospheres great promise for future biomedical applications.