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Ultralong organic phosphorescence (UOP), enabling of persistent luminescence after removal of external excitation light, shows great promise in biological applications such as bioimaging in virtue of antibackground fluorescence interference. Despite of good biocompatibility and outstanding phosphorescent properties, most current organic phosphors are hydrophobic with poor water solubility in the form of bulk crystal with large size, limiting their potential in the biological field. Here, a facile and versatile approach is provided to obtain nanoscale hydrophilic phosphorescent phosphors (HPPs) by physically loading ultralong organic phosphors into hollow mesoporous silica nanoparticles. The as-prepared HPPs can be well suspended in aqueous solution and effectively internalized by HeLa cells with very low cytotoxicity. Such HPPs are successfully applied for afterglow bioimaging in living nude mice with a very high signal-to-noise ratio up to 31. The current study not only provides a universal strategy to realize UOP in aqueous media but also demonstrates their great potential for biomedical purposes as an advanced imaging indicator with long-lived emission lifetime., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: To improve the outcome of cancer treatment, the combination of multiple therapy models has proved to be effective and promising. Gas therapy (GT) and chemodynamic therapy (CDT), mainly targeting the mitochondrion and nucleus, respectively, are two emerging strategy for anti-cancer. The development of novel nanomedicine for integrating these new therapy models is greatly significant and highly desired., Methods: A new nanomedicine is programmed by successive encapsulation of MnO 2 nanoparticles and iron carbonyl (FeCO) into mesoporous silica nanoparticle. By decoding the nanomedicine, acidity in the lysosome drives MnO 2 to generate ROS, ·OH among which further triggers the decomposition of FeCO into CO, realizing the effective combination of chemodynamic therapy with gas therapy for the first time., Results: Acidity in the TEM drives MnO 2 to generate ROS, ∙OH among which further triggers the decomposition of FeCO into CO, realizing the effective combination of CDT and CDGT. The co-released ROS and CO do damage to DNA and mitochondria of various cancer cells, respectively. The mitochondrial damage can effectively cut off the ATP source required for DNA repair, causing a synergetic anti-cancer effect in vitro and in vivo., Conclusions: The combination of CDT and CDGT causing a synergetic anti-cancer effect in vitro and in vivo. The proposed therapy concept and nanomedicine designing strategy might open a new window for engineering high-performance anti-cancer nanomedicine.

Mesoporous silica nanoparticles functionalized with peptides are developed for sequential drug delivery. The RGD peptide is used for vasculature/cell membrane targeting and the TAT peptide for nuclear targeting. Using this delivery strategy, a tumor in a murine xenograft model is successfully regressed., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

To achieve the accurate diagnosis and efficient in situ therapy of malignant tumors is encouraging but still remains a big challenge. The integration of upconversion nanoparticles and mesoporous silica that can combine the diagnostic/therapeutic functions within a single platform, may provide a more advanced way for the efficient theranostics of cancer. In this study, sub-80 nm rattle-structured multifunctional Gd-UCNPs core/mesoporous silica shell nanotheranostics (UCMSNs) were successfully constructed for the co-delivery of a radio-/photo-sensitizer hematoporphyrin (HP) and a radiosensitizer/chemodrug docetaxel (Dtxl). Upon NIR excitation and X-ray irradiation, the complete tumor elimination has been achieved by the synergetic chemo-/radio-/photodynamic tri-modal therapy under the assistance of simultaneous magnetic/upconversion luminescent (MR/UCL) bimodal imaging. To the best of our knowledge, this study is the first example of achieving tri-modal synergetic therapy in one single nanotheranostic system, and we anticipate that it may serve as a particularly useful platform for the clinical diagnosis and efficient treatment of cancer from bench to beside., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Mesoporous silica nanoparticles (MSNs), as one of the most promising inorganic drug carriers, have attracted ever increasing attention due to their unique structural, physicochemical, and biochemical features. Drug delivery systems (DDSs) based on MSNs could easily escape from endosomes after endocytosis and protect the loaded drugs from bioerosion by stable MSN carriers, efficiently deliver drugs intracellularly in a sustained release way, and consequently kill cancer cells at enhanced efficacy. However, the underlying pathways and mechanisms of cancer cell death induced by MSN-mediated drug delivery have not been well explored. In this study, we introduce gene expression analyses to evaluate the pathways and mechanisms of cancer cell death induced by a MSN-based drug delivery system. Unique changes in gene expressions and gene ontology terms, which were caused only by the MSN-based DDS (DOX-loaded MSNs, DOX@MSNs) but not by free drug doxorubicin (DOX) and/or the carrier MSNs, were discovered and proposed to be responsible for the varied cell death mechanisms, including the greatly enhanced necrosis due to amplified oxidative stress and the apoptosis related with DNA/RNA synthesis and cell cycle inhibitions. By virtue of a certain kind of synergetic biological effect between the drug and the carrier, the DOX@MSNs DDS was found capable of increasing the intracellular levels of reactive oxygen species and triggering the mitochondria-related autophagic lysosome pathway, consequently activating a specific pathway of necrosis, which is different from those by the free drug and the carrier.

In the anti-cancer war, there are three main obstacles resulting in high mortality and recurrence rate of cancers: the severe toxic side effect of anti-cancer drugs to normal tissues due to the lack of tumor-selectivity, the multi-drug resistance (MDR) to free chemotherapeutic drugs and the deadly metastases of cancer cells. The development of state-of-art nanomedicines based on mesoporous silica nanoparticles (MSNs) is expected to overcome the above three main obstacles. In the view of the fast development of anti-cancer strategy, this review highlights the most recent advances of MSN anti-cancer nanomedicines in enhancing chemotherapeutic efficacy, overcoming the MDR and inhibiting metastasis. Furthermore, we give an outlook of the future development of MSNs-based anti-cancer nanomedicines, and propose several innovative and forward-looking anti-cancer strategies, including tumor tissue-cell-nuclear successionally targeted drug delivery strategy, tumor cell-selective nuclear-targeted drug delivery strategy, multi-targeting and multi-drug strategy, chemo-/radio-/photodynamic-/ultrasound-/thermo-combined multi-modal therapy by virtue of functionalized hollow/rattle-structured MSNs., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The development of multidrug resistance (MDR) in cancer cells is one of major obstacles to the effective cancer chemotherapy. In this report we demonstrate the effective circumvention of multidrug resistance in cancer cells by an active nuclear-targeted drug delivery system that was constructed by conjugating TAT peptide onto the surface of mesoporous silica nanoparticles (MSNs-TAT). The conjugation of TAT peptide facilitated the intranuclear localization of MSNs-TAT and the release of the encapsulated drugs directly within the nucleoplasm. The direct intranuclear drug delivery of doxorubicin (DOX) in multidrug resistant MCF-7/ADR cancer cells was capable of increasing the intracellular as well as intranuclear drug concentrations much more effectively than free DOX or delivered by MSNs in the absence of TAT peptide. With the nuclear drug delivery fashion, DOX-MSNs-TAT presents a promising strategy in overcoming MDR in cancer cells and improving the therapeutic index of currently available chemotherapeutics by enhancing therapeutic efficacy and reducing side effects., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A hierarchical theranostic nanostructure with carbon and Si nanocrystals respectively encapsulated in the mesopores and within the framework of mesoporous silica nanoparticles (CS-MSNs) was constructed by a bottom-up self-assembly strategy combining an in situ one-step carbonization/crystallization approach. CS-MSNs exhibited narrow size distribution, high payload of insoluble drugs and unique NIR-to-Vis luminescence imaging feature. The bio-conjugated CS-MSNs with a PEGylated phospholipid compound and hyaluronic acid showed excellent dispersivity and could specifically target cancer cells overexpressing CD44, deliver insoluble drugs into these cells and consequently kill them effectively, and also fluorescently image them simultaneously in a unique and attractive NIR-to-Vis luminescence imaging fashion, providing a promising opportunity for cancer theranostics., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Most present nanodrug delivery systems have been developed to target cancer cells but rarely nuclei. However, nuclear-targeted drug delivery is expected to kill cancer cells more directly and efficiently. In this work, TAT peptide has been employed to conjugate onto mesoporous silica nanoparticles (MSNs-TAT) with high payload for nuclear-targeted drug delivery for the first time. Monodispersed MSNs-TAT of varied particle sizes have been synthesized to investigate the effects of particle size and TAT conjugation on the nuclear membrane penetrability of MSNs. MSNs-TAT with a diameter of 50 nm or smaller can efficiently target the nucleus and deliver the active anticancer drug doxorubicin (DOX) into the targeted nucleus, killing these cancer cells with much enhanced efficiencies. This study may provide an effective strategy for the design and development of cell-nuclear-targeted drug delivery.

The extremely low longitudinal relaxivity (r(1)) of manganese oxide has severely impeded their substitution for cytotoxic gadolinium-based contrast agents for safe clinical magnetic resonance imaging (MRI). Here, we report on a synthetic strategy of chemical oxidation/reduction reaction in-situ in mesopores, followed by hydrogen reduction, for the fabrication of non-toxic manganese oxide/MSNs-based MRI-T(1) contrast agents with highly comparable imaging performance to commercial Gd-based agents. This strategy involves a "soft-templating" process to prepare mesoporous silica nanoparticles, in-situ reduction of MnO(4)(-) by the "soft templates" in mesopores and heat treatment under reducing atmosphere, to disperse manganese oxide nanoparticles within mesopores. This special nanostructure combines the merits of nanopores for maximum manganese paramagnetic center accessibility for water molecules for enhanced MRI performance and encapsulation/sustained release/intracellular delivery of drugs. The synthesized manganese oxide/MSNs were successfully assessed as a high performance contrast agent for MRI-T(1) both in intro and in vivo, and meanwhile, was also demonstrated as an effective anti-cancer drug delivery (doxorubicin) vehicle, therefore, a family of manganese-based theranostics was successfully demonstrated based on the manganese oxide/MSNs composite., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The effective modulation of pore sizes for nanoporous silica nanoparticles still remains a great challenge not satisfactorily solved. In this paper, the pore sizes in the shell of hollow silica nanocapsules are well-tuned by a reversible Si-O bond breakage and reformation process under mildly alkaline conditions (e.g., Na(2) CO(3) solution). The pores in nanosized hollow silica capsules can be modulated from 3.2 nm to larger than 10 nm by a novel, surfactant-directing alkaline-etching (SDAE) strategy. Interestingly, the pores can be fully filled through the regrowth of the dissoluted silicates by bonding to silanols (Si-OH) on the wall surface to generate the nonporous hollow silica nanocapsules. The large-sized pore hollow silica nanocapsules exhibit excellent siRNA-loading capabilities and intracellular transfection efficiencies in vitro. In addition, the large pores in the shell of hollow silica nanocapsules are explored as channels for collecting superparamagnetic, small-sized Fe(3) O(4) nanoparticles as contrast agents for magnetic resonance imaging, initiating a special approach towards pore-size modulation and multifunctionalization of silica-based nanostructural materials for nanobiomedical applications., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Multidrug resistance (MDR) is one of the major obstacles for successful chemotherapy in cancer. One of the effective approaches to overcome MDR is to use nanoparticle-mediated drug delivery to increase drug accumulation in drug resistant cancer cells. In this work, we first report that the performance and mechanism of an inorganic engineered delivery system based on mesoporous silica nanoparticles (MSNs) loading doxorubicin (DMNs) to overcome the MDR of MCF-7/ADR (a DOX-resistant and P-glycoprotein (P-gp) over-expression cancer cell line). The experimental results showed that DMNs could enhance the cellular uptake of doxorubicin (DOX) and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells. The IC(50) of DMNs against MCF-7/ADR cells was 8-fold lower than that of free DOX. However, an improved effect of DOX in DMNs against MCF-7 cells (a DOX-sensitive cancer cell line) was not found. The increased cellular uptake and nuclear accumulation of DOX delivered by DMNs in MCF-7/ADR cells was confirmed by confocal laser scanning microscopy, and could result from the down-regulation of P-gp and bypassing the efflux action by MSNs themselves. The cellular uptake mechanism of DMNs indicated that the macropinocytosis was one of the pathways for the uptake of DMNs by MCF-7/ADR cells. The in vivo biodistribution showed that DMNs induced a higher accumulation of DOX in drug resistant tumors than free DOX. These results suggested that MSNs could be an effective delivery system to overcome multidrug resistance.

A type of pH-responsive nano multi-drug delivery systems (nano-MDDSs) with uniform particle size (100 ± 13 nm) and excellent monodispersity was developed by in situ co-self-assembly among water-insoluble anti-cancer drug (doxorubicin, DOX), surfactant micelles (CTAB) as chemosensitiver and silicon species forming drugs/surfactant micelles-co-loaded mesoporous silica nanoparticles (drugs@micelles@MSNs or DOX@CTAB@MSNs) via a micelles-MSNs self-assembly mechanism. The nano-MDDS DOX@CTAB@MSNs had a highly precise pH-responsive drug release behavior both in vitro and in vivo, and exhibited high drug efficiencies against drug-resistant MCF-7/ADR cells as well as drug-sensitive MCF-7 cells by the MSNs-mediated transmembrane delivery, the sustained drug release and the high anti-cancer and multi-drug resistance (MDR)-overcoming efficiencies. The MDR-overcoming mechanism was proved to be a synergistic cell cycle arrest/apoptosis-inducing effect resulted from the chemosensitization of the surfactant CTAB. These results demonstrated a very promising nano-MDDS for the pH-responsive controlled drug release and the cancer MDR overcoming., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A novel glucose-responsive controlled release of insulin system is constructed through coating enzyme multilayers on mesoporous silica particles (MSPs). The MSPs serve as the drug reservoir, and the enzyme multilayers cross-linked with glutaraldehyde act as a valve to control the release of insulin in response to the external glucose level., (This journal is © The Royal Society of Chemistry 2011)

Oxygen-deficient luminescent mesoporous silica nanoparticles with uniform morphology/size and integrated mesoporosity-luminescent property in a single nanoparticle are successfully synthesized by a bottom-up self-assembly route followed by a post-calcination process, and can be used to facilely load/deliver drugs into cells and luminescently image cells.

A composite scaffold drug delivery system (CS-DDS) for osteoarticular tuberculosis therapy has been prepared by loading bi-component drugs into a mesoporous silica nanoparticles (MSNs)-coated porous β-TCP scaffold, which was followed by an additional bioactive glass coating. Such a CS-DDS showed high performances in the local and extremely sustained delivery of the bi-component antitubercular drugs and excellent biocompatibility. N(2) sorption isotherms indicated greatly increased surface area of the composites compared to pure β-TCP scaffold, and the mesopores were around 2.6 nm which were large enough to encapsulate drugs such as isoniazide and rifampicin. The in vitro and in vivo release tests demonstrated extra sustained co-release profiles of rifampicin and isoniazide from such a CS-DDS, and both drug concentrations kept higher than their effective values to kill mycobacterium tuberculosis for as long as 42 days. The hepatic and renal function tests indicated that the CS-DDS had neglectable long-term lesions to liver and kidney., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The in vivo biodistribution and urinary excretion of spherical mesoporous silica nanoparticles (MSNs) are evaluated by tail-vein injection in ICR mice, and the effects of the particle size and PEGylation are investigated. The results indicate that both MSNs and PEGylated MSNs of different particle sizes (80-360 nm) distribute mainly in the liver and spleen, a minority of them in the lungs, and a few in the kidney and heart. The PEGylated MSNs of smaller particle size escape more easily from capture by liver, spleen, and lung tissues, possess longer blood-circulation lifetime, and are more slowly biodegraded and correspondingly have a lower excreted amount of degradation products in the urine. Neither MSNs nor PEGylated MSNs cause tissue toxicity after 1 month in vivo., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Three types of surfactant-templated mesoporous silica nanoparticles (Surf@MSNs) of 150-660 nm in diameter were developed as anticancer drug delivery systems. The Surf@MSNs exhibit the high drug (surfactant) loading capacities, the sustained drug (surfactant) release profiles and the high and long-term anticancer efficacy. The effects of the Surf@MSNs concentration, the type of the contained surfactants and the incubation time on the cytotoxicity and proliferative activity of MCF-7 cells were evaluated. A common anticancer drug CPT-11 was also loaded into surfactant-free MSNs (CPT@MSNs) and used as a reference for estimating the anticancer efficacies of Surf@MSNs. Surfactant-extracted MSNs exhibited neglectable cytotoxicity to MCF-7 cell, and free surfactants exhibited higher cytotoxicity than free CPT-11 at the same concentration. The endocytosis enhanced the drug uptake by MCF-7 cells and the anticancer efficacies of Surf@MSNs and CPT@MSNs, and more surfactants would be released in a longer term, which led to the more significant enhancement of the cytotoxicity, than CPT-11 with the process of incubation. Among the investigated Surf@MSNs, CTAB-contained MSNs (CTAB@MSNs) show remarkably higher long-term anticancer efficacy than CPT-11-loaded surfactant-free MSNs (CPT@MSNs), even at very low concentrations of 2-15 microg mL(-1)., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Highly ordered MCM-41-type mesoporous silica nanoparticles (MSNs) with particle sizes of 150 +/- 20 nm were prepared and PEGylated by covalently grafting PEGxk chains of different molecular weights (x = 4, 6, 10, 20) and chain densities (0.05 wt%-3.75 wt%) on the outer surface. The influence of molecular weights and chain densities of PEGxk on the nonspecific binding of PEGylated MSNs to human serum protein (HSA) was investigated. The results revealed that the optimal molecular weights should be not less than 10k, and the corresponding optimal chain densities for PEG10k-MSNs and PEG20k-MSNs were 0.75 wt% and 0.075 wt%, respectively, and the resultant minimum HSA adsorbance (2.5%) on PEGxk-MSNs was far less than that on MSNs (18.7%) without PEGylation. Under the optimal conditions for the minimum HSA adsorbance, the phagocytosis of human THP-1 monocytic leukemia cell line-derived macrophages (THP-1 macrophages) and the hemolysis of human red blood cells (HRBCs) were investigated with MSNs and PEGylated MSNs. A minimum THP-1 phagocytosis percentage (0.1%) and a very low HRBCs hemolysis percentage (0.9%) of PEG10k-MSNs were obtained, which were much lower than those (8.6% and 14.2%, respectively) of MSNs., ((c) 2009 Elsevier Ltd. All rights reserved.)

This work evaluates the cytotoxicity of spherical mesoporous silica (MS) nano- and microparticles and investigates the effects of particle size, concentration, biodegradation products of MS, residual surfactant, and surfactant removal by extraction and calcination on the cytotoxicity. The results from the intracellular localization of spherical MS nano- and microparticles with different sizes reveal the mechanism for their cytotoxicity and that the smaller particles in nanoscale are more easily endocytosed and consequently located within lysosomes.