Mesoporous Organosilica Research Articles

Synthesis of dithioglycol-functionalized periodic mesoporous organosilicas for the simultaneous removal of mercury ions and organic dyes from water

Synthesis of PMOs containing thiol and thioether groups for simultaneous removal of Hg(ii) and RhB from simulated sewage is reported.

Controlling the optical properties of chiral nematic mesoporous organosilica films with bioadditives.

Chiral nematic mesoporous organosilica (CNMO) films have unique iridescent properties that make them attractive candidates for decorations, sensing and photonics. However, it has proven difficult to control the colour and porosity of CNMO films. Here, we have explored the addition of a range of biodegradable and eco-friendly additives to tune the helical pitch and, hence, the colour of the CNMO materials. It was found that the controlled integration of additives allows for the colour of the materials to be tuned across the visible spectrum, but cannot be used to tune the porosity of the films. This work opens up new prospects for preparation of CNMO materials with adjustable optical properties.

Super-assembled periodic mesoporous organosilica membranes with hierarchical channels for efficient glutathione sensing.

Bioinspired nanochannel-based sensors have elicited significant interest because of their excellent sensing performance, and robust mechanical and tunable chemical properties. However, the existing designs face limitations due to material constraints, which hamper broader application possibilities. Herein, a heteromembrane system composed of a periodic mesoporous organosilica (PMO) layer with three-dimensional (3D) network nanochannels is constructed for glutathione (GSH) detection. The unique hierarchical pore architecture provides a large surface area, abundant reaction sites and plentiful interconnected pathways for rapid ionic transport, contributing to efficient and sensitive detection. Moreover, the thioether groups in nanochannels can be selectively cleaved by GSH to generate hydrophilic thiol groups. Benefiting from the increased hydrophilic surface, the proposed sensor achieves efficient GSH detection with a detection limit of 1.2 μM by monitoring the transmembrane ionic current and shows good recovery ranges in fetal bovine serum sample detection. This work paves an avenue for designing and fabricating nanofluidic sensing systems for practical and biosensing applications.

Acetylacetone functionalized periodic mesoporous organosilicas: from sensing to catalysis

“acac-PMO” with the acac-functionality intact and embedded in the organic environment of the linker.

Controllable synthesis of hollow mesoporous organosilica nanoparticles with pyridine-2,6-bis-imidazolium frameworks for CO2 conversion.

A series of hard-template-derived hollow mesoporous organosilica nanoparticles (HMONs) with pyridine-2,6-bis-imidazolium frameworks have been described for the first time. As a part of the investigation, to evaluate the effects of the hard template nature, the Si/CTAB and organosilica/TEOS molar ratios, and the stepwise addition of precursors, four reaction conditions denoted as methods A-D were designed. In the presence of polystyrene latex as a hard template, the HMONs that we wished to synthesize were not yielded with a Si/CTAB molar ratio of 3 (method A), but we could synthesize the desired HMONs with a Si/CTAB molar ratio of 9 and an organosilica : TEOS ratio of 1 : 99 (method B). The ratio of organosilica to TEOS could be improved up to 2.5 : 97.5 if the precursor additions are made in a stepwise manner rather than by simultaneous additions (method C). Using sSiO2 as a hard template, a yolk-shell morphology was observed by adopting a Si/CTAB molar ratio of 3 (method D). The HMONs were modified by iodide ions and their activity was explored toward the coupling of CO2 with epoxides. Among the catalysts, I-HMON-L-C-2.5 exhibited excellent results under mild reaction conditions. Well-oriented pore sizes and short channel length facilitated easy mass transfer from one side and the integration of the interior hollow regions of the catalyst particles from the other side improved the CO2 retention time around pores where the imidazolium organocatalysts were located, which made I-HMON-L-C-2.5 an effective catalyst for title CO2 utilization. The catalyst was reused at least six times without exhibiting any changes in its activity. HMONs can also be used as solid CNC ligands for the preparation of copper catalysts for the click reaction between phenyl acetylene and benzyl azide.

Inhibition of thioredoxin reductase and upregulation of apoptosis genes for effective anti-tumor sono-chemotherapy using a meso-organosilica nanomedicine.

The thioredoxin system is involved in cancer development and therefore is a promising target for cancer chemotherapy. Thioredoxin reductase (TrxR) is a key component of the thioredoxin (Trx) system, and is overexpressed in many cancers to inhibit apoptosis-related proteins. Alternatively, inhibition of thioredoxin reductase and upregulation of apoptosis factors provide a therapeutic strategy for anti-tumor treatment. In this study, an ultrasound-activatable meso-organosilica nanomedicine was prepared by integrating chloroquine (CQ) into hollow mesoporous organosilica (CQ@MOS). The meso-organosilica nanomedicine can inhibit the activity of thioredoxin reductase, elevate cellular reactive oxygen species (ROS) levels, upregulate the pro-apoptotic factors in the c-Jun N-terminal kinase (JNK) apoptosis pathway and induce autophagy inhibition, further resulting in mitochondrial membrane potential (MMP) depolarization and cellular ATP content decrease, ultimately causing significant damage to tumor cells. Moreover, CQ@MOS can efficiently deliver chloroquine into cancer cells and promote an enhanced sonodynamic effect for effective anti-tumor chemotherapy and sonodynamic therapy. This study may enlighten us on a new anti-tumor strategy and suggest its promising applications in cancer treatments.

Glutathione depletion based Pt(IV) hybrid mesoporous organosilica delivery system to conquer cisplatin chemoresistance: A “one stone three birds” strategy

The occurrence of acquired resistance to cisplatin (DDP) that induces the toxic drug effects has always been a huge challenge and urgently needs to be resolved in the cancer treatment. The combination of anticancer drugs with different mechanisms can remarkably improve the chemotherapeutic efficiency. Given that glutathione (GSH) plays as the driving factors in the resistance of DDP, here we have firstly proposed a “three birds, one stone” based nanoplatform to achieve triple synergetic effects simultaneously addressing DDP resistance in non-small cell lung cancer (NSCLC). Specifically, we initially designed and synthesized a DDP prodrug [Pt(IV)] bridged silsesquioxane precursor (Pt-Si). Then Pt-Si and bis[3-(triethoxysilyl)propyl]diselenide (BTESePD) were integrated into the framework of mesoporous organosilica nanoparticles (MONs) to obtain a nanocarrier MONPt/Se. After loading with norcantharidin (NCTD) and modifying with the aptamer AS1411 based G-quadruplex (Apt), the Apt@NCTD@MONPt/Se exhibit impressive tumor homing capability. Once being endocytosed, (I) the diselenide and -O-Pt(IV)-O- rich scaffold can be reduced by the excessive GSH, followed by (II) breaking the redox homeostasis via GSH depletion and precise release of the DDP. Next, the encapsulated NCTD is also released along with the degradation of the nanocarriers thereby (III) achieving the GSH depletion and synergistic anti-tumor effect of NCTD and DDP. Taken together, we believe this “one stone, three birds” strategy may be a promising paradigm to conquer drug resistance for clinical care.

PH responsive curcumin released from urea-amine group functionalized mesoporous organosilica nanoparticles.

Studies on natural products with anticancer properties have gained more importance in recent years in order to not damage healthy tissues during cancer treatments or to perform the treatment causing the least damage. Curcumin is a common natural product with anticancer properties, but its low solubility, instability, and bioavailability have limited its use in clinical applications in cancer research. As a proposed solution to this problem, a new mesoporous organosilica nanocarrier (MON-A) functionalized with a 1,2-diphenylethane-1,2-diamine structure capable of pH-controlled release was prepared in this study. MON-A was characterized by TGA, BET, XRD, FT-IR, and SEM-EDS analyses. Dispersion of MON-A into curcumin stock solution in ethanol afforded a curcumin-loaded MON-A-Cur system. Elevated loading capacity and pH-controlled release were provided by the Schiff base reaction that occurred during loading of curcumin with 1,2-diphenylethane-1,2-diamine placed on the silica wall of the nanocarrier system. The encapsulation efficiency was 25% for MON-A-Cur. In in vitro release experiments, curcumin release from the MON-A-Cur system was 0.5% at physiological and endosomal pH values. The resulting low release percentage indicates the presence of very strong interactions between the nanocarrier MON-A and curcumin. This strong interaction showed that MON-A nanocarrier could carry 99.5% of the curcumin without leakage under physiological and endosomal pH conditions without using pore capping agents. At a lower acidic pH value (pH 4.5), 26.3% curcumin release was obtained. These findings showed that the cumulative release of curcumin from the MON-A-Cur system can be achieved in a long-term and pH-controlled manner.

Nickel Supported on Mesoporous Organosilica Nanoparticles Incorporating Pyridine-Based SNS Ligand as an Efficient Recoverable Catalyst for Chemical Fixation of CO2

Nickel Supported on Mesoporous Organosilica Nanoparticles Incorporating Pyridine-Based SNS Ligand as an Efficient Recoverable Catalyst for Chemical Fixation of CO₂

Glutathione-Responsive Organosilica Hybrid Nanosystems for Targeted Dual-Starvation Therapy in Luminal Breast Cancer.

Starvation therapy is an innovative approach in cancer treatment aimed at depriving cancer cells of necessary resources by impeding tumor angiogenesis or blocking the energy supply. In addition to the commonly observed anaerobic glycolysis energy supply mode, adipocyte-rich tumor tissue triggers the fatty acid energy supply pathway, which fuels the proliferation and metastasis of cancer cells. To completely disrupt these dual-energy-supply pathways, we developed an exceptional nanoreactor. This nanoreactor consisted of yolk-shell mesoporous organosilica nanoparticles (YSMONs) loaded with a fatty acid transport inhibitor (Dox), conjugated with a luminal breast-cancer-specific targeting aptamer, and integrated with a glucose oxidation catalyst (GOx). Upon reaching cancer cells with the assistance of the aptamer, the nanoreactor underwent a structural collapse of the shell triggered by the high concentration of glutathione within cancer cells. This collapse led to the release of GOx and Dox, achieving targeted delivery and exhibiting significant efficacy in starving therapy. Additionally, the byproducts of glucose metabolism, gluconic acid and H2O2, enhanced the acidity and reactive oxygen species levels of the intracellular microenvironment, inducing oxidative damage to cancer cells. Simultaneously, released Dox acted as a potent broad-spectrum anticancer drug, inhibiting the activity of carnitine palmitoyltransferase 1A and exerting marked effects. Combining these effects ensures high anticancer efficiency, and the "dual-starvation" nanoreactor has the potential to establish a novel synergistic therapy paradigm with considerable clinical significance. Furthermore, this approach minimizes damage to normal organs, making it highly valuable in the field of cancer treatment.

Nanopore surface engineering of molecular imprinted mesoporous organosilica for rapid and selective detection of L-thyroxine

To develop a biosensing platform for precise diagnosis and management of thyroid-related diseases, the sensitive and selective recognition and identification of L-thyroxine (T4), a thyroid hormone, remains challenging. We herein introduce T4-imprinted mesoporous organosilica (T4-IMO) for sensitive and specific detection of T4 via the sophisticated engineering of pore surfaces using additives with different polarities. The pore surface of T4-IMO emitting a stable fluorescence signal is simply modified by fixed additives. Additives embedded in the pore surface promote the rebinding response of T4 into the recognized cavities, subsequently sensitizing T4 detection. Notably, T4-IMO containing abundant fluorine elements on the pore surface shows a high affinity toward T4, remarkably boosting the rebinding capacity. In addition to good selectivity to T4, the “turn-off” fluorescent signal exhibits a linear relationship with the logarithm of T4 concentration in a range of 0–500nM with a detection limit of 0.47nM in synthetic urine samples. Our findings can establish an insightful strategy for the rational design of molecular-recognition-based sensor systems for the selective and sensitive detection of target analytes.

Suzuki-Miyaura Cross-Coupling Reaction Using Palladium Catalysts Supported on Phosphine Periodic Mesoporous Organosilica.

Phosphine periodic mesoporous organosilicas (R-P-PMO-TMS: R=Ph, tBu), which possess electron-donating alkyl substituents on the phosphorus atom, were synthesized using bifunctional compounds with alkoxysilyl- and phosphino groups, bis[3-(triethoxysilyl)propyl]phenylphosphine borane (1 a) and bis[3-(triethoxysilyl)propyl]-tert-butylphosphine borane (1 b). Immobilization of Pd(0) species was performed to give R-P-Pd-PMO-TMS: R=Ph (2 a), tBu (3 a), respectively. The Pd(0) immobilized 2 a and 3 a were applicable as catalysts for Suzuki-Miyaura cross-coupling reactions of aryl chlorides with phenylboronic acid. It was revealed that 3 a bearing more electron-donating tBu groups exhibited higher catalytic activity. Various functional groups including both electron withdrawing and donating substituents were compatible in the system. The recyclability of 3 a was examined to support its moderate utility for the recycle use.

Redox/Near-Infrared Dual-Responsive Hollow Mesoporous Organosilica Nanoparticles for Pesticide Smart Delivery.

Extremely inefficient utilization of pesticides has prompted a study of low-cost, sustainable, and smart application systems. Herein, as a promising pesticide nanocarrier, hollow mesoporous organosilica nanoparticles (HMONs) were first synthesized by using inexpensive CaCO3 nanoparticles as the hollow templates. A redox/near-infrared light dual-triggered pesticide release system was further achieved via loading avermectin (AVM) into the HMONs and coating a layer of polydopamine (PDA). The as-prepared AVM@HMONs@PDA displays a favorable pesticide load capability (24.8 wt %), outstanding photothermal performance, and high adhesion to leaves. In addition, with glutathione (GSH), the AVM cumulative release from AVM@HMONs@PDA was 3.5 times higher than that without GSH. Under ultraviolet light irradiation, the half-life of AVM@HMONs@PDA was prolonged by 17.0-fold compared to that of the AVM technical. At day 21 after treatment in the insecticidal activity, the median lethal concentrations (LC50) values displayed that the toxicity of AVM@HMONs@PDA for Panonychus citri (McGregor) was enhanced 4.0-fold compared with the commercial emulsifiable concentrate. In the field trial, at day 28 after spraying, AVM@HMONs@PDA was significantly more control effective than AVM-EC in controlling the P. citri (McGregor), even at a 50% reduced dosage. Moreover, HMONs@PDA was safe for crops. This research presents a novel preparation approach for HMONs, and it also offers a promising nanoplatform for the precise release of pesticides.

Asymmetric Monolayer Mesoporous Nanosheets of Regularly Arranged Semi-Opened Pores via a Dual-Emulsion-Directed Micelle Assembly.

Constructing asymmetric two-dimensional (2D) mesoporous nanomaterials with new pore structure, tunable monolayer architectures, and especially anisotropic surfaces remains a great challenge in materials science. Here, we report a dual-emulsion directed micelle assembly approach to fabricate a novel type of asymmetric monolayer mesoporous organosilica nanosheet for the first time. In this asymmetric 2D structure, numerous quasi-spherical semiopened mesopores (∼20 nm in diameter, 24 nm in opening size) were regularly arranged on a plane, endowing the porous nanosheets (several micrometers in size) with a typical surface anisotropy on two sides. Meanwhile, lots of triangular intervoids (4.0-5.0 nm in size) can also be found among each three semiopened mesopores, enabling the nanosheet to be interconnected. Vitally, such interconnected, anisotropic porous nanosheets exhibit ultrahigh accessible surface area (∼714 m2 g-1) and good lipophilicity properties owing to the abundant semiopened mesopores. Additionally, besides the nanosheet, the configuration of the asymmetric porous structure can also be transformed into a microcapsule when controlling the emulsification size via a facile ultrasonic treatment. As a demonstration, we show that the asymmetric microcapsule shows a high demulsification efficiency (>98%) and cyclic stability (>6 recycle times). Our protocol opens up a new avenue for developing next-generation asymmetric mesoporous materials for various applications.

Amine-bridged periodic mesoporous organosilica adsorbents for CO2 capture

Novel periodic mesoporous organosilica (PMOs) were synthesized using different commercial non-aminated and aminated bisilanes in order to incorporate aminated sites within the silica walls. Three different commercial bisilanes were employed: i)without amine groups, ii)with one amine group, and iii)with two amine groups. Moreover, materials were prepared with different molar ratios of non-aminated and aminated bisilanes. P123 was used as structure directing agent for the mesoporosity. The amino functional groups of the PMOs so prepared were incorporated within the silica walls of the obtained solid particles. Moreover, for comparative purposes, BEBA-0, that is a non-aminated PMO, was functionalized via grafting with N1-(3-trimethoxysilylpropyl)diethylenetriamine (DT) and impregnation with polyethyleneimine (PEI) to produce amino functionalized materials. All these materials were tested for CO2 capture through CO2 adsorption/desorption isotherms and TGA studies. It was observed that increasing the concentration of amine containing bisilane increased the CO2 capture capacity significantly from 21.4 mg/g to 47.3 mg/g. The PMO synthesized with the bisilane containing two amine groups had higher CO2 uptake than the one containing one amine group from 47.3 to 62.6 mg/g due to the presence of more functional groups in the final material (6.0 versus 9.4% wt N, respectively). The cyclic capacity of the adsorbents via a series of adsorption/desorption tests has also been determined, the results showing the low reactivity decay (less than 3%) of the novel PMOs and materials prepared by grafting during the first 10 cycles, when compared with the 13% of PEI-impregnated material.

One-step synthesis of hollow and yolk-shell mesoporous organosilica nanospheres for efficient separation of lead ions

In this work, we demonstrate that monodispersed hollow mesoporous organosilica nanospheres (MONs) and yolk-shell MONs possessing controlled core cavity and mesoporous shell is successfully synthesized through a one-pot approach, which involves co-condensation of 3-aminopropyltriethoxysilane and 1,2-bis(triethoxysilyl)ethane templated by lauryl sulfonate betaine and sodium dodecyl benzenesulfonate. The MONs present an open mesoporosity, hollow cavity with a morphology tailored by the various core templates, and high surface area (328 m2/g). In addition, the composition of the hollow MONs could be further tuned through the same approach. The as-prepared hollow MONs as adsorbent deliver an enormous adsorption capacity (414 mg/g) towards the removal of Pb2+ from water solution. Importantly, the prepared hollow MONs present acceptable recycling and stability, since the performance in Pb2+ removal from water remains above 80 % even after 5 consecutive cycles. The adsorption of Pb2+ on hollow MONs follows the pseudo-second-order mechanics and Langmuir isotherm models. The results confirm hollow MONs exhibit considerable promise for the remarkably efficient separation of Pb2+ ions in water solution.

Dual Delivery of Tetramethylpyrazine and miR-194-5p Using Soft Mesoporous Organosilica Nanoparticles for Acute Lung Injury Therapy.

The respiratory system is intensely damaged by acute lung injury (ALI). The anti-inflammatory effects of tetramethylpyrazine (TMP) against ALI have been confirmed, but it exhibits a short half-life. miR-194-5p could directly target Rac1, but the internalization rate of miRNA cells was low. To explore the potential of the soft mesoporous organic silica nanoplatform (NPs) as carriers for delivery of TMP and miR-194-5p through the tail vein. NPs@TMP and NPs@PEI@miR-194-5p were added to the HUVEC cell-lines, in vitro, to observe the cell uptake and cytotoxic effects. In vivo experiments were conducted by injecting fluorescently labeled NPs through the tail vein and tracking distribution. Therapeutic and toxic side-effects were analyzed systemically. In vitro study exhibited that NPs have no toxic effect on HUVECs within the experimental parameters and have excellent cellular uptake. The IVIS Spectrum Imaging System shows that NPs accumulate mainly in the lungs. NPs@TMP treatment can improved oxidative stress and inflammation levels in ALI mice and inhibited the TLR4/NLRP3/caspase 1 pathway. NPs@PEI@miR-194-5p can inhibit the Rac1/ZO-1/occludin pathway and improved endothelial cell permeability in ALI mice. The co-treatment of NPs@TMP and NPs@PEI@miR-194-5p can significantly improved the survival rates of the mice, reduced pulmonary capillary permeability and improved pathological injury in ALI mice. This study combined traditional Chinese medicine, bioinformatics, cellular molecular biology and nanobiomedicine to study the pathogenesis and treatment of ALI. The rate of cellular internalization was improved by changing the shape and hardness of nanoparticles. NPs@TMP and NPs@PEI@miR-194-5p combined application can significantly improve the survival condition and pathological injury of mice. NPs loaded with TMP and miR-194-5p showed a greater therapeutic effect in ALI mice.

Tumor microenvironment-responsive DNA-based nanomedicine triggers innate sensing for enhanced immunotherapy

Lack of proper innate sensing inside the tumor microenvironment could reduce both innate and adaptive immunity, which remains a critical cause of immunotherapy failure in various tumor treatments. Double-stranded DNA (dsDNA) has been evidenced to be a promising immunostimulatory agent to induce type I interferons (IFN-Is) production for innate immunity activation through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, yet the unsatisfactory delivery and susceptibility to nuclease degradation hindered its feasibility for further clinical applications. Herein, we report on the constructed tumor microenvironment-responsive DNA-based nanomedicine loaded by dendritic mesoporous organosilica nanoparticles (DMONs), which provide efficient delivery of dsDNA to induce intratumoral IFN-Is production for triggering innate sensing for enhanced anti-tumor immunotherapy. Extensive in vitro and in vivo evaluations have demonstrated the dramatic IFN-Is production induced by dsDNA@DMONs in both immune cells and tumor cells, which facilitates dendritic cells (DCs) maturation and T cells activation for eliciting the potent innate immune and adaptive immune responses. Desirable biosafety and marked therapeutic efficacy with a tumor growth inhibition (TGI) of 51.0% on the murine B16-F10 melanoma model were achieved by the single agent dsDNA@DMONs. Moreover, dsDNA@DMONs combined with anti-PD-L1 antibody further enhanced the anti-tumor efficacy and led to almost complete tumor regression. Therefore, this work highlighted the immunostimulatory DNA-based nanomedicine as a promising strategy for overcoming the resistance to immunotherapy, by promoting the IFN-Is production for innate immunity activation and remodeling the tumor microenvironment.Graphical abstract

GSH-Triggered/Photothermal-Enhanced H2S Signaling Molecule Release for Gas Therapy.

Traditional treatment methods for tumors are inefficient and have severe side effects. At present, new therapeutic methods such as phototherapy, chemodynamic therapy, and gasodynamic therapy have been innovatively developed. High concentrations of hydrogen sulfide (H2S) gas exhibit cancer-suppressive effects. Herein, a Prussian blue-loaded tetra-sulfide modified dendritic mesoporous organosilica (PB@DMOS) was rationally constructed with glutathione (GSH)-triggered/photothermal-enhanced H2S signaling molecule release properties for gas therapy. The as-synthesized nanoplatform confined PB nanoparticles in the mesoporous structure of organosilica silica due to electrostatic adsorption. In the case of a GSH overexpressed tumor microenvironment, H2S gas was controllably released. And the temperature increases due to the photothermal effects of PB nanoparticles, further enhancing H2S release. At the same time, PB nanoparticles with excellent hydrogen peroxide catalytic performance also amplified the efficiency of tumor therapy. Thus, a collective nanoplatform with gas therapy/photothermal therapy/catalytic therapy functionalities shows potential promise in terms of efficient tumor therapy.

Tumor Microenvironment-Activated Nanocomposite for Self-Amplifying Chemodynamic/Starvation Therapy Enhanced IDO-Blockade Tumor Immunotherapy.

Disrupting intracellular redox homeostasis combined with immune checkpoint blockade therapy is considered as an effective way to accelerate tumor cell death. However, suppressed tumor immune microenvironment and lower cargo delivery restrict the efficiency of tumor therapy. In this study, a multifunctional tumor microenvironment (TME)-responsive nanocomposite is constructed using manganese tetroxide (Mn3 O4 )-decorated disulfide-bond-incorporated dendritic mesoporous organosilica nanoparticles (DMONs) to co-deliver indoleamine 2,3-dioxygenase (IDO) inhibitor Epacadostat (IDOi) and glucose oxidase (GOx) following modification with polyethylene glycol. Owing to the responsiveness of Mn3 O4 -decorated DMONs to the mildly acidic and glutathione (GSH) overexpressed TME, the nanocomposite can rapidly decompose and release inner contents, thus substantially improving the cargo release ability. Mn3 O4 can effectively catalyze hydrogen peroxide (H2 O2 ) decomposition to generate oxygen, enhance the ability of GOx to consume glucose to produce H2 O2 , and further promote the generation of hydroxyl radicals (•OH) by Mn2+ . Furthermore, Mn2+ -mediated GSH depletion and the production of •OH can disrupt intracellular redox homeostasis, contributing to immunogenic cell death. Simultaneously, IDOi can inhibit IDO to reverse inhibited immune response. The results show that self-amplifying chemodynamic/starvation therapy combined IDO-blockade immunotherapy synergistically inhibits tumor growth and metastasis in vivo.