CD133-Targeted Hybrid Nanovesicles for Fluorescent/Ultrasonic Imaging-Guided HIFU Pancreatic Cancer Therapy.

Background: Pancreatic cancer is regarded as one of the most lethal types of tumor in the world, and optional way to treat the tumor are urgently needed. Cancer stem cells (CSCs) play a key role in the occurrence and development of pancreatic tumors. CD133 is a specific antigen for targeting the pancreatic CSCs subpopulation. Previous studies have shown that CSC-targeted therapy is effective in inhibiting tumorigenesis and transmission. However, CD133 targeted therapy combined with HIFU for pancreatic cancer is absent. Purpose: To improve therapeutic efficiency and minimize side effects, we carry a potent combination of CSCs antibody with synergist by an effective and visualized delivery nanocarrier to pancreatic cancer. Materials and Methods: Multifunctional CD133-targeted nanovesicles (CD133-grafted Cy5.5/PFOB@P-HVs) with encapsulated perfluorooctyl bromide (PFOB) in a 3-mercaptopropyltrimethoxysilane (MPTMS) shell modified with poly ethylene glycol (PEG) and superficially modified with CD133 and Cy 5.5 were constructed following the prescribed order. The nanovesicles were characterized for the biological and chemical characteristics feature. We explored the specific targeting capacity in vitro and the therapeutic effect in vivo. Results: The in vitro targeting experiment and in vivo FL and ultrasonic experiments showed the aggregation of CD133-grafted Cy5.5/PFOB@P-HVs around CSCs. In vivo FL imaging experiments demonstrated that the nanovesicles assemble for the highest concentration in the tumor at 24 h after administration. Under HIFU irradiation, the synergistic efficacy of the combination of the CD133-targeting carrier and HIFU for tumor treatment was obvious. Conclusion: CD133-grafted Cy5.5/PFOB@P-HVs combined with HIFU irradiation could enhance the tumor treatment effect not only by improving the delivery of nanovesicles but also by enhancing the HIFU thermal and mechanical effects in the tumor microenvironment, which is a highly effective targeted therapy for treating pancreatic cancer.

In Situ Structure Transformation of a Sprayed Gel for pH-Ultrasensitive Nano-Catalytic Antibacterial Therapy.

Nano-catalytic bacterial killing provides new opportunities to address ever-increasing antibiotic resistance. However, the intrinsic catalytic activity usually depends on a much lower pH conditions (pH = 2-5) than that in the weakly acidic bacterial microenvironments (pH = 6-7) for reactive oxygen species production by Fenton reactions. Herein, a MnSiO3 -based pH-ultrasensitive "in situ structure transformation" is first reported to significantly promote the adhesion between material and bacteria, and shorten the diffusion distance (<20 nm) to compensate ultra-short life (<200 ns) of ·OH generated by Mn2+ -mediated Fenton-like reaction, finally enhancing its nano-catalytic antibacterial performance in weakly acidic conditions. A separated spray bottle is further designed to achieve in situ gelation at the wound site, which demonstrates excellent shape adaptability to complicated and rough surfaces of wounds, allowing for long-term nano-catalyst release. As a result, bacterial-infected wound healing is efficiently promoted. Herein, the in situ sprayed nano-catalytic antibacterial gel presents a promising paradigm for bacterial infection treatment.

Confined Construction of Ultrasmall Molybdenum Disulfide-Loaded Porous Silica Particles for Efficient Tumor Therapy.

Recently, molybdenum sulfide (MoS2) has shown great application potential in tumor treatment because of its good photothermal properties. Unfortunately, most of the current molybdenum disulfide-based nanotherapeutic agents suffer from complex preparation processes, low photothermal conversion efficiencies, and poor structural/compositional regulation. To address these issues, in this paper, a facile "confined solvothermal" method is proposed to construct an MoS2-loaded porous silica nanosystem (designated as MoS2@P-hSiO2). The maximum photothermal efficiency of 79.5% of molybdenum-based materials reported in the literature at present was obtained due to the ultrasmall MoS2 nanoclusters and the rich porous channels. Furthermore, both in vitro and in vivo experiments showed that the cascade hybrid system (MoS2/GOD@P-hSiO2) after efficient loading of glucose oxidase (GOD) displayed a significant tumor-suppressive effect and good biosafety through the combined effects of photothermal and enzyme-mediated cascade catalytic therapy. Consequently, this hybrid porous network system combining the in situ solvothermal strategy of inorganic functional components and the efficient encapsulation of organic enzyme macromolecules can provide a new pathway to construct synergistic agents for the efficient and safe treatment of tumors.

A "Valve-Closing" Starvation Strategy for Amplification of Tumor-Specific Chemotherapy.

Starvation-dependent differential stress sensitization effect between normal and tumor cells provides a potentially promising strategy to amplify chemotherapy effects and reduce side effects. However, the conventional starvation approaches such as glucose oxidase (Gox)-induced glucose depletion and nanomedicine-enabled vascular embolism usually suffer from aggravated tumor hypoxia, systemic toxicity, and unpredictable metabolic syndrome. Herein, a novel "valve-closing" starvation strategy is developed to amplify the chemotherapy effects via closing the "valve" of glucose transported into tumor cells, which is accomplished by a glucose transporters 1 (GLUT1, valve of glucose uptake) inhibitor (Genistein, Gen) and chemotherapeutic agent (Curcumin, Cur) coloaded hybrid organosilica-micelles nanomedicine (designated as (Gen + Cur)@FOS) with controllable stability. In vitro and in vivo results demonstrate that (Gen + Cur)@FOS can effectively reduce glucose/adenosine triphosphate levels in tumor cells by inhibiting GLUT1 expression (i.e., "valve-closing") to induce the starvation of tumor cells, thus weakening the resistance of tumor cells to apoptosis caused by chemotherapy, and consequently contributing to the remarkably improved antitumor efficiency and minimized side effects based on the stress sensitization effect mediated by GLUT1 inhibition-induced starvation. This "valve-closing" starvation strategy provides a promising paradigm for the development of novel nanotherapeutics with amplified chemotherapy effect.

Interfacial-confined coordination to single-atom nanotherapeutics.

Pursuing and developing effective methodologies to construct highly active catalytic sites to maximize the atomic and energy efficiency by material engineering are attractive. Relative to the tremendous researches of carbon-based single atom systems, the construction of bio-applicable single atom materials is still in its infancy. Herein, we propose a facile and general interfacial-confined coordination strategy to construct high-quality single-atom nanotherapeutic agent with Fe single atoms being anchored on defective carbon dots confined in a biocompatible mesoporous silica nanoreactor. Furthermore, the efficient energy conversion capability of silica-based Fe single atoms system has been demonstrated on the basis of the exogenous physical photo irradiation and endogenous biochemical reactive oxygen species stimulus in the confined mesoporous network. More importantly, the highest photothermal conversion efficiency with the mechanism of increased electron density and narrow bandgap of this single atom structure in defective carbon was proposed by the theoretical DFT calculations. The present methodology provides a scientific paradigm to design and develop versatile single atom nanotherapeutics with adjustable metal components and tune the corresponding reactions for safe and efficient tumor therapeutic strategy.

A confined crosslinking strategy towards an intelligent organosilica-micellar hybrid drug delivery system.

An ideal drug delivery system must have a high level of stability to ensure effective circulation and passive aggregation, good retention performance, and dynamic delivery and treatment monitoring. Thus, the development of a smart drug delivery carrier with both precise drug release and real-time detection remains a challenge. Herein, we propose a confined crosslink protocol to prepare an intelligent hybrid delivery system for auto-fluorescent monitoring, protonation-induced retention and precise drug release. The construction of this system involves the hydrolysis and condensation of (3-aminopropyl)triethoxysilane (APTES) silanes inside the Pluronic polymer micelles and thereafter a confined Schiff base crosslinking between glutaraldehyde (GA) and residual silane amino groups. The size of the intelligent docetaxel (DTX)-loaded nanosystem changes from ∼25 nm in blood circulation or normal tissues (pH ∼ 7.4) to ∼250 nm in slightly acidic environments (pH ∼ 6.5-7.0) owing to intra-molecular hydrogen bond-induced aggregation and imine cleavage-induced disintegration in the endosome (pH ∼ 5.0-6.2) along with auto-fluorescent monitoring contributing to the high-efficiency chemotherapy. This work provides a new method to construct smart, acid-responsive and fluorescent-guided drug-delivery carrier systems for efficient and safe tumor chemotherapy.

Superstable and Large-Scalable Organosilica-Micellar Hybrid Nanosystem via a Confined Gelation Strategy for Ultrahigh-Dosage Chemotherapy.

Although various drug nanocarriers have been developed for treating solid tumors, their clinical transformation is greatly limited by the difficulties in quantity production and unpredictable in vivo toxic effects. Herein, a facile "confined-gelation" strategy is developed to quantity-produce intelligent pluronic organosilica micelles (designated as IPOMs) with an undetectable critical micelle concentration (CMC), which features the self-assembly induced core confinement by block copolymers, the inner hydrolysis-condensation of silane to the oligomer skeleton, and oxidative cross-linking of disulfide skeleton to core gelation. The docetaxel-loaded IPOMs (DTX@IPOMs) with precise glutathione (GSH) responsiveness not only display an ultrahigh tolerated dose (360 mg/kg) in healthy Kunming mice model but also exhibit a remarkable tumor inhibition efficacy in both subcutaneous and orthotopic mice tumor models upon an extraordinarily large dosage (50 mg/kg). The present confined-gelation strategy provides a novel pathway to design and quantity-produce low-toxic and high-efficacy organic-inorganic hybrid nanodrugs in future clinical transformations.

Peroxisome inspired hybrid enzyme nanogels for chemodynamic and photodynamic therapy.

Peroxisome, a special cytoplasmic organelle, possesses one or more kinds of oxidases for hydrogen peroxide (H2O2) production and catalase for H2O2 degradation, which serves as an intracellular H2O2 regulator to degrade toxic peroxides to water. Inspired by this biochemical pathway, we demonstrate the reactive oxygen species (ROS) induced tumor therapy by integrating lactate oxidase (LOx) and catalase (CAT) into Fe3O4 nanoparticle/indocyanine green (ICG) co-loaded hybrid nanogels (designated as FIGs-LC). Based on the O2 redistribution and H2O2 activation by cascading LOx and CAT catalytic metabolic regulation, hydroxyl radical (·OH) and singlet oxygen (1O2) production can be modulated for glutathione (GSH)-activated chemodynamic therapy (CDT) and NIR-triggered photodynamic therapy (PDT), by manipulating the ratio of LOx and CAT to catalyze endogenous lactate to produce H2O2 and further cascade decomposing H2O2 into O2. The regulation reactions of FIGs-LC significantly elevate the intracellular ROS level and cause fatal damage to cancer cells inducing the effective inhibition of tumor growth. Such enzyme complex loaded hybrid nanogel present potential for biomedical ROS regulation, especially for the tumors with different redox state, size, and subcutaneous depth.

Ultrasensitive Chemodynamic Therapy: Bimetallic Peroxide Triggers High pH-Activated, Synergistic Effect/H2 O2 Self-Supply-Mediated Cascade Fenton Chemistry.

Recently, nanoparticle-triggered in situ catalytic Fenton/Fenton-like reaction is widely explored for tumor-specific chemodynamic therapy (CDT). However, despite the great potential of CDT in tumor treatment, insensitive response to the relatively high pH of the tumor sites and the insufficient intratumoral H2 O2 level leads to limited efficiency of most Fenton/Fenton-like reactions, which greatly imped its clinical conversion. This paper reports the fabrication of Fenton-type bimetallic peroxides for ultrasensitive chemodynamic therapy with high pH-activated, synergistic effect/H2 O2 self-supply-mediated cascade Fenton chemistry for the first time. The observations reveal that these bimetallic peroxides exhibit an ultrasensitive acid-activated decomposition-mediated Fenton-like reaction at the relatively high pH of 6.5-7.0, accompanied with highly increased •OH generation efficiency (especially, 40-60-fold increase at pH 7.0) by the metal-mediated synergistic effect-enhanced Fenton chemistry as well as in situ self-generated H2 O2 supplement. Moreover, the bimetallic peroxides exhibit high tumor accumulation which along with a high-efficiency tumor catalytic-therapeutic with negligible side effects in vivo. Developing these novel bimetallic peroxides, together with the already demonstrated capacity of the key metals (Fe, Mn, Cu, etc.) for magnetic resonance imaging or photodynamic/immune-enhanced therapy, will propel interest in development of smart high-efficiency nanoplatform for cancer theranostics.

Effective and safe delivery of GLP-1AR and FGF-21 plasmids using amino-functionalized dual-mesoporous silica nanoparticles in vitro and in vivo.

Nanomaterials have attracted increased attention because of their excellent drug-carrying capacity. However, these nanomaterials are rarely used in the treatment of metabolic diseases. Liraglutide, a glucagon-like peptide-1 receptor agonist, has been widely used in the treatment of type 2 diabetes mellitus (T2DM). Furthermore, fibroblast growth factor 21 (FGF-21) has been found to improve glucose metabolism and insulin resistance (IR). To investigate whether these two molecules have synergistic effects in vivo, we developed a novel drug delivery system using amino-functionalized and embedded dual-mesoporous silica nanoparticles (N-EDMSNs) to simultaneously carry liraglutide and FGF-21, and observed their biological effects. The resultant N-EDMSNs possessed unique hierarchical porous structures consisting of open large pores (>10 nm) and small mesopores (~2.5 nm) in the silica framework, highly positively charged surfaces and good disperisity in aqueous solution. We found that N-EDMSNs had a high loading capacity for exogenous genes and low toxicity to Hepa1-6 cells. Moreover, N-EDMSNs can simultaneously carry FGF-21 plasmids and liraglutide and successfully transfect them into Hepa1-6 cells. The transfection efficiency of N-EDMSNs was higher than that of Lipofectamine 2000 in vitro. In mice experiments, N-EDMSNs/pFGF21 treatment resulted in higher FGF-21 expression in the liver than pFGF21 treatment with hydrodynamic delivery. Compared with both pFGF21 and liraglutide, N-EDMSNs/pFGF21/Lira treatment significantly reduced the food intake, body weight, and blood glucose; increased the energy expenditure and improved hepatic IR in high-fat diet (HFD)-fed mice. Our results demonstrated that the biological effects of N-EDMSNs/pFGF21/Lira complexes were better than those of pFGF21 combined with liraglutide in vivo.

Spatio-Temporally Reporting Dose-Dependent Chemotherapy via Uniting Dual-Modal MRI/NIR Imaging.

Unpredictable in vivo therapeutic feedback of hydroxyl radical (. OH) efficiency is the major bottleneck of chemodynamic therapy. Herein, we describe novel Fenton-based nanotheranostics NQ-Cy@Fe&GOD for spatio-temporally reporting intratumor . OH-mediated treatment, which innovatively unites dual-channel near-infrared (NIR) fluorescence and magnetic resonance imaging (MRI) signals. Specifically, MRI signal traces the dose distribution of Fenton-based iron oxide nanoparticles (IONPs) with high-spatial resolution, meanwhile timely fluorescence signal quantifies . OH-mediated therapeutic response with high spatio-temporal resolution. NQ-Cy@Fe&GOD can successfully monitor the intracellular release of IONPs and . OH-induced NQO1 enzyme in living cells and tumor-bearing mice, which makes a breakthrough in conquering the inherent unpredictable obstacles on spatio-temporally reporting chemodynamic therapy, so as to manipulate dose-dependent therapeutic process.

In Situ 3D-to-2D Transformation of Manganese-Based Layered Silicates for Tumor-Specific T1-Weighted Magnetic Resonance Imaging with High Signal-to-Noise and Excretability.

Recently, Mn(II)-based T1-weighted magnetic resonance imaging (MRI) contrast agents (CAs) have been explored widely for cancer diagnosis. However, the "always-on" properties and poor excretability of the conventional Mn(II)-based CAs leads to high background signals and unsatisfactory clearance from the body. Here, we report an "in situ three-dimensional to two-dimensional (3D-to-2D) transformation" method to prepare novel excretable 2D manganese-based layered silicates (Mn-LSNs) with extremely high signal-to-noise for tumor-specific MR imaging for the first time. Our observations combined with density functional theory (DFT) calculations reveal that 3D metal (Mn, Fe, Co) oxide nanoparticles are initially formed from the molecular precursor solution and then in situ transform into 2D metal (Mn, Fe, Co)-based layered silicates triggered by the addition of tetraethyl orthosilicate, which provides a time-saving and versatile way to prepare novel 2D silicate nanomaterials. The unique ion-exchangeable capacity and high host layer charge density endow Mn-LSNs with an "ON/OFF" pH/GSH stimuli-activatable T1 relaxivity with superb high signal-to-noise (640-, 1200-fold for slightly acidic and reductive changes, respectively). Further in vivo MR imaging reveals that Mn-LSNs exhibit a continuously rapid T1-MRI signal enhancement in tumor tissue and no visible signal enhancement in normal tissue, indicating an excellent tumor-specific imaging. In addition, Mn-LSNs exhibit a rapid excretion from the mouse body in 24 h and invisible organ toxicity, which could help to solve the critical intractable degradation issue of conventional inorganic CAs. Moreover, the tumor microenvironment (pH/GSH/H2O2) specific degradability of Mn-LSNs could help to improve the penetration depth of particles into the tumor parenchyma. Developing this novel Mn-LSNs contrast agent, together with the already demonstrated capacity of layered silicates for drug and gene delivery, provides opportunities for future cancer theranostics.

Structure Engineering of a Lanthanide-Based Metal-Organic Framework for the Regulation of Dynamic Ranges and Sensitivities for Pheochromocytoma Diagnosis.

Exploring innovative technologies to precisely quantify biomolecules is crucial but remains a great challenge for disease diagnosis. Unfortunately, the humoral concentrations of most biotargets generally vary within rather limited scopes between normal and pathological states, while most literature-reported biosensors can detect large spans of targets concentrations, but are less sensitive to small concentration changes, which consequently make them mostly unsatisfactory or even unreliable in distinguishing positives from negatives. Herein, a novel strategy of precisely quantifying the small concentration changes of a certain biotarget by editing the dynamic ranges and sensitivities of a lanthanide-based metal-organic framework (Eu-ZnMOF) biosensor is reported. By elaborately tailoring the biosensor's structure and surface areas, the tunable Eu-ZnMOF is developed with remarkably enhanced response slope within the "optimized useful detection window," enabling it to serve as a powerful signal amplifier (87.2-fold increase) for discriminating the small concentration variation of urinary vanillylmandelic acid (an early pathological signature of pheochromocytoma) within only three times between healthy and diseased subjects. This study provides a facile approach to edit the biosensors' performances through structure engineering, and exhibits promising perspectives for future clinical application in the non-invasive and accurate diagnosis of severe diseases.

Upconversion Nanoparticle-Based Organosilica-Micellar Hybrid Nanoplatforms for Redox-Responsive Chemotherapy and NIR-Mediated Photodynamic Therapy.

Upconversion nanoparticles (UCNPs) can convert near-infrared light (NIR, 980 or 808 nm) to ultraviolet (UV) or visible light, which can be widely used to improve tissue penetration depth in photodynamic therapy (PDT). Herein, we develop a kind of UCNP-based organosilica-micellar hybrid nanoplatform for redox-responsive chemotherapy and NIR-mediated PDT. The nanoplatform was constructed by the self-assembly of block copolymers polystyrene-b-poly (acrylic acid) and oil-soluble UCNPs in the oil/water system and the subsequent organosilica coating with 3-mercaptopropyltrimethoxysilane molecules. To endow the nanosystem with more stability in biological media, polyethylene glycol molecules were further modified via the Michael addition reaction. As a promising nanocarrier, chlorin e6 (Ce6) and doxorubicin (DOX) molecules were loaded into the hydrophobic core and the disulfide-doped organosilica shell, respectively. With endocytosis by SMMC-7721 tumor cells, the Ce6 and DOX coloaded nanosystem was activated by UCNPs through luminescence resonance energy transfer under the irradiation of 808 nm laser, thus generating cytotoxic 1O2 for NIR-mediated PDT. Meanwhile, DOX was selectively released because of the redox-responsive biodegradation of the disulfide-doped organosilica shell in the glutathione over-expressed SMMC-7721 tumor cells. Based on these, the chemotherapy/PDT combination toxic feature of the multifunctional nanosystem was further demonstrated in the DOX-resistant MCF-7 tumor cells. On the other hand, the Ce6 and DOX coloaded nanosystem exhibited negligible toxicity to the normal 3T3 cell because of the protective effects of organosilica coating. We envision that the resultant hybrid nanoplatform provides us a promising nanocarrier for the combination therapy of redox-responsive safe chemotherapy and efficient NIR-mediated PDT.

Gradient Redox-Responsive and Two-Stage Rocket-Mimetic Drug Delivery System for Improved Tumor Accumulation and Safe Chemotherapy.

Recent drug delivery nanosystems for cancer treatment still suffer from the poor tumor accumulation and low therapeutic efficacy due to the complex in vivo biological barriers. To resolve these problems, in this work, a novel gradient redox-responsive and two-stage rocket-mimetic drug nanocarrier is designed and constructed for improved tumor accumulation and safe chemotherapy. The nanocarrier is constructed on the basis of the disulfide-doped organosilica-micellar hybrid nanoparticles and the following dual-functional modification with disulfide-bonded polyethylene glycol (PEG) and amido-bonded polyethylenimine (PEI). First, prolonged circulation duration in the bloodstream is guaranteed due to the shielding of the outer PEG chains. Once the nanocarrier accumulates at the tumoral extracellular microenvironment with low glutathione (GSH) concentrations, the first-stage redox-responsive behavior with the separation of PEG and the exposure of PEI is triggered, leading to the improved tumor accumulation and cellular internalization. Furthermore, with their endocytosis by tumor cells, a high concentration of GSH induces the second-stage redox-responsiveness with the degradation of silsesquioxane framework and the release of the encapsulated drugs. As a result, the rocket-mimetic drug carrier displays longer circulation duration in the bloodstream, higher tumor accumulation capability, and improved antitumor efficacy (which is 2.5 times higher than that with inseparable PEG). It is envisioned that the rocket-mimetic strategy can provide new solutions for improving tumor accumulation and safety of nanocarriers in further cancer chemotherapy.

Magnetic/Gold Core-Shell Hybrid Particles for Targeting and Imaging-Guided Photothermal Cancer Therapy.

The development of hybrid particles for tumor diagnosis and therapy has received considerable attention because they are capable of combining tumor diagnosis and treatment concurrently. So far hybrid particles for efficient and safe tumor theranostics are still very limited. Herein we have designed a new type of hybrid particles and evaluated its potential to be used in image-guided cancer diagnosis and therapy without the need of any toxic anticancer or contrast agents. The hybrid particles, consist of magnetic nanoparticles which are embedded in the poly(methyl methacrylate) (PMMA) cores and gold shells on chitosan (CTS) (γ-Fe2O3 @PMMA/CTS@Au). The hybrid particles were synthesized through initial formation of the core-shell structured γ-Fe2O3 @PMMA/CTS particles containing approximately 20% loading of magnetic nanoparticles. A gold layer was then built on top of the core-shell magnetic particles via a reduction of gold salt by amines from the chitosan assisted with the reducing agent NaBH4, followed by growing to complete gold shells in the presence of ascorbic acid (42.6% Au content). The properties of the composite particles including their chemical composition, morphology, particle size, size distribution, surface charge, magnetic responsiveness and photothermal ability were systematically characterized. The potential application of the γ-Fe2O3 @PMMA/CTS@Au hybrid particles in tumor diagnosis and therapy was assessed in vitro and in vivo using 4T1 tumor cells and 4T1 tumor-bearing mice through combining magnetic targeting, photoacoustic (PA)/computed tomography (CT) imaging and photothermal therapy. Results suggest that the γ-Fe2O3 @PMMA/CTS@Au particles can serve as a multifunctional tumor theranostic nanoplatform for magnetically targeted photothermal therapy. Breast cancer has been effectively eliminated without the use of any anticancer drugs or contrast agents. Therefore, this type of core-shell hybrid particles represents a new composite particle design for effective and safe tumor theranostics.

Biodegradable organosilica magnetic micelles for magnetically targeted MRI and GSH-triggered tumor chemotherapy.

Recently, block copolymer micelles have attracted widespread attention due to their controlled biodegradability and excellent loading capability. Unfortunately, the poor in vivo stability and low delivery efficiency of drug-loaded micelles greatly hampered their biomedical applications. Herein, we develop a new kind of biodegradable magnetite/doxorubicin (Fe3O4/DOX) co-loaded PEGylated organosilica micelles (designated as FDPOMs) with both high circulating stability and smart GSH-triggered biodegradability for magnetically targeted magnetic resonance imaging (MRI) and tumor chemotherapy. The FDPOMs are prepared by the self-assembly of biodegradable polycaprolactone-block-poly(glutamic acid) (PCL-b-PGA), a chemotherapeutic DOX drug and Fe3O4 nanoparticles in an oil/water system, subsequent organosilica cross-linking with 3-mercaptopropyltrimethoxysilane (MPTMS) molecules and surface PEGylation. The resultant FDPOMs exhibit excellent dispersity and stability in biological media, remarkable T2-weighted MR imaging capability, unique GSH-responsive release behavior and selective toxicity to tumor cells. The in vivo experiments show that the FDPOMs not only have improved MR tumor imaging capability, but also exhibit high anti-tumor efficacy due to the strong magnetic targeting ability under an external magnetic field. Consequently, the FDPOMs are promising candidates for magnetically targeted MR imaging and imaging-guided tumor chemotherapy.

Confined growth of multiple gold nanorices in dual-mesoporous silica nanospheres for improved computed tomography imaging and photothermal therapy.

INTRODUCTION: In this work, we have developed a novel "confined-growth" strategy to synthesize PEGylated multiple gold nanorices-encapsulated dual-mesoporous silica nanospheres (designated as PEGylated MGNRs@DMSSs) containing both small mesopores (2.5 nm) in the shell and large mesopores (21.7 nm) in the core based on a well-established, seed-mediated growth method. The photothermal effect and CT imaging ability were also studied. METHODS: The nanoparticles were characterized by Fourier transform infrared (FT-IR) spectra, N2 absorption isotherms, Field-emission scanning electron microscopy (FE-SEM), Transmission electron microscopy (TEM), Inductively coupled plasma atomic emission spectroscopy (ICP-AES) and Confocal microscopy. RESULTS: The longitudinally-localized surface (LSPR) absorption properties of MGNRs@DMSSs can be easily tuned by altering the amount of HAuCl4 in the gold growth solution. Additionally, the resultant PEGylated MGNRs@DMSSs have monodispersed, spherical morphology and good colloidal stability in an aqueous solution. More importantly, when exposed to NIR irradiation, the PEGylated MGNRs@DMSSs exhibit both higher temperature increments and better photothermal effects than that of single PEGylated gold nanorods at nearly an equivalent LSPR absorption. In addition, as CT contrast agents, the PEGylated MGNRs@DMSSs display a better CT imaging performance, in comparison with single PEGylated gold nanorods at the same Au concentration. CONCLUSION: Taken together, results indicate the potential for MGNRs@DMSSs used in CT imaging-guided photothermal therapy. Such a simple "confined-growth" strategy within a porous matrix offers a promising platform to design and prepare novel metal(s) oxide@silica nanocomposites for use in further cancer bio-imaging and therapy.

Facile synthesis of organosilica-capped mesoporous silica nanocarriers with selective redox-triggered drug release properties for safe tumor chemotherapy.

As drug-delivery carriers for cancer chemotherapy, gatekeeper-capped mesoporous silica nanoparticles (MSNs) have been widely studied due to their high drug-loading capability, controlled drug release property and good biocompatibility. However, the currently reported gatekeeper-capped MSNs suffer from complex synthetic procedures, potential toxicity of gatekeepers, unsatisfactory control on drug stimuli-release, etc. In this work, we develop a simple but efficient approach to fabricate PEGylated organosilica-capped mesoporous silica nanoparticles (POMSNs) by employing a disulfide-doped organosilica coating as the gatekeeper formed by the hydrolysis and condensation of a silane coupling agent 3-(mercaptopropyl)trimethoxysilane (MPTMS) to block the mesopores of MSNs. Owing to the glutathione (GSH)-responsive biodegradation behavior of the disulfide-doped organosilica gatekeeper, the DOX-loaded POMSNs exhibit only 20% cell viability towards SMMC-7721 tumor cells, and almost no toxicity towards L-02 cells at a DOX concentration of 50 µg mL-1 was measured, demonstrating their selective cytotoxicity in vitro. More importantly, it is demonstrated that the DOX-loaded POMSNs exhibit a tumor inhibition rate of 71.3% and negligible systematic toxicity. Consequently, the resultant POMSNs show great potential as drug nanocarriers for redox-responsive drug release and passive-targeting tumor chemotherapy.