Near-Infrared Light-Controlled and Real-Time Detection of Osteogenic Differentiation in Mesenchymal Stem Cells by Upconversion Nanoparticles for Osteoporosis Therapy.

Osteoporosis (OP) is one of the most common diseases in the elderly, and it is not effectively solved by current treatments. Mesenchymal stem cells (MSCs) have multiple differentiation potentials, which can induce osteogenic differentiation to treat OP; however, it is important to understand how to remotely control and detect osteogenic differentiation in vivo in real time. Here, we developed an upconversion nanoparticle (UCNP)-based photoresponsive nanoplatform for near-infrared (NIR) light-mediated control of intracellular icariin (ICA) release to regulate the osteogenic differentiation of MSCs for OP therapy. We simultaneously detected osteogenic differentiation in vivo in real time to evaluate the treatment effects. The Tm/Er-doped UCNPs were synthesized and coated with mesoporous silica (UCNP@mSiO2) first. Then, the photocaged linker 4-(hydroxymethyl)-3-nitrobenzoic acid (ONA) and the PEG linker (OH-PEG4-MAL) were linked to the surface of UCNP@mSiO2 to conjugate to the cap ß-cyclodextrin (ß-CD) and the Arg-Gly-Asp (RGD)-targeted peptide/matrix metalloproteinase 13 (MMP13)-sensitive peptide-BHQ (CGPLGVRGK-BHQ3) to form the UCNP nanoplatform (UCNP@mSiO2-peptide-BHQ-ONA-CD) for drug loading. Under 980 nm NIR light, the upconverted UV from the UCNPs triggered the cleavage of cap ß-CD and the intracellular release of ICA to induce the osteogenic differentiation of MSCs for OP therapy. Meanwhile, MMP13, which was produced by osteogenic differentiation of MSCs, cleaved the MMP13-sensitive peptide to remove BHQ and recover the fluorescence of UCNPs, allowing real-time detection of osteogenic differentiation and the evaluation of the OP treatment effect. This photoresponsive UCNP nanoplatform has the potential to be used for the remote control and real-time detection of osteogenic differentiation of MSCs for OP therapy by NIR.

Influence of biofilms on the adsorption behavior of nine organic emerging contaminants on microplastics in field-laboratory exposure experiments.

Microplastics (MPs) are ubiquitous in aquatic environments, which are important carriers of emerging contaminants (ECs). Biofilms can be attached to the surface of MPs in a natural aquatic environment, which may influence chemical adsorption; however, knowledge of its impact is still limited. This study investigated the effect of biofilms on MPs on the adsorption of ECs through field-laboratory exposure experiments. Three types of MPs were naturally colonized with biofilms in lake. Then, biofilm-absent/biofilm-attached MPs were exposed to nine EC solutions at a concentration of 8 µg/L of each compound in laboratory. Most compounds exhibited 3.8 times lower concentrations on biofilm-attached MPs than on biofilm-absent MPs; only a few compounds showed enhanced adsorption. Pseudo-equilibrium was achieved within 72 h based on adsorption kinetics, implying fast adsorption of ECs on biofilm-attached MPs. The partition coefficients (Kd) for biofilm-attached MPs were 0.14 (diclofenac) to 535 (miconazole) L/kg and were positively correlated with octanol/water partition coefficients (Kow). This indicated that chemical properties (such as Kow) of the compounds determined their final adsorption amounts on MPs, although these were influenced by the presence of the biofilm. Hence, multiple influencing factors should be considered when evaluating the carrier potential of MPs for ECs in aquatic environments.

Near-Infrared Light-Controlled Activation of Adhesive Peptides Regulates Cell Adhesion and Multidifferentiation in Mesenchymal Stem Cells on an Up-Conversion Substrate.

Cell adhesion and differentiation can be regulated through material engineering, but current methods have low temporal and spatial accuracy to control invivo. Here, we developed an up-conversion nanoparticle (UCNP) substrate to regulate cell adhesion and multidifferentiation in mesenchymal stem cells (MSCs) by near-infrared (NIR) light. First, the cell-adhesive peptide Arg-Gly-Asp (RGD) was conjugated on the surface of UCNPs, and the photocleavage 4-(hydroxymethyl)-3-nitrobenzoic acid (ONA) was connected to RGD. Then, the photoactivated UCNPs were linked to cover glass to form UCNP-substrate. Under the NIR, the up-convert UV from UCNPs triggered the release of ONA and exposed RGD to change the cell-matrix interactions dynamically for cell adhesion and spreading. Moreover, MSCs cultured on UCNP-substrate could be specifically induced to multidifferentiate adipocytes or osteoblasts via different power and periods of NIR irradiation in vitro and in vivo. Our work demonstrates a new way to control cell adhesion and multidifferentiation by light for regeneration medicine.

Photocontrolled chondrogenic differentiation and long-term tracking of mesenchymal stem cells in vivo by upconversion nanoparticles.

Mesenchymal stem cells (MSCs) have multiple differentiation potentials and their clinical application is limited by controlled cell differentiation and long-term tracing in vivo. Here, we developed an upconversion nanoparticle (UCNP)-based nanoplatform for the photocontrolled chondrogenic differentiation and long-term tracking of MSCs in vivo. The UCNP nanoplatform could convert 980 nm near-infrared (NIR) light into UV/blue light (365/475 nm) and green/red light (545/647 nm) through Tm/Er doping. Then, the upconverted UV/blue light was used to drive the photosensitive molecule azobenzene (azo) that was modified in mesoporous silica to constantly change its conformation to trigger the release of kartogenin (KGN) from the UCNPs to induce the chondrogeni differentiation of MSCs, achieving photocontrolled cell differentiation. Both in vitro and in vivo experiments demonstrated the effective induction of chondrogenic differentiation in MSCs by NIR light with the UCNP nanoplatform incubation. In addition, after inducing differentiation, the UCNP nanoplatform that remained in the cytoplasm was used as a nanoprobe to monitor the MSCs in vitro and in vivo using the upconverted green/red light under the NIR light. Therefore, the UCNP nanoplatform displayed potential to be a powerful tool for the control of cell differentiation and the simultaneous long-term tracking of MSCs in vivo for regenerative medicine.

Profile and removal of bisphenol analogues in hospital wastewater, landfill leachate, and municipal wastewater in South China.

The presence of bisphenol analogues (BPs) in wastewater can have adverse effects to organisms in the environment. However, knowledge of the wastewater sources, such as hospitals and landfills, as well as the removal of BPs are still limited. Fifteen BPs were investigated in hospital, landfills, and municipal wastewater treatment plants (WWTPs) in South China. Eleven BPs were detected in various source wastewaters, and bisphenol A (BPA) is generally the dominant pollutant. In 4 hospitals, the total concentrations of BPs (∑BPs) in hospital wastewater and treated wastewater ranged from 122 to 1040 ng/L. In the landfill, ∑BPs in leachate and treated leachates were 32,130 and 145 ng/L, respectively. In 5 municipal WWTPs, ∑BPs was up to 17,200 ng/L in influents, 502 ng/L in effluents, and 291 ng/g in sludges. The modified A2/O process exhibited best removal profile for BPs, while the UNITANK process had no advantages. The annual mass load estimates of hospital treated wastewater, landfill treated leachate, and WWTP effluents in Guangdong Province, South China, were 630, 9.46, and 4697 kg/y, respectively. The risk quotient values in source effluents revealed low to medium estrogenic risks to receiving rivers. Control measures should be applied to further remove BPs not only from WWTP effluents but also from other sources.

Base-Mediated Borylsilylation/Silylation of Ammonium Salts with Silylborane.

This work describes a base-mediated borylsilylation of benzylic ammonium salts to synthesize geminal silylboronates bearing benzylic proton under mild reaction conditions. Deaminative silylation of aryl ammonium salts was also achieved in the presence of LiOtBu. This strategy which is featured with high efficiency, mild reaction conditions, and good functional group tolerance provides efficient routes for late-stage functionalization of amines.

Controllable synthesis of iron-polyphenol colloidal nanoparticles with composition-dependent photothermal performance.

Iron-polyphenol nanoparticles are usually prepared with nontoxic plant polyphenols as a main building block, which are an emerging photothermal agent for photothermal therapy. However, till now, few works have been made on the controllable synthesis of iron-polyphenol nanoparticles with tunable composition, as well as investigation of the relationship between material composition and photothermal property. In the present study, iron-polyphenol colloidal nanoparticles with tunable diameter (21-303 nm) and ion content (9.2-97.6 mg/g), as well as high colloidal stability are successfully synthesized using different polyphenols (such as tannic acid, epigallocatechin gallate, gallic acid, epicatechin and proanthocyanidin) as a ligand. In addition, photothermal performance is highly dependent on the organic ligand, iron content and particle size. Higher iron content and smaller diameter can contribute to higher photothermal performance. The iron-polyphenol nanoparticles with the optimal iron content and particle size are selected as a photothermal agent. They can effectively inhibit the tumour growth in vivo. The current work demonstrates a general synthesis strategy for iron-polyphenol colloidal nanoparticles with tailorable composition and clarifies the relationship between material composition and photothermal performance. Moreover, it is conductive to the rational design of polyphenol-based photothermal agents for theranostic applications.

Evaluation of the ex vivo liver viability using a nuclear magnetic resonance relaxation time-based assay in a porcine machine perfusion model.

There is a dearth of effective parameters for selecting potentially transplantable liver grafts from expanded-criteria donors. In this study, we used a nuclear magnetic resonance (NMR) relaxation analyzer-based assay to assess the viability of ex vivo livers obtained via porcine donation after circulatory death (DCD). Ex situ normothermic machine perfusion (NMP) was utilized as a platform for viability test of porcine DCD donor livers. A liver-targeted contrast agent, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), was injected into the perfusate during NMP, and the dynamic biliary excretion of the Gd-EOB-DTPA was monitored by measuring the longitudinal relaxation time (T1). The longitudinal relaxation rate (R1) of the bile was served as a parameter. The delay of increase in biliary R1 during early stage of NMP indicated the impaired function of liver grafts in both warm and cold ischemia injury, which was correlated with the change of alanine aminotransferase. The preservative superiority in cold ischemia of dual hypothermic oxygenated machine perfusion could also be verified by assessing biliary R1 and other biochemical parameters. This study allows for the dynamic assessment of the viability of porcine DCD donor livers by combined usage of ex situ NMP and NMR relaxation time based assay, which lays a foundation for further clinical application.

Precise Tumor Photothermal Therapy Guided and Monitored by Magnetic Resonance/Photoacoustic Imaging using A Safe and pH-Responsive Fe(III) Complex.

Photothermal agents with strong near infrared (NIR) optical absorbance and excellent biocompatibility and traceability are highly desired for precise photothermal therapy. This study reports the development of a dual-functional Fe3+ complex (Fe-ZDS) for imaging-guided, precise photothermal therapy of tumors. The complex has stable structure and obvious zwitterionic features, resulting in excellent biocompatibility and efficient renal clearance. The iron-dopa core structure renders the complex capable of generating magnetic resonance imaging (MRI) contrast, while synergistically exhibiting optical absorption in the red and NIR regions. Interestingly, the optical absorption of the complex is pH-sensitive, with significantly higher absorption intensity in a weakly acidic environment than in a neutral environment. Thus the complex can respond to acidic tumor stimuli and confine the energy of the laser to the tumor tissue. The MRI contrast and photoacoustic signal of the complex is taken advantage of to monitor the probe injection process and optimize the injection position and dosage for maximally covering the tumor tissue and assessing the activation of the complex in tumor tissues. The evolution of temperature inside the tissue during the laser irradiation is also monitored. Using Fe-ZDS as the theranostic probe, satisfactory treatment outcomes are achieved for photothermal therapy of tumors.

Correction: Delivering siRNA to control osteogenic differentiation and real-time detection of cell differentiation in human mesenchymal stem cells using multifunctional gold nanoparticles.

Correction for 'Delivering siRNA to control osteogenic differentiation and real-time detection of cell differentiation in human mesenchymal stem cells using multifunctional gold nanoparticles' by Qian Wu et al., J. Mater. Chem. B, 2020, 8, 3016-3027, DOI: .

Correction: Near-infrared control and real-time detection of osteogenic differentiation in mesenchymal stem cells by multifunctional upconversion nanoparticles.

Correction for 'Near-infrared control and real-time detection of osteogenic differentiation in mesenchymal stem cells by multifunctional upconversion nanoparticles' by Kaipeng Wang et al., Nanoscale, 2020, 12, 10106-10116, DOI: 10.1039/D0NR00872A.

Near-infrared control and real-time detection of osteogenic differentiation in mesenchymal stem cells by multifunctional upconversion nanoparticles.

Finding a method to control and detect the differentiation of stem cells in real time remains a challenge for regenerative medicine. Here we developed the multifunctional upconversion nanoparticle (UCNP) approach for both near-infrared (NIR) control and the real-time detection of osteogenic differentiation in mesenchymal stem cells (MSCs). We first synthesized Tm/Er doped core-shell UCNPs (NaYF4:Yb/Tm/Er@NaYF4), and the core-shell UCNPs were coated with mesoporous silica for drug loading and installing photomechanical azobenzene (azo). Then the Arg-Gly-Asp (RGD) peptide and the matrix metalloproteinase 13 (MMP13) sensitive peptide-black hole quencher-3 group (CGPLGVRGK-BHQ-3) were conjugated on the surface of UCNPs for cell targeting and detection of cell differentiation. The final multifunctional UCNPs are called UCNP@mSiO2-azo-peptide-BHQ-3. The drug icariin (ICA), which can induce the osteogenic differentiation of MSCs, was loaded into UCNP@mSiO2-azo-peptide-BHQ-3 to form the UCNP nanocomplexes. ICA could be released from UCNP nanocomplexes in a NIR-controlled manner that is based on the transformation of the trans-isomer of azo into the cis isomer under the upconverted UV and visible light. Meanwhile, UCNP@mSiO2-azo-peptide-BHQ-3 could also be used as a nanoprobe to detect the activity of the MMP13 enzyme by enzyme digestion and UCNP fluorescence recovery. By detecting MMP13, which is produced by osteogenic differentiation, a real-time detection of cell differentiation in living differentiated MSCs could be achieved using UCNP nanoprobes. Thus, the multifunctional UCNPs combined the control of cell differentiation with the real-time detection of cell differentiation in MSCs, which makes them a powerful tool for regulating and detecting the differentiation of MSCs in regenerative medicine.

Synthesis of gadolinium/iron-bimetal-phenolic coordination polymer nanoparticles for theranostic applications.

Integration of diagnostic and therapeutic components into a single coordination polymer nanoparticle is desirable for theranostic applications, but still challenging. Herein, we report the synthesis of bimetal-phenolic coordination polymer nanoparticles using gadolinium nitrate and ferrous sulphate as a metal source, and plant polyphenols (i.e., tannic acid) as an organic ligand via a metal-catechol coordination assembly process. Such coordination polymers show a tunable molar ratio of Gd/Fe and high dispersibility and stability in aqueous solution. The coordination polymers reveal composition-dependent performance for longitudinal relaxivity and photothermal conversion. The longitudinal relaxivity is positively related to the molar ratio of Gd/Fe, while the photothermal performance is negatively related to the molar ratio of Gd/Fe in the coordination polymers. The coordination polymers with an optimized molar ratio of Gd/Fe exhibit an ultra-small hydrodynamic diameter (∼23 nm), a high r1 value (9.3 mM-1 s-1) with low r2/r1 (1.26) and high photothermal conversion efficiency (η = 37%). They can be used as a contrast agent for T1-weighted magnetic resonance imaging of EMT-6 tumor bearing mice, which can effectively enhance the signals of tumors. They can also effectively suppress tumor growth via photothermal therapy. This work brings new insights for the synthesis of multifunctional coordination polymer nanoparticles and extending their potential applications in theranostics.

Delivering siRNA to control osteogenic differentiation and real-time detection of cell differentiation in human mesenchymal stem cells using multifunctional gold nanoparticles.

Controlling and detecting cell differentiation in human mesenchymal stem cells (hMSCs) for regenerative medicine remain challenging at present. Here, we developed multifunctional gold nanoparticles (AuNPs) to control and detect osteogenic differentiation in human mesenchymal stem cells (hMSCs) in real-time. The polyethyleneimine (PEI) capped AuNPs (Au-PEI) were synthesized first and were then conjugated with a matrix metalloproteinase 13 (MMP13)-sensitive peptide-FITC group (EGPLGVRGKG-FITC) to obtain multifunctional AuNPs (AuNP-PEI-peptide-FITC). AuNP-PEI-peptide-FITC could bind siRNA with PEI by electrostatic interactions to form the AuNP-PEI-peptide-FITC/siRNA nanocomplexes, allowing efficient siRNA delivery in hMSCs. The adipogenic-related gene peroxisome proliferator-activated receptor γ (PPARγ) was targeted for silencing by the AuNP-PEI-peptide-FITC/siRNA nanocomplexes to control osteogenic differentiation in hMSCs. After demonstrating that the AuNP nanocomplexes could control cell differentiation, the versatility of this tool was illustrated by showing that it can be used as a nanoprobe for real time detection of the osteogenic differentiation of hMSCs. This was done by measuring the activity of the MMP13 enzyme (produced during osteogenic differentiation) through the recovery of FITC fluorescence. This multifunctional AuNP showed a robust new methodology for controlling cell fate and simultaneously detecting cell differentiation in real-time for hMSCs, which is promising for multiple applications in regenerative medicine.

A pH-Sensitive Zwitterionic Iron Complex Probe with High Biocompatibility for Tumor-Specific Magnetic Resonance Imaging.

Accurate diagnosis of tumor characteristics, including its location and boundary, is of immense value to subsequent therapy. Activatable magnetic resonance imaging (MRI) contrast agents that respond to tumor-specific microenvironments, such as the redox state, pH, and enzyme activity, enable better mapping of tumor tissue. However, the practical application of most reported activatable agents is hampered by problems including potential toxicity, inefficient elimination, and slow activation. In this study, we developed a zwitterionic iron complex (Fe-ZDS) as a positive MRI contrast agent for tumor-specific imaging. Fe-ZDS could dissociate in weakly acidic solution rapidly, accompanied by clear longitudinal relaxivity (r1 ) enhancement, which enabled the complex to act as a pH-sensitive contrast agent for tumor-specific MR imaging. In vivo experiments showed that Fe-ZDS rapidly enhanced the tumor-to-normal contrast ratio by >40 %, which assisted in distinguishing the tumor boundary. Furthermore, Fe-ZDS circulated freely in the bloodstream and was excreted relatively safely via kidneys owing to its zwitterionic nature. Therefore, Fe-ZDS is an ideal candidate for a tumor-specific MRI contrast agent and holds considerable potential for clinical translation.

Gram-Scale Preparation of Iron Oxide Nanoparticles with Renal Clearance Properties for Enhanced T1-Weighted Magnetic Resonance Imaging.

Extremely small-sized iron oxide nanoparticles (ESIONs) have been accepted as a potential alternative to gadolinium-based contrast agents for enhanced T1-weighted MR imaging. Recently developed zwitterion-coated ESIONs showed a high T1 contrast power and efficient renal clearing ability, but the tedious preparation steps that required high-cost, unfriendly experimental conditions and a sophisticated phase transition process would likely hinder their clinical translation. Herein, we present a one-pot gram-scale synthesis of zwitterion-capped ultrasmall iron oxide nanoparticles (ZUIONs). The nanoparticles have a core size as small as 3.7 nm and display high colloidal stability in various buffers. The r1 relaxivity of 2.4 mM-1 s-1 and r2/r1 ratio as low as 2.2 at 1.0 T guarantee their application as effective T1 MRI contrast agents. In vivo studies showed that ZUIONs could induce a significant contrast enhancement in blood pool and be eliminated from the body mainly through the renal excretion pathway. The combined advantageous features including facile preparation, excellent biocompatibility, strong T1 MRI contrast effect, appropriate circulation time, and renal clearable property would render ZUIONs attractive for practical applications.

RGD peptide-modified fluorescent gold nanoclusters as highly efficient tumor-targeted radiotherapy sensitizers.

Radiotherapy is a leading treatment approach of cancer therapy. While it is effective in killing tumor cells, it can also cause serious damage to surrounding normal tissue. Targeted radiotherapy with gold nanoparticle-based radiosensitizers is actively being investigated, and considered as a promising means to enhance the efficacy of radiotherapy against tumors under a relatively low and safe radiation dose. In this work, we report a green and one-step strategy to synthesize fluorescent gold nanoclusters by using a commercialized cyclic arginine-glycine-aspartic acid (c(RGDyC)) peptide as the template. The nanoclusters inherit special properties of both the Au core (red/NIR fluorescence emission and strong radiosensitizing effect) and c(RGDyC) shell (active cancer cell-targeting ability and good biocompatibility), and can be applied as fluorescent probes to stain αvß3 integrin-positive cancer cells, as well as radiosensitizing agents to boost the killing efficacy of radiotherapy. Our data suggest that the as-designed gold nanoclusters have excellent biocompatibility, bright red/NIR fluorescence, active tumor targeting property, and strong radiosensitizing effect, making them highly promising towards potential clinical translation.

Gd3+-Functionalized gold nanoclusters for fluorescence-magnetic resonance bimodal imaging.

Multimodal imaging that aims to advance imaging by strategically combining existing technologies with uniquely designed probes has attracted great interest in recent years. In this work, Gd3+-functionalized gold nanoclusters were prepared with a straightforward and scalable approach by using proteins as templates. The impact of the synthesis approach on the conjugation efficiency of Gd chelators to proteins, as well as the fluorescence quantum yield of gold nanoclusters was carefully studied. The effect of protein size on the relaxivities of the probes was also investigated. By using the optimal conditions, dual function probes with intense red fluorescence emission and longitudinal relaxivity as high as 9.7 mM-1 s-1 could be obtained. The probes were applied for cell staining and in vivo contrast-enhanced magnetic resonance imaging (MRI). The MR images showed that the dual function probes circulated freely in the blood pool without undesirable accumulation in the liver and spleen. Meanwhile, the material could be removed from the body through renal clearance, making it attractive for practical multimodal imaging.

Glutathione-capped, renal-clearable CuS nanodots for photoacoustic imaging and photothermal therapy.

The development of functional nanomaterials that undergo renal clearance is of fundamental importance to their in vivo biomedical applications. In this work, we report a one-pot method for the preparation of ultrasmall copper sulfide nanodots capped with a small natural tripeptide glutathione (GSH-CuS NDs). The GSH-CuS NDs had a hydrodynamic diameter of 5.8 nm, smaller than the reported polymer-coated CuS NDs with similar core sizes, and exhibited strong optical absorption and conversion at the near-infrared (NIR) region, leading to a sufficient photohyperthermic effect under the irradiation of a 980 nm laser. In vivo studies showed that the GSH-CuS NDs could induce significant photoacoustic imaging signal enhancement and remarkable photothermal therapy efficacy. Importantly, biodistribution studies and MRI imaging showed that the GSH-CuS NDs could freely circulate in the blood pool without undesirable accumulation in the liver and spleen, and could be naturally removed from the body through renal clearance, making them attractive for practical theranostic applications.

MRI-visualized, dual-targeting, combined tumor therapy using magnetic graphene-based mesoporous silica.

Targeting peptide-modified magnetic graphene-based mesoporous silica (MGMSPI) are synthesized, characterized, and developed as a multifunctional theranostic platform. This system exhibits many merits, such as biocompatibility, high near-infrared photothermal heating, facile magnetic separation, large T2 relaxation rates (r2), and a high doxorubicin (DOX) loading capacity. In vitro and in vivo results demonstrate that DOX-loaded MGMSPI (MGMSPID) can integrate magnetic resonance imaging, dual-targeting recognition (magnetic targeting and receptor-mediated active targeting), and chemo-photothermal therapy into a single system for a visualized-synergistic therapy of glioma. In addition, it is observed that the MGMSPID system has heat-stimulated, pH-responsive, sustained release properties. All of these characteristics would provide a robust multifunctional theranostic platform for visualized glioma therapy.