Bottom-Up Synthesis of Metal-Ion-Doped WS₂ Nanoflakes for Cancer Theranostics

Recently, two-dimensional transition metal dichalcogenides (TMDCs) have received tremendous attention in many fields including biomedicine. Herein, we develop a general method to dope different types of metal ions into WS₂ nanoflakes, a typical class of TMDCs, and choose Gd³⁺-doped WS₂ (WS₂:Gd³⁺) with polyethylene glycol (PEG) modification as a multifunctional agent for imaging-guided combination cancer treatment. While WS₂ with strong near-infrared (NIR) absorbance and X-ray attenuation ability enables contrasts in photoacoustic (PA) imaging and computed tomography (CT), Gd³⁺ doping offers the nanostructure a paramagnetic property for magnetic resonance (MR) imaging. As revealed by trimodal PA/CT/MR imaging, WS₂:Gd³⁺-PEG nanoflakes showed efficient tumor homing after intravenous injection. <i>In vivo</i> cancer treatment study further uncovered that WS₂:Gd³⁺-PEG could not only convert NIR light into heat for photothermal therapy (PTT) but also enhance the ionizing irradiation-induced tumor damage to boost radiation therapy (RT). Owing to the improved tumor oxygenation after the mild PTT, the combination of PTT and RT induced by WS₂:Gd³⁺-PEG resulted in a remarkable synergistic effect to destroy cancer. Our work highlights the promise of utilizing inherent physical properties of TMDC-based nanostructures, whose functions could be further enriched by elementary doping, for applications in multimodal bioimaging and synergistic cancer therapy

Oxidase Heterotetramer Completes 1‑Azabicyclo[3.1.0]hexane Formation with the Association of a Nonribosomal Peptide Synthetase

Ficellomycin, azinomycins, and vazabitide A are nonribosomal peptide natural products characterized by an amino acid unit that contains a similar 1-azabicyclo[3.1.0]hexane (ABCH) pharmacophore. This unit is derived from diamino-dihydroxy-heptanic acid (DADH); however, the process through which linear DADH is cyclized to furnish an ABCH ring system remains poorly understood. Based on the reconstitution of the route of the ABCH-containing unit by blending genes/enzymes involved in the biosynthesis of ficellomycin and azinomycins, we report that ABCH formation is completed by an oxidase heterotetramer with the association of a nonribosomal peptide synthetase (NRPS). The DADH precursor was prepared in Escherichia coli to produce a conjugate subjected to in vitro enzymatic hydrolysis for offloading from an amino-group carrier protein. To furnish an aziridine ring, DADH was processed by C7-hydroxyl sulfonation and sulfate elimination-coupled cyclization. Further cyclization leading to an azabicyclic hexane pharmacophore was proved to occur in the NRPS, where the oxidase heterotetramer functions in trans and catalyzes α,β-dehydrogenation to initiate the formation of a fused five-membered nitrogen heterocycle. The identity of ABCH was validated by utilization of the resultant ABCH-containing unit in the total biosynthesis of ficellomycin. Biochemical characterization, crystal structure, and site-specific mutagenesis rationalize the catalytic mechanism of the unusual oxidase heterotetramer

Double Weibull Model parameters of wild type strain and its mutant derivatives in loamy sand (4A), sandy loam (4B), and silty clay (4C).

<p>Double Weibull Model parameters of wild type strain and its mutant derivatives in loamy sand (4A), sandy loam (4B), and silty clay (4C).</p

Primers for mutants' construction and multiplex PCR.

<p>Primers for mutants' construction and multiplex PCR.</p

Effects of clay content (%), soil organic carbon (OC, %), total nitrogen (T-N, %), water extractable organic carbon (WEOC, mg/kg) <i>Td</i>.

<p>Gray, white, and black columns represent loamy sand, sandy loam, and silty clay, respectively.</p

Bacterial strains and plasmids.

<p>Rif^r, rifampicin resistance; Km^r, kanamycin resistance; Cm^r, chloramphenicol; Ap^r, ampicillin resistance.</p

Growth curves of wild type strain (•) and its derivative mutants strains, Δ<i>stx</i>₁ (◊), Δ<i>eae</i> (▴), Δ<i>stx</i>₂ (□), and Δ<i>stx</i>_1–2 (○).

<p>The data represent the average of triplicate measurements.</p

Survival of the wild type (•) and its mutant derivatives, Δ<i>stx</i>₁ (◊), Δ<i>eae</i> (▴), Δ<i>stx</i>₂ (□), and Δ<i>stx</i>_1–2 (○), in loamy sand (3A), sandy loam (3B), and silty clay (3C).

<p>The data represent the average of triplicate experiments.</p

Au@MnS@ZnS Core/Shell/Shell Nanoparticles for Magnetic Resonance Imaging and Enhanced Cancer Radiation Therapy

Although conventional radiotherapy (RT) has been widely used in the clinic to treat cancer, it often has limited therapeutic outcomes and severe toxic effects. There is still a need to develop theranostic agents with both imaging and RT-enhancing functions to improve the accuracy and efficiency of RT. Herein we synthesize Au@MnS@ZnS core/shell/shell nanoparticles with polyethylene glycol (PEG) functionalization, yielding Au@MnS@ZnS-PEG nanoparticles with great stability in different physiological solutions and no significant cytotoxicity. It is found that Au@MnS@ZnS-PEG nanoparticles can enhance the cancer cell killing efficiency induced by RT, as evidenced by multiple in vitro assays. Owing to the existence of paramagnetic Mn²⁺ in the nanoparticle shell, our Au@MnS@ZnS-PEG can be used as a contrast agent for T1-weighted magnetic resonance (MR) imaging, which reveals the efficient accumulation and retention of nanoparticles in the tumors of mice after intravenous injection. Importantly, by exposing tumor-bearing mice that were injected with Au@MnS@ZnS-PEG to X-ray irradiation, the tumor growth can be significantly inhibited. This result shows clearly improved therapeutic efficacy compared to RT alone. Furthermore, no obvious side effect of Au@MnS@ZnS-PEG is observed in the injected mice. Therefore, our work presents a new type of radiosensitizing agent, which is promising for the imaging-guided enhanced RT treatment of cancer

Bacteria-Activated Theranostic Nanoprobes against Methicillin-Resistant <i>Staphylococcus aureus</i> Infection

Despite numerous advanced imaging and sterilization techniques available nowadays, the sensitive <i>in vivo</i> diagnosis and complete elimination of drug-resistant bacterial infections remain big challenges. Here we report a strategy to design activatable theranostic nanoprobes against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) infections. This probe is based on silica nanoparticles coated with vancomycin-modified polyelectrolyte-cypate complexes (SiO₂-Cy-Van), which is activated by an interesting phenomenon of bacteria-responsive dissociation of the polyelectrolyte from silica nanoparticles. Due to the aggregation of hydrophobic cypate fluorophores on silica nanoparticles to induce ground-state quenching, the SiO₂-Cy-Van nanoprobes are nonfluorescent in aqueous environments. We demonstrate that MRSA can effectively pull out the vancomycin-modified polyelectrolyte-cypate complexes from silica nanoparticles and draw them onto their own surface, changing the state of cypate from off (aggregation) to on (disaggregation) and leading to <i>in vitro</i> MRSA-activated near-infrared fluorescence (NIRF) and photothermal elimination involving bacterial cell wall and membrane disruption. <i>In vivo</i> experiments show that this <i>de novo</i>-designed nanoprobe can selectively enable rapid (4 h postinjection) NIRF imaging with high sensitivity (10⁵ colony-forming units) and efficient photothermal therapy (PTT) of MRSA infections in mice. Remarkably, the SiO₂-Cy-Van nano­probes can also afford a long-term tracking (16 days) of the development of MRSA infections, allowing real-time estimation of bacterial load in infected tissues and further providing a possible way to monitor the efficacy of antimicrobial treatment. The strategy of bacteria-activated polyelectrolyte dissociation from nanoparticles proposed in this work could also be used as a general method for the design and fabrication of bacteria-responsive functional nanomaterials that offer possibilities to combat drug-resistant bacterial infections