Sustainable extraction of ligustilide and ferulic acid from Angelicae Sinensis Radix, for antioxidant and anti-inflammatory activities.

The 2030 Agenda for Sustainable Development envisions a rational use of energy and resources in all technological processes. However, in the extraction methods of compounds from medicinal plants and herbs, there is an urgent to reduce the use of organic solvents and increase the energy efficiency of these methods. Therefore, a sustainable extraction method (enzyme and ultrasonic co-assisted aqueous two-phase extraction, EUA-ATPE) of simultaneous extraction and separation of ferulic acid and ligustilide from Angelicae Sinensis Radix (ASR) was developed by integrating enzyme-assisted extraction (EAE) with ultrasonic-assisted aqueous two-phase extraction (UAE- ATPE). The effects of different enzymes, extraction temperature, pH, ultrasonic time, liquid-to-materials ratio, etc., were optimized by single-factor experiments and central composite design (CCD). Under the optimum conditions, the highest comprehensive evaluation value (CEV) and extraction yield were obtained by EUA-ATPE. Furthermore, recovery (R), partition coefficient (K), and scanning electron microscopy (SEM) analysis revealed that enzyme and ultrasonic treatment improved mass transfer diffusion and increased the degree of cell disruption. Besides, the EUA-ATPE extracts have shown great antioxidant and anti-inflammatory activity in vitro. Finally, compared to different extraction methods, EUA-ATPE achieved higher extraction efficiency and higher energy efficiency due to the synergistic effect between EAE and UAE-ATPE. Therefore, the EUA-ATPE provides a sustainable method for extracting bioactive compounds from medicinal plants and herbs, contributing to Sustainable Development Goals (SDG), including SDG-6, SDG-7, SDG-9, SDG-12, and SDG-15.

Thrombin Based Photothermal-Responsive Nanoplatform for Tumor-Specific Embolization Therapy.

The specific coagulation in the tumor vasculature has the potential for the ablation of solid tumors by cutting off the blood supply. However, the safe delivery of effective vessel occluding agents in the tumor-specific embolization therapy remains challenging. Herein, it is reported that the photothermal responsive tumor-specific embolization therapy based on thrombin (Thr) is delivered by intravenous injection via the phase-change materials (PCM)-based nanoparticles. The wax sealing profile of PCM enables safe delivery and prevents the preleakage of Thr in the blood circulation. While in the tumor site, the thermal effect induced by IR780 triggers the melting of PCM and rapidly releases Thr to generate coagulation in the tumor blood vessels. Based on the safe delivery and controllable release of Thr, thermal responsive tumor-specific embolization therapy could be achieved with high efficiency and no significant damage to normal organs and tissues. The safe administration of Thr to induce vascular infarction in tumors based on PCM nanoparticles in this work shows a promising strategy for improving the therapeutic specificity and efficacy of coagulation-based tumor therapy.

A conserved and seemingly redundant Escherichia coli biotin biosynthesis gene expressed only during anaerobic growth.

Biotin is an essential metabolic cofactor and de novo biotin biosynthetic pathways are widespread in microorganisms and plants. Biotin synthetic genes are generally found clustered into bio operons to facilitate tight regulation since biotin synthesis is a metabolically expensive process. Dethiobiotin synthetase (DTBS) catalyzes the penultimate step of biotin biosynthesis, the formation of 7,8-diaminononanoate (DAPA). In Escherichia coli, DTBS is encoded by the bio operon gene bioD. Several studies have reported transcriptional activation of ynfK a gene of unknown function, under anaerobic conditions. Alignments of YnfK with BioD have led to suggestions that YnfK has DTBS activity. We report that YnfK is a functional DTBS, although an enzyme of poor activity that is poorly expressed. Supplementation of growth medium with DAPA or substitution of BioD active site residues for the corresponding YnfK residues greatly improved the DTBS activity of YnfK. We confirmed that FNR activates transcriptional level of ynfK during anaerobic growth and identified the FNR binding site of ynfK. The ynfK gene is well conserved in γ-proteobacteria.

Infection microenvironment-activated nanoparticles for NIR-II photoacoustic imaging-guided photothermal/chemodynamic synergistic anti-infective therapy.

Subcutaneous abscesses caused by drug-resistant bacteria pose huge challenges to human health. The design of infection microenvironment-activated biomaterials has an advantage for the diagnosis and treatment of infective diseases due to its high specificity and efficiency. Herein, a novel theranostic platform based on Cu2O nanoparticles (NPs) is successfully constructed via a simple, fast and low-cost approach. The Cu2O NPs exhibit high sensitivity to overexpressed H2S and H2O2 in the bacterial infection microenvironment. After in situ injection, the Cu2O NPs will rapidly react with the endogenous H2S to generate Cu9S8 NPs, which exhibits high absorbance in the second near-infrared (NIR-II) biowindow. The Cu9S8 NPs serving as NIR-II photoacoustic contrast agents can exactly distinguish between inflammatory and normal tissues. With the guidance of NIR-II photoacoustic imaging (PAI), H2S-activated photothermal antibacterial therapy (PTAT) can realize excellent antibacterial performance under 1060 nm laser irradiation. Meanwhile, the Cu2O NPs can effectively catalyze H2O2 at the site of inflammation to produce hydroxyl radicals with strong antibacterial property via Fenton-like reaction, resulting in the damage of bacterial cell membrane. Furthermore, the application of Cu2O NPs can enhance epidermic migration and facilitate the re-epithelialization of the infected skin. In vivo experiment shows that 97.9% methicillin-resistant Staphylococcus aureus are eliminated by the synergistic PTAT and chemodynamic antibacterial therapy.

An acidity-responsive polyoxometalate with inflammatory retention for NIR-II photothermal-enhanced chemodynamic antibacterial therapy.

Subcutaneous abscesses caused by drug-resistant pathogens pose a serious challenge to human health. To overcome this problem, herein an acidity-responsive aggregated W/Mo-based polyoxometalate (POM) was developed for photothermal-enhanced chemodynamic antibacterial therapy in the second near-infrared (NIR) region. The POM can self-assemble into larger-sized aggregates with stronger absorption in the NIR region, making it remain in the acidic infected tissue. Furthermore, the hydrogen peroxide at the site of infection can be converted to a hydroxyl radical for chemodynamic therapy (CDT) and simultaneously the glutathione in organisms is consumed by the POM to further enhance the CDT effect. More importantly, under laser irradiation, the hyperthermia produced by the POM not only can kill drug-resistant Staphylococcus aureus, but also enhance the performance of CDT. Benefitting from the inflammatory retention and acidity-responsive photothermal-enhanced CDT properties, the POM exhibits an obvious therapeutic effect against drug-resistant bacterial infection without significant side effects under 1060 nm laser irradiation.

On-demand drug release nanoplatform based on fluorinated aza-BODIPY for imaging-guided chemo-phototherapy.

Intelligent drug delivery systems (DDS), integrating with multi-modal imaging guidance and controlled drug release, have practical significance in enhancing the therapeutic efficiency of tumors. Herein, fluorinated aza-boron-dipyrromethene (NBF) with high near-infrared absorption is synthesized by introducing nonadecafluorodecanoic acid into aza-BODIPY via the amide bond. Through the co-precipitation methods, nanoparticles (NPs) based on NBF are fabricated and the obtained NBF NPs can not only load with DOX with a high loading efficiency (25%, DNBF NPs), but also absorb PFC droplets (1H-perfluoropentane) with bp of 42 °C because of the fluorinated chains inside NBF NPs (PDNBF NPs). Under 808-nm laser irradiation, the hyperthermia effect of NBF could induce the liquid-gas phase transition of PFC droplets, triggering the burst release of DOX and enhancing echo signals for ultrasound imaging as well. With efficient enrichment of PDNBF NPs at tumor site as revealed by in vivo ultrasound imaging and photoacoustic imaging, significant improvement in inhibiting tumor growth is achieved with PDNBF NPs under laser irradiation without noticeable side effects. The work presents a multifunctional organic DDS with great biocompatibility, high drug loading efficiency and light-stimuli-responsive drug release, which provides a new strategy for the manufacture of intelligent composite theranostic nanoplatform.

Fe-Doped Polyoxometalate as Acid-Aggregated Nanoplatform for NIR-II Photothermal-Enhanced Chemodynamic Therapy.

The combination of reactive oxygen species-involved chemodynamic therapy (CDT) and photothermal therapy (PTT) holds great promise in enhancing anticancer effects. Herein, a multifunctional Fe-doped polyoxometalate (Fe-POM) cluster is fabricated via a simple method. The Fe-POM can not only be utilized as PTT agents to generate a hyperthermia effect for cancer cell killing under near-infrared (NIR) II laser (1060 nm) irradiation, but also can be used as CDT agents to convert endogenous less-reactive H2 O2 into harmful ·OH and simultaneously deplete glutathione for an amplified CDT effect. Notably, the hyperthermia induced by PTT can further enhance the CDT effect, achieving a synergistic PTT/CDT effect. Owing to the self-assembling properties at lowered pH values, the Fe-POM exhibits high tumor accumulation as revealed by photoacoustic imaging. More importantly, Fe-POM enables effective destruction of tumors without inducing noticeable damage to normal tissues under 1060 nm laser irradiation. The work presents a new type of multifunctional agent with high PTT/CDT efficacy, providing promising methods for PTT-enhanced CDT in a NIR-II biowindow.

Mo2 C-Derived Polyoxometalate for NIR-II Photoacoustic Imaging-Guided Chemodynamic/Photothermal Synergistic Therapy.

To overcome the current limitations of chemodynamic therapy (CDT), a Mo2 C-derived polyoxometalate (POM) is readily synthesized as a new CDT agent. It permits synergistic chemodynamic and photothermal therapy operating in the second near-infrared (NIR-II) biological transparent window for deep tissue penetration. POM aggregated in an acidic tumor micro-environment (TME) whereby enables specific tumor targeting. In addition to the strong ability to produce singlet oxygen (1 O2 ) presumably via Russell mechanism, its excellent photothermal conversion enhances the CDT effect, offers additional tumor ablation modality, and permits NIR-II photoacoustic imaging. Benefitting from the reversible redox property of molybdenum, the theranostics based on POM can escape from the antioxidant defense system. Moreover, combining the specific responsiveness to TME and localized laser irradiation, side-effects shall be largely avoided.

Photothermal-pH-hypoxia responsive multifunctional nanoplatform for cancer photo-chemo therapy with negligible skin phototoxicity.

Highly specific and effective cancer phototherapy remains as a great challenge. Herein, a smart nanoplatform (TENAB NP) sequentially responsive to light, low pH and hypoxia is demonstrated for multi-mode imaging guided synergistic cancer therapy with negligible skin phototoxicity. Upon 808-nm laser irradiation, TENAB NPs can generate hyperthermia to melt the phase change material (PCM-LASA) coat and thereafter release chemo-drug tirapazamine (TPZ). Meanwhile, under acidic pH, photosensitizer ENAB would turn "off" its charge-transfer state, generating prominent 1O2 for photodynamic therapy (PDT) and heat for photothermal therapy (PTT), respectively. Accompanied with PDT-induced hypoxia, the released TPZ can be activated into its cytotoxic form for tumor cells killing. Notably, owing to phase change material LASA coat and ENAB's pH sensitivity, TENAB NPs show negligible photosensitization to skin and normal tissues. As the multi-stimuli responsive mechanism, TENAB NPs demonstrate a promising future in cancer photo-chemo theranostics with excellent skin protection.

Functional black phosphorus nanosheets for mitochondria-targeting photothermal/photodynamic synergistic cancer therapy.

Organelle-targeting nanosystems are envisioned as promising tools for phototherapy, which can generate heat or reactive oxygen species (ROS) induced cytotoxicity in the targeted location but leave the surrounding biological tissues undamaged. In this work, an imaging-guided mitochondria-targeting photothermal/photodynamic nanosystem has been developed on the basis of functionalized black phosphorus (BP) nanosheets (NSs). In the nanosystem, BP NSs are coated with polydopamine (PDA) and then covalently linked with both chlorin e6 (Ce6) and triphenyl phosphonium (TPP) through carbodiimide reaction between the amino group and the carboxyl group, forming BP@PDA-Ce6&TPP NSs. Due to the strong absorbance of BP@PDA in the near-infrared region and the highly efficient ROS generation of Ce6, the as-prepared nanosystem with mitochondria-targeting capacity (TPP moiety) shows remarkably enhanced efficiency in cancer cell killing. Combined photothermal and photodynamic therapy is implemented and monitored by in vivo fluorescence imaging, achieving excellent performance in inhibiting tumor growth. This study presents a novel nanotheranostic agent for mitochondria-targeting phototherapy, which may open new horizons for biomedicine.

YLT-11, a novel PLK4 inhibitor, inhibits human breast cancer growth via inducing maladjusted centriole duplication and mitotic defect.

Polo-like kinase 4 (PLK4) is indispensable for precise control of centriole duplication. Abnormal expression of PLK4 has been reported in many human cancers, and inhibition of PLK4 activity results in their mitotic arrest and apoptosis. Therefore, PLK4 may be a valid therapeutic target for antitumor therapy. However, clinically available small-molecule inhibitors targeting PLK4 are deficient and their underlying mechanisms still remain not fully clear. Herein, the effects of YLT-11 on breast cancer cells and the associated mechanism were investigated. In vitro, YLT-11 exhibited significant antiproliferation activities against breast cancer cells. Meanwhile, cells treated with YLT-11 exhibited effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication and mitotic defects, sequentially making tumor cells more vulnerable to chemotherapy. Furthermore, YLT-11 could strongly regulate downstream factors of PLK4, which was involved in cell cycle regulation, ultimately inducing apoptosis of breast cancer cell. In vivo, oral administration of YLT-11 significantly suppressed the tumor growth in human breast cancer xenograft models at doses that are well tolerated. In summary, the preclinical data show that YLT-11 could be a promising candidate drug for breast tumor therapy.

Iodine-131-labeled, transferrin-capped polypyrrole nanoparticles for tumor-targeted synergistic photothermal-radioisotope therapy.

Combining different therapeutic functions within single tumor-targeted nanoscale delivery systems is promising to overcome the limitations of conventional cancer therapies. Herein, transferrin that recognizes transferrin receptors up-regulated on tumor cells is pre-labeled with iodine-131 (131I) and then utilized as the stabilizer in the fabrication of polypyrrole (PPy) nanoparticles. The obtained transferrin-capped PPy@Tf-131I nanoparticles could be used for tumor-targeted radioisotope therapy (RIT) and photothermal therapy (PTT), by employing beta-emission from 131I and the intrinsic high near-infrared (NIR) absorbance of PPy, respectively. Owing to the transferrin-mediated tumor targeting, PPy@Tf-131I nanoparticles exhibit obviously enhanced in vitro cancer cell binding and in vivo tumor uptake compared to its non-targeting counterpart. The combined RIT and PTT based on PPy@Tf-131I nanoparticles is then conducted, achieving a remarkable synergistic therapeutic effect. This work thus demonstrates a rather simple one-step approach to fabricate tumor-targeting nanoparticles based on protein-capped conjugated polymers, promising for combination cancer therapy with great efficacy and high safety.

Photosensitizer-Conjugated Albumin-Polypyrrole Nanoparticles for Imaging-Guided In Vivo Photodynamic/Photothermal Therapy.

Conjugated polymers with strong absorbance in the near-infrared (NIR) region have been widely explored as photothermal therapy agents due to their excellent photostability and high photothermal conversion efficiency. Herein, polypyrrole (PPy) nanoparticles are fabricated by using bovine serum albumin (BSA) as the stabilizing agent, which if preconjugated with photosensitizer chlorin e6 (Ce6) could offer additional functionalities in both imaging and therapy. The obtained PPy@BSA-Ce6 nanoparticles exhibit little dark toxicity to cells, and are able to trigger both photodynamic therapy (PDT) and photothermal therapy (PTT). As a fluorescent molecule that in the meantime could form chelate complex with Gd(3+), Ce6 in PPy@BSA-Ce6 nanoparticles after being labeled with Gd(3+) enables dual-modal fluorescence and magnetic resonance (MR) imaging, which illustrate strong tumor uptake of those nanoparticles after intravenous injection into tumor-bearing mice. In vivo combined PDT and PTT treatment is then carried out after systemic administration of PPy@BSA-Ce6, achieving a remarkably improved synergistic therapeutic effect compared to PDT or PTT alone. Hence, a rather simple one-step approach to fabricate multifunctional nanoparticles based on conjugated polymers, which appear to be promising in cancer imaging and combination therapy, is presented.

Nano-assemblies of J-aggregates based on a NIR dye as a multifunctional drug carrier for combination cancer therapy.

The combination of chemotherapy with photothermal therapy, which may lead to improved therapeutic efficacies and reduced side effects of conventional chemotherapy, would require safe drug delivery systems (DDSs) with strong near-infrared (NIR) absorbance, efficient drug loading, and effective tumor homing ability. Herein, we fabricate nano-assemblies containing J-aggregates of a NIR dye, IR825, for drug delivery and combined photothermal & chemotherapy of cancer. It is found that IR825 could be complexed with a low-molecular-weight cationic polymer polyethylenimine (PEI), forming IR825@PEI J-aggregates with greatly enhanced NIR absorbance red-shifted to 915 nm. Those nano-assemblies of J-aggregates are further modified with polyethylene glycol (PEG), obtaining IR825@PEI-PEG nano-complex which exhibits great dispersity in physiological solutions, excellent photostability, and is able to efficiently load chemotherapeutic drug doxorubicin (DOX) via a unique strategy different from drug loading in conventional amphiphilic polymer-based DDSs. In vivo animal experiments uncover that IR825@PEI-PEG/DOX upon intravenous injection into tumor-bearing mice shows rather high tumor uptake as illustrated by photoacoustic imaging. In vivo combined photothermal & chemotherapy is then carried out, demonstrating great synergistic anti-tumor therapeutic effect remarkably superior to those achieved by the respective mono-therapies. Hence, we present a novel type of nanoscale DDSs based on nano-assemblies of small molecules without involving amphiphilic polymers, promising for imaging-guided combination cancer therapy.

Iron oxide decorated MoS2 nanosheets with double PEGylation for chelator-free radiolabeling and multimodal imaging guided photothermal therapy.

Theranostics for in vivo cancer diagnosis and treatment generally requires well-designed nanoscale platforms with multiple integrated functionalities. In this study, we uncover that functionalized iron oxide nanoparticles (IONPs) could be self-assembled on the surface of two-dimensional MoS2 nanosheets via sulfur chemistry, forming MoS2-IO nanocomposites, which are then modified with two types of polyethylene glycol (PEG) to acquire enhanced stability in physiological environments. Interestingly, (64)Cu, a commonly used positron-emitting radioisotope, could be firmly adsorbed on the surface of MoS2 without the need of chelating molecules, to enable in vivo positron emission tomography (PET) imaging. On the other hand, the strong near-infrared (NIR) and superparamagnetism of MoS2-IO-PEG could also be utilized for photoacoustic tomography (PAT) and magnetic resonance (MR) imaging, respectively. Under the guidance by such triple-modal imaging, which uncovers efficient tumor retention of MoS2-IO-(d)PEG upon intravenous injection, in vivo photothermal therapy is finally conducted, achieving effective tumor ablation in an animal tumor model. Our study highlights the promise of constructing multifunctional theranostic nanocomposites based on 2D transitional metal dichalcogenides for multimodal imaging-guided cancer therapy.

J-aggregates of organic dye molecules complexed with iron oxide nanoparticles for imaging-guided photothermal therapy under 915-nm light.

Recently, the development of nano-theranostic agents aiming at imaging guided therapy has received great attention. In this work, a near-infrared (NIR) heptamethine indocyanine dye, IR825, in the presence of cationic polymer, polyallylamine hydrochloride (PAH), forms J-aggregates with red-shifted and significantly enhanced absorbance. After further complexing with ultra-small iron oxide nanoparticles (IONPs) and the followed functionalization with polyethylene glycol (PEG), the obtained IR825@PAH-IONP-PEG composite nanoparticles are highly stable in different physiological media. With a sharp absorbance peak, IR825@PAH-IONP-PEG can serve as an effective photothermal agent under laser irradiation at 915 nm, which appears to be optimal in photothermal therapy application considering its improved tissue penetration compared with 808-nm light and much lower water heating in comparison to 980-nm light. As revealed by magnetic resonance (MR) imaging, those nanoparticles after intravenous injection exhibit high tumor accumulation, which is then harnessed for in vivo photothermal ablation of tumors, achieving excellent therapeutic efficacy in a mouse tumor model. This study demonstrates for the first time that J-aggregates of organic dye molecules are an interesting class of photothermal material, which when combined with other imageable nanoprobes could serve as a theranostic agent for imaging-guided photothermal therapy of cancer.