Fullerene Covalent Passivation of Black Phosphorus Nanosheets toward Enhanced Near-Infrared-II Photothermal Therapy.

Photothermal therapy (PTT) triggered by near-infrared-II (NIR-II, 1000-1700 nm) light is developed as a potential tumor therapy technique with deeper tissue penetration capacity and higher allowable laser power density of the skin than NIR-I (750-1000 nm) biowindow. Black phosphorus (BP) with excellent biocompatibility and favorable biodegradability demonstrates promising applications in PTT but suffers from low ambient stability and limited photothermal conversion efficiency (PCE), and utilization of BP in NIR-II PTT is scarcely reported. Herein, we develop novel fullerene covalently modified few-layer BP nanosheets (BPNSs) with ∼9-layer thickness through an easy one-step esterification process (abbreviated BP-ester-C60), bringing about the dramatically enhanced ambient stability of BPNSs due to bonding of the hydrophobic C60 with high stability and the lone electron pair on the phosphorus atom. BP-ester-C60 is then applied as a photosensitizer in NIR-II PTT, delivering a much higher PCE than the pristine BPNSs. Under 1064 nm NIR-II laser irradiation, in vitro and in vivo antitumor studies reveal that BP-ester-C60 exhibits dramatically enhanced PTT efficacy with considerable biosafety relative to the pristine BPNSs. This is interpreted by the boost of NIR light absorption on account of the modulation of the band energy level resulting from intramolecular electron transfer from BPNSs to C60.

Metallic Carbonitride MXene Based Photonic Hyperthermia for Tumor Therapy.

Photothermal therapy (PTT) as a noninvasive hyperthermia exhibits high potential for anti-cancer treatments. The explosion of efficient photothermal agents (PTAs) keeps developing rapidly. MXene stands out due to its intriguing structures, fantastic photodynamic properties, and good biocompatibility. However, the potential of MXenes has not been sufficiently explored in PTT. Its versatile chemical compositions of MXenes provide vast opportunities to discover new candidates. Considering that the metallic feature is mainly attributed to the metal element, anionic modulation may open a distinct avenue to propel efficient PTAs with metallic nature, which is expected for high light-harvesting over near-infrared (NIR)-I and NIR-II. As a paradigm, metal carbonitride is chosen to visualize the influences of anionic modulation. Taking advantage of electron injection from nitrogen, the distinct carbonitride Ti3 C1.15 N0.85 F0.88 O0.56 (OH)0.56 exhibits a strong NIR absorption (36.6 L g-1 cm-1 at 808 nm, 43.5 L g-1 cm-1 at 1064 nm), resulting in efficient photonic hyperthermia against tumors in vitro and in vivo. Looking through a large family of MXenes, this proof-of-principle demonstration offers a deep understanding between atomic composition and physicochemical properties, which further solidifies MXenes with all the potential for biomedical applications.

Potato growth, photosynthesis, yield, and quality response to regulated deficit drip irrigation under film mulching in a cold and arid environment.

The effects of the amount and timing of regulated deficit drip irrigation under plastic film on potato ('Qingshu 168') growth, photosynthesis, yield, water use efficiency, and quality were examined from 2017 to 2019 in cold and arid northwestern China. In the four stages of potato growth (seedling, tuber initiation, tuber bulking, starch accumulation), eight treatments were designed, with a mild deficit was in treatments WD1 (seedling), WD2 (tuber initiation), WD3 (tuber bulking), and WD4 (starch accumulation); and a moderate deficit in WD5 (seedling), WD6 (tuber initiation), WD7 (tuber bulking), and WD8 (starch accumulation). The net photosynthetic rate, stomatal conductance, and transpiration rate decreased significantly under water deficit in the tuber formation and starch accumulation stages. Although water deficit reduced potato yields, a mild deficit in the seedling stage resulted in the highest yield and water use efficiency at 43,961.91 kg ha-1 and 8.67 kg m-3, respectively. The highest overall quality was in potatoes subjected to mild and moderate water deficit in the seedling stage. Principal component analysis identified mild water stress in the seedling stage as the optimum regulated deficit irrigation regime. The results of this study provide theoretical and technical references for efficient water-saving cultivation and industrialization of potato in northwestern China.

Phototherapy Facilitates Tumor Recruitment and Activation of Natural Killer T cells for Potent Cancer Immunotherapy.

Adoptively transferred natural killer T (NKT) cells confer distinct cancer surveillance without causing obvious side effects, making them a promising candidate for cancer immunotherapy. However, their therapeutic efficacy is limited by inefficient tumor infiltration and inadequate activation in an immunosuppressive tumor microenvironment. To overcome these obstacles, we develop a strategy of using photothermal therapy (PTT) to promote the antitumor ability of adoptively transferred NKT cells. The transferred NKT cells are efficiently recruited to PTT-treated tumors in response to PTT-created inflammation. Moreover, PTT treatment promotes the activation of NKT cells and enhances the NKT cell-initiated immune cascade. As a consequence, the combined therapy of PTT plus NKT cell transfer exhibits excellent growth inhibition of local tumors. Moreover, it efficiently rejects distant tumors and elicits long-term immunological memory to prevent tumor recurrence. Overall, the current study opens new paths to the clinical translation of NKT cells for cancer immunotherapy.

Pre- and post-irradiation mild hyperthermia enabled by NIR-II for sensitizing radiotherapy.

The clinical application of cancer radiotherapy is critically impeded by hypoxia-induced radioresistance, insufficient DNA damage, and multiple DNA repair mechanisms. Herein we demonstrate a dual-hyperthermia strategy to potentiate radiotherapy by relieving tumor hypoxia and preventing irradiation-induced DNA damage repair. The tumor hyperthermia temperature was well-controlled by a near infrared laser with minimal side effects using PEGylated nanobipyramids (PNBys) as the photo-transducer. PNBys have narrow longitudinal localized surface plasmon resonance peak in NIR-II window with a high extinction coefficient (2.0 × 1011 M-1 cm-1) and an excellent photothermal conversion efficiency (44.2%). PNBys-induced mild hyperthermia (MHt) prior to radiotherapy enables vessel dilation, blood perfusion, and hypoxia relief, resulting in an increased susceptibility of tumor cells response to radiotherapy. On the other hand, MHt after radiotherapy inhibits the repair of DNA damage generated by irradiation. The PNBys exert hierarchically superior antitumor effects by the combination of MHt pre- and post-radiotherapy in murine mammary tumor EMT-6 model. Consequently, different from the simple combination of RT and MHt, the coupling of pre- and post-MHt with RT by PNBys open intriguing avenues towards new promising antitumor efficacy.

Chemotaxis-driven delivery of nano-pathogenoids for complete eradication of tumors post-phototherapy.

The efficacy of nano-mediated drug delivery has been impeded by multiple biological barriers such as the mononuclear phagocyte system (MPS), as well as vascular and interstitial barriers. To overcome the abovementioned obstacles, we report a nano-pathogenoid (NPN) system that can in situ hitchhike circulating neutrophils and supplement photothermal therapy (PTT). Cloaked with bacteria-secreted outer membrane vesicles inheriting pathogen-associated molecular patterns of native bacteria, NPNs are effectively recognized and internalized by neutrophils. The neutrophils migrate towards inflamed tumors, extravasate across the blood vessels, and penetrate through the tumors. Then NPNs are rapidly released from neutrophils in response to inflammatory stimuli and subsequently taken up by tumor cells to exert anticancer effects. Strikingly, due to the excellent targeting efficacy, cisplatin-loaded NPNs combined with PTT completely eradicate tumors in all treated mice. Such a nano-platform represents an efficient and generalizable strategy towards in situ cell hitchhiking as well as enhanced tumor targeted delivery.

Near-Infrared II Phototherapy Induces Deep Tissue Immunogenic Cell Death and Potentiates Cancer Immunotherapy.

The deep and inner beds of solid tumors lack lymphocytic infiltration and are subjected to various immune escape mechanisms. Reversing immunosuppression deep within the tumor is vital in clinical cancer therapy, however it remains a huge challenge. In this work, we have demonstrated the use of a second window near-infrared (NIR(II)) photothermal treatment to trigger more homogeneous and deeper immunogenic cancer cell death in solid tumors, thereby eliciting both innate and adaptive immune responses for tumor control and metastasis prevention. Specifically, photothermal transducers with similar components, structures, and photothermal conversion efficiencies, but different absorptions in red light, NIR(I), and NIR(II) biowindows, were constructed by controlling the self-assembly of gold nanoparticles on fluidic liposomes. In vitro, photothermal treatments induced immunogenic cell death (ICD) that were accompanied by the release of damage-associated molecular patterns (DAMPs) regardless of the wavelength of incident lasers. In vivo, NIR(II) light resulted in a more homogeneous release and distribution of DAMPs in the deeper parts of the tumors. With the induction of ICD, NIR(II) photothermal therapy simultaneously triggered both innate and adaptive immune responses and enabled efficient tumor control with 5/8 of the mice remaining tumor-free in the cancer vaccination assay. Additionally, the NIR(II) photothermal treatment in combination with checkpoint blockade therapy exerted long-term tumor control over both primary and distant tumors. Finally, using systemically administered two-dimensional polypyrrole nanosheets as a NIR(II) transducer, we achieved striking therapeutic effects against whole-body tumor metastasis via a synergistic photothermal-immunological response.

Facile syntheses of conjugated polymers for photothermal tumour therapy.

Development of photothermal materials which are able to harness sunlight and convert it to thermal energy seems attractive. Besides carbon-based nanomaterials, conjugated polymers are emerging promising photothermal materials but their facile syntheses remain challenging. In this work, by modification of a CBT-Cys click condensation reaction and rational design of the starting materials, we facilely synthesize conjugated polymers poly-2-phenyl-benzobisthiazole (PPBBT) and its dihexyl derivative with good photothermal properties. Under the irradiation of either sunlight-mimicking Xe light or near-infrared laser, we verify that PPBBT has comparable photothermal heating-up speed to that of star material single-wall carbon nanotube. Moreover, PPBBT is used to fabricate water-soluble NPPPBBT nanoparticles which maintain excellent photothermal properties in vitro and photothermal therapy effect on the tumours exposed to laser irradiation. We envision that our synthetic method provides a facile approach to fabricate conjugated polymers for more promising applications in biomedicine or photovoltaics in the near future.

The complete nucleotide sequence of chloroplast genome of Gentiana apiata (Gentianaceae), an endemic medicinal herb in China.

Gentiana apiata N. E. Brown (Gentianaceae) is a perennial herb plant and only grows in Qinba Mountains in China. Here, we first characterized the complete nucleotide sequence of chloroplast (cp) genome of G. apiata via Illumina next generation sequencing platform. The complete chloroplast genome of G. apiata was 144,274 bp in length, comprising of a large single copy (LSC) region of 77,353 bp, a small single copy (SSC) region of 17,009 bp, and two inverted repeat regions (IRs) of 24,956 bp. The cp genome contains 127 genes, including 82 protein-coding genes, 35 tRNA, eight rRNA genes, and two pseudogenes. Phylogenetic analysis based on 18 cp genome sequences showed that G. apiata closely related to congeneric species.

Enzyme Degradable Hyperbranched Polyphosphoester Micellar Nanomedicines for NIR Imaging-Guided Chemo-Photothermal Therapy of Drug-Resistant Cancers.

Multidrug resistance (MDR) is the major cause for chemotherapy failure, which constitutes a formidable challenge in the field of cancer therapy. The synergistic chemo-photothermal treatment has been reported to be a potential strategy to overcome MDR. In this work, rationally designed enzyme-degradable, hyperbranched polyphosphoester nanomedicines were developed for reversing MDR via the codelivery of doxorubicin and IR-780 (hPPEDOX&IR) as combined chemo-photothermal therapy. The amphiphilic hyperbranched polyphosphoesters with phosphate bond as the branching point were synthesized via a simple but robust one-step polycondensation reaction. The self-assembled hPPEDOX&IR exhibited good serum stability, sustained release, preferable tumor accumulation, and enhanced drug influx of doxorubicin in resistant MCF-7/ADR cells. Moreover, the degradation of hPPEDOX&IR was accelerated in the presence of alkaline phosphatase, which was overexpressed in various cancers, resulting in the fast release of encapsulated doxorubicin. The enzyme-degradable polymer generated synergistic chemo-photothermal cytotoxicity against MCF-7/ADR cells and, thus, the efficient ablation of DOX-resistant tumor without regrowth. This delivery system may open a new avenue for codelivery of chemo- and photothermal therapeutics for MDR tumor therapy.

Adaptive immune cells are necessary for the enhanced therapeutic effect of sorafenib-loaded nanoparticles.

Sorafenib is a kinase inhibitor approved for the treatment of primary kidney cancer, advanced primary liver cancer, and radioactive iodine resistant advanced thyroid carcinoma. However, sorafenib usually causes serious side effects, which limit its antitumor effect. Nanoparticle based drug delivery systems have been widely used to enhance the therapeutic effects and reduce the side effects of this drug by the enhanced permeability and retention (EPR) effect. Herein, to improve the therapeutic effect of sorafenib, we developed poly(ethylene glycol)-b-poly(lactic acid-co-glycolic acid) (PEG-PLGA) based nanoparticles by a dialysis method for sorafenib encapsulation. After intravenous injection of the sorafenib loaded nanoparticles (NPsorafenib), the tumor growth of mice bearing B16-F10, MC38 and LLC tumor was significantly inhibited. Meanwhile, the dose of sorafenib was reduced to one ninth and the side effects on the hematopoietic system and immune system were abrogated. More importantly, the tumor growth inhibition effect of NPsorafenib was dramatically reduced in B16-F10 bearing Rag1-/- mice which are adaptive immune cell defective, indicating that the antitumor effects of NPsorafenib are dependent on the adaptive immune cells. These results emphasize the indispensable role of the adaptive immune system in nano-drug mediated antitumor effects and the adaptive immune system should be considered as an important factor for clinical applications.

Extracellular biosynthesis of copper sulfide nanoparticles by Shewanella oneidensis MR-1 as a photothermal agent.

Photothermal therapy (PTT) is a minimally invasive and effective cancer treatment method and has a great potential for innovating the conventional chemotherapy approaches. Copper sulfide (CuS) exhibits photostability, low cost, and high absorption in near infrared region, and is recognized as an ideal candidate for PTT. However, CuS, as a photothermal agent, is usually synthesized with traditional chemical approaches, which require high temperature, additional stabilization and hydrophilic modification. Herein, we report, for the first time, the preparation of CuS nanoparticles as a photothermal agent by a dissimilatory metal reducing bacterium Shewanella. oneidensis MR-1. The prepared nanoparticles are homogenously shaped, hydrophilic, small-sized (∼5nm) and highly stable. Furthermore, the biosynthesized CuS nanoparticles display a high photothermal conversion efficiency of 27.2% because of their strong absorption at 1100nm. The CuS nanoparticles could be effectively used as a PTT agent under the irradiation of 1064nm. This work provides a simple, eco-friendly and cost-effective approach for fabricating PTT agents.

Using SV119-gold nanocage conjugates to eradicate cancer stem cells through a combination of photothermal and chemo therapies.

Cancer stem cells (CSCs) are believed to be responsible for the long-term growth of a tumor, as well as its metastasis and recurrence after conventional therapies. Here, it is demonstrated that the sigma-2 receptor is overexpressed on the surface of breast CSCs, and thus could serve as a biomarker for the purpose of targeting. Breast CSCs are targeted with Au nanocages (AuNCs) by functionalizing their surfaces with SV119, a synthetic small molecule capable of binding to the sigma-2 receptor with high specificity. The interiors of the AuNCs could also be loaded with an anticancer drug to be selectively delivered to breast CSCs and released in a controllable fashion. The results demonstrate that the SV119-AuNC conjugate can serve as a new platform to carry out photothermal and chemo therapies simultaneously, eradicating breast CSCs more effectively through a synergetic effect.

Mitochondrial protective effects of Myrica rubra extract against acetaminophen-induced toxicity.

The present study investigates the hepatoprotective activity of Myrica rubra Sieb. et Zucc. extract (MCE) against acetaminophen (AAP)-induced liver damage and elucidates the possible mechanisms behind the hepatoprotection observed. Serum alanine aminotransferase and serum aspartate aminotransferase activities were detected and liver histopathology was observed. Mitochondrial swelling, mitochondrial membrane potential, and voltage-dependent anion channel (VDAC) gene transcription were also investigated. The results showed that 50, 150, and 450 mg/kg MCE could restore AAP-induced changes in mice liver in a dose-dependent manner. The mechanisms behind the hepatoprotective effects of MCE may be related to the mitochondrial protection of liver cells, especially of VDAC, an important protein on the outer membrane of the mitochondria.

Tumoricidal effects of a selenium (Se)-polysaccharide from Ziyang green tea on human osteosarcoma U-2 OS cells.

Selenium(Se)-enriched green tea consumption in human diets is well-known to reduce the risk of a variety of diseases. Here, we isolated a Se-polysaccharide (Se-ZYTP) from Se-enriched Ziyang green tea and investigated its antitumor activity on human osteosarcoma U-2 OS cells in vitro and in vivo. Se-ZYTP contained 94.5% of carbohydrate and 2.1% of uronic acid, as well as 2.14 µg/g Se, revealing that Se-ZYTP was an acidic Se-conjugated polysaccharide. Monosaccharide composition analysis indicated that Se-ZYTP consisted of mannose, rhamnose and fucose in molar ratios of 2.4:1.5:1.2:0.2:0.1:0.3:0.3. In vitro, both MTT and LTH assays proved that Se-ZYTP (25, 50, 100 and 200 µg/ml) could significantly inhibit the proliferation of human osteosarcoma U-2 OS cells in a concentration-dependent fashion (P<0.05 or P<0.01). In U-2 OS cancer xenograft model in BALB/c athymic mice, Se-ZYTP oral administration at three doses of 100, 200 and 400mg/kg body weight (B.W.) daily for 28 days resulted in obvious tumor regression as compared to model control (P<0.05 or P<0.01). In addition, body weights of mice in control or Se-ZYTP treated groups did not differ significantly and no mice died during experiment, suggesting the safety of Se-ZYTP. Therefore, we postulate that Se-ZYTP might have cancer-preventive and cancer-therapeutic benefit for human osteosarcoma.

Comparison study of gold nanohexapods, nanorods, and nanocages for photothermal cancer treatment.

Gold nanohexapods represent a novel class of optically tunable nanostructures consisting of an octahedral core and six arms grown on its vertices. By controlling the length of the arms, their localized surface plasmon resonance peaks could be tuned from the visible to the near-infrared region for deep penetration of light into soft tissues. Herein we compare the in vitro and in vivo capabilities of Au nanohexapods as photothermal transducers for theranostic applications by benchmarking against those of Au nanorods and nanocages. While all these Au nanostructures could absorb and convert near-infrared light into heat, Au nanohexapods exhibited the highest cellular uptake and the lowest cytotoxicity in vitro for both the as-prepared and PEGylated nanostructures. In vivo pharmacokinetic studies showed that the PEGylated Au nanohexapods had significant blood circulation and tumor accumulation in a mouse breast cancer model. Following photothermal treatment, substantial heat was produced in situ and the tumor metabolism was greatly reduced for all these Au nanostructures, as determined with (18)F-flourodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT). Combined together, we can conclude that Au nanohexapods are promising candidates for cancer theranostics in terms of both photothermal destruction and contrast-enhanced diagnosis.

Neuroprotective effects of formononetin against NMDA-induced apoptosis in cortical neurons.

Formononetin (FMNT) is an isoflavone found in many herbs including Trifolium pratense L., Spatholobus suberectus Dunn., and Astragalus mongholicus Bunge. The purpose of this study is to investigate pharmacological properties of FMNT on neurotoxicity induced by N-methyl-D-asparate (NMDA) in primary-cultured cortical neurons. The cell viability was significantly decreased after exposure to NMDA (200 µM) for 40 min. Pretreatment of FMNT (10 µM) for 12 h significantly attenuated the cell loss induced by NMDA exposure. Flow cytometry analysis revealed that treatment of FMNT attenuated the number of apoptotic cells, especially the early phase apoptotic cells, induced by NMDA exposure. Western blot analysis showed that FMNT regulated the expression of apoptosis-related proteins by increasing the levels of Bcl-2 and pro-caspase-3 and decreasing the levels of Bax and caspase-3. These findings demonstrate that FMNT is capable of protecting neurons from NMDA-evoked excitotoxic injury and has a potential perspective to the clinical treatment for neurodegenerative disorders in central nervous system.

Myrica rubra Extracts Protect the Liver from CCl(4)-Induced Damage.

The relationship between the expression of mitochondrial voltage-dependent anion channels (VDACs) and the protective effects of Myrica rubra Sieb. Et Zucc fruit extract (MCE) against carbon tetrachloride (CCl(4))-induced liver damage was investigated. Pretreatment with 50 mg kg(-1), 150 mg kg(-1) or 450 mg kg(-1) MCE significantly blocked the CCl(4)-induced increase in both serum aspartate aminotransferase (sAST) and serum alanine aminotransferase (sALT) levels in mice (P < .05 or .01 versus CCl(4) group). Ultrastructural observations of decreased nuclear condensation, ameliorated mitochondrial fragmentation of the cristae and less lipid deposition by an electron microscope confirmed the hepatoprotection. The mitochondrial membrane potential dropped from -191.94 ± 8.84 mV to -132.06 ± 12.26 mV (P < .01) after the mice had been treated with CCl(4). MCE attenuated CCl(4)-induced mitochondrial membrane potential dissipation in a dose-dependent manner. At a dose of 150 or 450 mg kg(-1) of MCE, the mitochondrial membrane potentials were restored (P < .05). Pretreatment with MCE also prevented the elevation of intra-mitochondrial free calcium as observed in the liver of the CCl(4)-insulted mice (P < .01 versus CCl(4) group). In addition, MCE treatment (50-450 mg kg(-1)) significantly increased both transcription and translation of VDAC inhibited by CCl(4). The above data suggest that MCE mitigates the damage to liver mitochondria induced by CCl(4), possibly through the regulation of mitochondrial VDAC, one of the most important proteins in the mitochondrial outer membrane.