Moderate Fields, Maximum Potential: Achieving High Records with Temperature-Stable Energy Storage in Lead-Free BNT-Based Ceramics.

The increasing awareness of environmental concerns has prompted a surge in the exploration of lead-free, high-power ceramic capacitors. Ongoing efforts to develop lead-free dielectric ceramics with exceptional energy-storage performance (ESP) have predominantly relied on multi-component composite strategies, often accomplished under ultrahigh electric fields. However, this approach poses challenges in insulation and system downsizing due to the necessary working voltage under such conditions. Despite extensive study, bulk ceramics of (Bi0.5Na0.5)TiO3 (BNT), a prominent lead-free dielectric ceramic family, have seldom achieved a recoverable energy-storage (ES) density (Wrec) exceeding 7 J cm-3. This study introduces a novel approach to attain ceramic capacitors with high ESP under moderate electric fields by regulating permittivity based on a linear dielectric model, enhancing insulation quality, and engineering domain structures through chemical formula optimization. The incorporation of SrTiO3 (ST) into the BNT matrix is revealed to reduce the dielectric constant, while the addition of Bi(Mg2/3Nb1/3)O3 (BMN) aids in maintaining polarization. Additionally, the study elucidates the methodology to achieve high ESP at moderate electric fields ranging from 300 to 500 kV cm-1. In our optimized composition, 0.5(Bi0.5Na0.4K0.1)TiO3-0.5(2/3ST-1/3BMN) (B-0.5SB) ceramics, we achieved a Wrec of 7.19 J cm-3 with an efficiency of 93.8% at 460 kV cm-1. Impressively, the B-0.5SB ceramics exhibit remarkable thermal stability between 30 and 140 °C under 365 kV cm-1, maintaining a Wrec exceeding 5 J cm-3. This study not only establishes the B-0.5SB ceramics as promising candidates for ES materials but also demonstrates the feasibility of optimizing ESP by modifying the dielectric constant under specific electric field conditions. Simultaneously, it provides valuable insights for the future design of ceramic capacitors with high ESP under constraints of limited electric field.

Ultrahigh Electrostrictive Effect in Lead-Free Ferroelectric Ceramics Via Texture Engineering.

The electrostrictive effect, which induces strain in ferroelectric ceramics, offers distinct advantages over its piezoelectric counterpart for high-precision actuator applications, including anhysteretic behavior even at high frequencies, rapid reaction times, and no requirement for poling. Historically, commercially available electrostrictive materials have been lead oxide-based. However, global restrictions on the use of lead in electronic components necessitate the exploration of lead-free electrostrictive ceramics with a high strain performance. Although various engineering strategies for producing materials with high strain have been proposed, they typically come at the expense of increased strain hysteresis. Here, we describe the extraordinary electrostrictive response of (Ba0.95Ca0.05)(Ti0.88Sn0.12)O3 (BCTS) ceramics with ultrahigh electrostrictive strain and negligible hysteresis achieved through texture engineering leveraging the anisotropic intrinsic lattice contribution. The BCTS ceramics exhibit a high unipolar strain of 0.175%, a substantial electrostrictive coefficient Q33 of 0.0715 m4 C-2, and an ultralow hysteresis of less than 0.8%. Notably, the Q33 value is three times greater than that of high-performance lead-based Pb(Mg1/3Nb2/3)O3 electrostrictive ceramics. Multiscale structural analyses demonstrate that the electrostrictive effect dominates the BCTS strain response. This research introduces a novel approach to texture engineering to enhance the electrostrictive effect, offering a promising paradigm for future advancements in this field.

Conformally Large-Area Single-Crystal Piezocomposites with High Performance for Acoustic Transducers.

Large-area and conformal piezoelectric elements are highly desired for acoustic transducers to possess a large power source level and wide detecting range. To date, single-crystal piezocomposites attract much attention on enhancing the power source level and bandwidth for next-generation acoustic transducers, owing to their higher piezoelectric and electromechanical coupling properties compared to traditional piezocomposites. Unfortunately, it is still challenging to achieve large-area and conformal single-crystal piezocomposites because of the fragile nature, large anisotropy, and the limited grown size of piezoelectric single crystals. Here, we successfully fabricate the conformally large-area single-crystal piezocomposite with an area of 160 × 50 mm2 and a bending angle of 162° by a modified 3D-printing-assisted inserting method. The single-crystal piezocomposite exhibits a high thickness electromechanical coupling factor kt of 85% and a large piezoelectric coefficient d33 of 1150 pC/N, surpassing those of the reported large-area piezocomposites. The influence of the volume fraction and curvature radius of single-crystal PCs and acoustic transducers was investigated. Furthermore, we designed an acoustic transducer based on the conformal single-crystal piezocomposite. Benefiting from the excellent piezoelectric and electromechanical properties of the single-crystal piezocomposite, the transducer indicates a high maximum transmitting voltage response of 171.8 dB. Especially, its bandwidth (-3 dB) achieves 60 kHz with a resonant frequency of 292 kHz, which is about 1.8 times superior to the conformal acoustic transducer based on the ceramic piezocomposite with a similar resonant frequency. This work may benefit the future design and fabrication of high-performance and complex-shape piezoelectric composites as key materials for next-generation transducers.

Effects of Lactobacillus plantarum fermented Shenling Baizhu San on gut microbiota, antioxidant capacity, and intestinal barrier function of yellow-plumed broilers.

The current study focused on the effects of Shenling Baizhu San (SLBZS) fermented by Lactobacillus plantarum (L. plantarum) on gut microbiota, antioxidant capacity, and intestinal barrier function of yellow-plumed broilers. Our results showed that the content of ginsenoside Rb1 was the highest when SLBZS were inoculated with 3% L. plantarum and fermented at 28°C for 24 h. One-day-old male broilers were divided into five treatment groups. Treatment consisted of a basal diet as a control (Con), 0.1% unfermented SLBZS (U-SLBZS), 0.05% fermented SLBZS (F-SLBZS-L), 0.1% fermented SLBZS (F-SLBZS-M), and 0.2% fermented SLBZS (F-SLBZS-H). On days 14, 28, and 42, six chickens from each group were randomly selected for blood collection and tissue sampling. The results showed that the addition of 0.1% fermented SLBZS could significantly increase average daily feed intake (ADFI) and average daily gain (ADG), and decrease feed conversion ratio (FCR) of broilers. The addition of 0.1 and 0.2% fermented SLBZS significantly increased the lymphoid organ index of broilers on day 28 and 42. The addition of 0.1 and 0.2% fermented SLBZS could improve the antioxidant capacity of broilers. Moreover, the addition of 0.1 and 0.2% fermented SLBZS could significantly increase the villus height/crypt depth of the ileum, and significantly increase the expression of tight junction. In addition, fermentation of SLBZS increase the abundance of Coprococcus, Bifidobacterium and Bilophila in the gut of broilers. These results indicate that the supplementation of fermented SLBZS in the diet could improve the growth performance, lymphoid organ index, antioxidant capacity, and positively affect the intestinal health of broilers.

Enhanced Energy Storage Properties in Lead-Free (Na0.5Bi0.5)0.7Sr0.3TiO3-Based Relaxor Ferroelectric Ceramics through a Cooperative Optimization Strategy.

Although relaxor ferroelectrics have been widely investigated owing to their various advantages, there are still impediments to boosting their energy-storage density (Wrec) and energy-storage efficiency (η). In this paper, we propose a cooperative optimization strategy for achieving comprehensive outstanding energy-storage performance in (Na0.5Bi0.5)0.7Sr0.3TiO3 (NBST)-based ceramics by triggering a nonergodic-to-ergodic transformation and optimizing the forming process. The first step of substituting NaNbO3 (NN) for NBST generated an ergodic state and induced polar nanoregions under the guidance of a phase-field simulation. The second step was to apply a viscous polymer process (VPP) to the 0.85NBST-0.15NN ceramics, which reduced porosity and increased compactness, resulting in a significant polarization difference and high breakdown strength. Consequently, 0.85NBST-0.15NN-VPP ceramics optimized by this cooperative two-step strategy possessed improved energy-storage characteristics (Wrec = 7.6 J/cm3, η = 90%) under 410 kV/cm as well as reliable temperature adaptability within a range of 20-120 °C, outperforming most reported (Na0.5Bi0.5) TiO3-based ceramics. The improved energy-storage performance validates the developed ceramics' practical applicability as well as the advantages of implementing a cooperative optimization technique to fabricate similar high-performance dielectric ceramics.

Transcriptome profiling Revealed the potential mechanisms of Shen Lin Bai Zhu San n-butanol extract on DSS induced Colitis in Mice and LC-MS analysis.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disorder in gastrointestinal tract. Shen Ling Bai Zhu San (SLBZS), which has a long history of use in Traditional Chinese Medicine (TCM), has been widely used to treat gastrointestinal diseases. The isolated fractions of TCM have also been proved to possess an important potential for treating diseases, which are due to their effective components. PURPOSE: In this study, we examined the possibility that SLBZS and its isolated active fractions may prevent DSS-induced colitis, and investigated the potential mechanisms by regulating genetic profile of colon. METHODS: Colitis mice were induced by 2.5% DSS for 7 days, and then SLBZS and different SLBZS extracts were administrated to protect the mice for 7 days. Body weight, diarrhea, bleeding in stool, colon length, spleen weight, cytokines of serum and colon and pathology of colon were assessed. The level of Ginsenoside Rg1, Re and Rb1 in different SLBZS extracts and qualitative analysis of n-butanol extract of SLBZS (S-Nb) was performed by HPLC and LC-MS, respectively. And the effects of S-Nb on the transcriptome in colitis were investigated. RESULTS: Our results showed that SLBZS and S-Nb significantly regained body weight, reduced DAI, splenomegaly and the length of colon and attenuated histological damage of the colon. Meanwhile, SLBZS and S-Nb markedly reduced the levels of TNF-α, IL-1ß and IL-6 and increased the level of IL-10 in serum and colon. These effects may be associated with the high levels of Ginsenoside Rg1, Re and Rb1 and rich variety of compounds in S-Nb including 6 ginsenosides, glycyrrhizin, L-tryptophan, and so on. Transcriptome analysis revealed that S-Nb selectively regulated 103 differentially expressed genes (DEGs), 36 of which were changed in DSS-induced mice. And the genes of Per2, Per3, Npy and Serpina3m were closely related to colitis and also restored by S-Nb with different extent. Remarkably, these DEGs modulated the biological functions of colitis mice, including extracellular region, response to external stimulus, MAPK signaling pathway and arginine and proline metabolism. CONCLUSIONS: These data indicated that SLBZS and S-Nb blunted DSS-induced colitis by modulating differentially expression gene profile and biological functions based on their ginsenosides and rich compounds.

Polyphenol Rich Forsythia suspensa Extract Alleviates DSS-Induced Ulcerative Colitis in Mice through the Nrf2-NLRP3 Pathway.

This study systematically evaluated the effect of Forsythia suspensa extract on dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) and determined its mechanism of action. The results showed that Forsythia suspensa extract significantly inhibited DSS-induced UC in mice. In vivo mechanistic studies revealed that Forsythia suspensa extract relieved the symptoms of colitis by enhancing antioxidant activity and inhibiting pyroptosis. Further in vitro experiments on the mechanism of Forsythia suspensa showed that it reduced the level of reactive oxygen species (ROS) in J774A.1 cells. We found that Forsythia suspensa extract enhanced cellular antioxidation activity and inhibited pyroptosis. After silencing NLRP3, it was found to play an important role in pyroptosis. In addition, after Nrf2 was silenced, the inhibitory effect of Forsythia suspensa extract on cell pyroptosis was eliminated, indicating an interaction between Nrf2 and NLRP3. Metabonomics revealed that Forsythia suspensa extract significantly improved metabolic function in colitis mice by reversing the abnormal changes in the levels of 9 metabolites. The main metabolic pathways involved were glutathione metabolism, aminoacyl-tRNA biosynthesis and linoleic acid metabolism. In conclusion, we found that Forsythia suspensa extract significantly alleviated DSS-induced UC injury through the Nrf2-NLRP3 pathway and relieved metabolic dysfunction.

High-Performance Curved Piezoelectric Single-Crystal Composites via 3D-Printing-Assisted Dice and Insert Technology for Underwater Acoustic Transducer Applications.

Piezoelectric single-crystal composites (PSCCs) have been studied and applied because of their improved resolution and power source level performance in underwater acoustic transducer applications relative to traditional piezoelectric ceramic composites (PCCs). Currently, the methods to fabricate curved PSCCs are mostly derived from PCCs, including molding with flexible backing, molding with heating, and molding with the casting rubber method. Unfortunately, the methods mentioned above are not suitable for preparing curved PSCCs for underwater acoustic transducer applications because of their brittleness, the large anisotropy of piezoelectric single crystals, and the high thickness (>2 mm) of PSCCs for achieving the low operating frequency (<700 kHz). In the present work, we proposed a preparation method, 3D-printing-assisted dice and insert technology, and successfully prepared curved PSCCs with high performance. Although the PSCCs have a low volume fraction of single crystals in this work (∼33%), a high thickness electromechanical factor kt of 86% and a large piezoelectric coefficient d33 of 1550 pC/N were achieved in the curved 1-3 PSCCs, which are superior to other reported PSCCs and PCCs with nearly the same volume fraction of single crystals and piezoelectric ceramics. This work presents a paradigm for fabricating curved PSCCs for underwater acoustic transducers, and this method shows the potential for large-area, special-shaped PSCCs, which are key materials for next-generation underwater acoustic transducers.

[Curcumin targeting miR-155-5p/TP53INP1 axis induced oxidative stress to regulate salivary gland tumor cell proliferation and apoptosis].

PURPOSE: To investigate the mechanism of curcumin targeting miR-155-5p/TP53INP1 axis to induce oxidative stress to regulate salivary gland tumor cell proliferation and apoptosis. METHODS: A253 cells were cultured by adding curcumin and transfected with miR-155-5p mimic and/or pcDNA3.1-TP53INP1. Cell proliferation was detected by CCK-8 assay cell apoptosis was detected by flow cytometry, cell migration ability was detected by scratch test. The targeting relationship between miR-155-5p and TP53INP1 was verified by dual luciferase reporter assay. miR-155-5p, TP53INP1 mRNA expression was detected by qRT-PCR. Western blot was performed to detect expression of TP53INP1, Caspase8, Caspase3, Bcl-2, Bax protein; and ELISA was used to determine SOD, Gpx, and MDA content. Statistical analysis was performed using SPSS 22.0 software package. RESULTS: Dual luciferase reporter assay confirmed that TP53INP1 was a downstream target regulatory molecule of miR-155-5p. Compared with DMSO group, cell apoptosis, Caspase8, Caspase3, Bax protein expression and TP53INP1 expression were significantly increased in curcumin group, while Bcl-2 protein expression, miR-155-5p mRNA and number of cell migration were significantly decreased(P<0.05). Compared with curcumin + miR-155-5p mimic group, cell apoptosis, Caspase8, Caspase3, Bax protein expression was significantly increased in curcumin + pcDNA3.1-TP53INP1 group and curcumin + miR-155-5p mimic + pcDNA3.1-TP53INP1 group; Bcl-2 protein expression was significantly increased(P<0.05), SOD, GSH-PX activities and number of cell migration were significantly decreased and MDA content was significantly increased in curcumin+pcDNA3.1-TP53INP1 group (P<0.05). CONCLUSIONS: Curcumin inhibited A253 cell proliferation and promoted A253 cell apoptosis. The mechanism may be related to targeting miR-155-5p/TP53INP1 axis to induce oxidative stress regulation.

Comparative Evaluation of Forsythiae Fructus From Different Harvest Seasons and Regions by HPLC/NIR Analysis and Anti-inflammatory and Antioxidant Assays.

Forsythiae Fructus (FF), the dry fruit of Forsythia suspensa (Thunb.) Vahl, has a long history of use in traditional Chinese Medicine for its heat-clearing and detoxifying properties. It possesses clinical therapeutic effects and biological functions showing efficacy in handling different diseases. To investigate the FF differences in Henan, Shanxi, and Shaanxi in August and October, the surface morphology, mid-infrared and near-infrared spectrums, and HPLC were analyzed. Concurrently, the anti-inflammatory and antioxidant effects on LPS-induced J774A.1 cells were evaluated by western blot and RT-qPCR. The results showed that FF from different Harvest Seasons and Regions are provided with different microstructures and mid-infrared and near-infrared spectrums, and the levels of forsythiaside A and phillyrin of FF from Shanxi in August and phillygenin of FF from Shaanxi in August were the highest. Meanwhile, FF from Shanxi and Shaanxi in August markedly reduced the levels of inflammatory cytokines and mediators (TNF-α, IL-1ß, NF-κB, and iNOS) and the protein expression levels of phosphorylated total IKKα/ß and nuclear NF-κB. In August, SXFF and SAXFF also promoted the mRNA expression levels of HO-1 and NQO1 and the protein expression levels of HO-1 and nuclear Nrf2 and suppressed the protein expression levels of KEAP1. Spearman correlation analysis showed that phillygenin had a strong correlation with the protein expression on LPS-induced J774A.1 cells. In summary, our results showed that FF from harvest seasons and regions contributed to the distinct differences in microstructure, the mid-infrared and near-infrared spectrums, and compound content. More importantly, FF from Shanxi and Shaanxi in August showed marked anti-inflammatory and antioxidant activities, but with some differences, which may be because of different contents of phillygenin and phillyrin of lignans in FF.

Extremely High Piezoelectric Properties in Pb-Based Ceramics through Integrating Phase Boundary and Defect Engineering.

An ultrahigh piezoelectric coefficient is always desired for electromechanical devices and systems. However, for a long time, a large d33 value in lead-based and lead-free piezoelectric ceramics was usually obtained at the expense of their Tc, and vice versa, limiting their practical applications. Here, we proposed a design concept, i.e., integrating phase boundary and defect engineering, to resolve the above challenges, based on a concrete example of Fe-modified 0.51Pb(Hf0.35Ti0.65)O3-0.49Pb(Nb2/3Ni1/3)O3 (0.51PHT-0.49PNN) ceramics. An abnormally high d33 value of 1124 pC/N and a Tc of 133 °C were achieved simultaneously in this study, which are obviously superior to those of other reported representative lead-based and lead-free piezoelectric ceramics, which made a giant step forward in both piezoelectric material research and electromechanical applications. A large strain response of 0.28% and low hysteresis were also obtained under an applied field of 20 kV/cm in the 0.51PHT-0.49PNN ceramic. The phase-field simulations and piezoresponse force microscopy demonstrated that the high piezoelectric performance should be attributed to the formation of mesoscopic domains resulting from morphotropic phase boundary and defect dipoles. Most importantly, this work provides an avenue for the development of piezoelectric ceramics with ultrahigh d33 and high Tc and has the potential to lead to the development of a range of high-performance Pb-based ceramics for electromechanical applications in the future.

Large-Area Piezoelectric Single Crystal Composites via 3-D-Printing-Assisted Dice-and-Insert Technology for Hydrophone Applications.

Compared with Pb(Zr,Ti)O3 (PZT) ceramics, piezoelectric ceramic composites (PCCs), and piezoelectric polyvinylidene fluoride (PVDF) polymer, piezoelectric single crystal composites (PSCCs) are thought to be the promising candidates for hydrophone applications because of their superior hydrostatic performance. However, due to the brittleness and small dimensions of single crystals, the preparation of large-area or conformal PSCCs is to be challenged. Herein, we prepared a large-area PSCC with dimensions of 50 mm × 50 mm × 5 mm using 3-D-printing-assisted dice-and-insert technology. The hydrostatic piezoelectric performances for PSCC were investigated using a quasi-static method. The hydrostatic figure-of-merit (HFOM) of PSCC is approximately [Formula: see text]/N, which is higher by 69.4% than that of PCC. Furthermore, PSCC shows advantages in the dielectric loss, frequency constant, electromechanical coupling coefficient, and hydrostatic pressure stability. The results suggest that PSCCs have great potential in substantially improving the sensitivity of hydrophones. In addition, 3-D-printing-assisted dice-and-insert technology breaks through the restriction of as-grown piezoelectric crystal size so as to make it possible for the applications where large-scale piezoelectric composites are required.

Quantitative imaging of intracellular nanoparticle exposure enables prediction of nanotherapeutic efficacy.

Nanoparticle internalisation is crucial for the precise delivery of drug/genes to its intracellular targets. Conventional quantification strategies can provide the overall profiling of nanoparticle biodistribution, but fail to unambiguously differentiate the intracellularly bioavailable particles from those in tumour intravascular and extracellular microenvironment. Herein, we develop a binary ratiometric nanoreporter (BiRN) that can specifically convert subtle pH variations involved in the endocytic events into digitised signal output, enabling the accurately quantifying of cellular internalisation without introducing extracellular contributions. Using BiRN technology, we find only 10.7-28.2% of accumulated nanoparticles are internalised into intracellular compartments with high heterogeneity within and between different tumour types. We demonstrate the therapeutic responses of nanomedicines are successfully predicted based on intracellular nanoparticle exposure rather than the overall accumulation in tumour mass. This nonlinear optical nanotechnology offers a valuable imaging tool to evaluate the tumour targeting of new nanomedicines and stratify patients for personalised cancer therapy.

Textured ferroelectric ceramics with high electromechanical coupling factors over a broad temperature range.

The figure-of-merits of ferroelectrics for transducer applications are their electromechanical coupling factor and the operable temperature range. Relaxor-PbTiO3 ferroelectric crystals show a much improved electromechanical coupling factor k33 (88~93%) compared to their ceramic counterparts (65~78%) by taking advantage of the strong anisotropy of crystals. However, only a few relaxor-PbTiO3 systems, for example Pb(In1/2Nb1/2)O3-Pb(Mg1/3Nb2/3)O3-PbTiO3, can be grown into single crystals, whose operable temperature range is limited by their rhombohedral-tetragonal phase transition temperatures (Trt: 60~120 °C). Here, we develop a templated grain-growth approach to fabricate <001>-textured Pb(In1/2Nb1/2)O3-Pb(Sc1/2Nb1/2)O3-PbTiO3 (PIN-PSN-PT) ceramics that contain a large amount of the refractory component Sc2O3, which has the ability to increase the Trt of the system. The high k33 of 85~89% and the greatly increased Trt of 160~200 °C are simultaneously achieved in the textured PIN-PSN-PT ceramics. The above merits will make textured PIN-PSN-PT ceramics an alternative to single crystals, benefiting the development of numerous advanced piezoelectric devices.

Characteristics and outcomes of Ludwig's angina in patients admitted to the intensive care unit: A 6-year retrospective study of 29 patients.

BACKGROUND/PURPOSE: Ludwig's angina (LA) still presents regularly and various characteristics are documented, but patients admitted to the Intensive Care Unit (ICU) has not been studied. The purpose of this study was to investigate the clinical characteristics and outcomes of patients with LA who were admitted to ICU. MATERIALS AND METHODS: We retrospectively reviewed all 29 patients with LA who were admitted to the ICU of a university hospital from January 2013 to October 2018. Results were evaluated via descriptive analysis. The Log-Rank test was used to analyze the hospital/ICU length of stay (LOS). RESULTS: The male: female ratio was 2.63:1. Mean age was 53.41 ±â€¯16.57 years (range 8-78 years). Concomitant conditions comprised diabetes mellitus in 10 patients (34.48%), and hypertension in six (20.69%). The main reason for ICU admission was surgical (44.83%). The mean Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA) scores were 13.52 ±â€¯3.18 and 3.83 ±â€¯2.89, respectively. Twenty-eight patients (96.55%) received respiratory support. Sixteen patients (55.17%) had positive bacterial culture results. Fourteen bacterial strains were detected, most of which were gram-positive (72.72%). Mean LOS was 6.89 ±â€¯14.39 days (range 0.5-73 days), and 24.79 ±â€¯16 days in the hospital. The ICU mortality rate was 10.34%. Compared with LA patients without descending necrotizing mediastinitis (DNM), those with DNM had longer ICU and hospital LOS. The laboratory investigations were higher. CONCLUSION: LA patients in ICU were predominantly male, with a wide range age, high incidence of complications, long hospital LOS.

A pH-Activatable nanoparticle for dual-stage precisely mitochondria-targeted photodynamic anticancer therapy.

Mitochondria-targeted photodynamic therapy (PDT) has emerged as one of the most efficient antitumor strategies. However, the therapeutic outcome of mitochondria-targeted PDT nanocarriers has been hampered by its poor capability of endosome escape and always-ON mode which induces normal tissue damage. To tackle these limitations, herein a novel pH-activatable nanoparticle is developed with dual-stage targeting capacity of early endosome and mitochondria for exponential activation of fluorescent signals and photodynamic efficacy. This nanoparticle is composed of pH-responsive mPEG-b-PDPA-Cy7.5 fluorescent copolymer and mitochondria-targeted photosensitizer (TPPa). The TPPa-encapsulated nanoparticles (M-TPPa) exhibit 111- and 151-fold enhancement in fluorescent signal and singlet oxygen generation (SOG) on encounting acidic pH environment, respectively. The M-TPPa can be quickly endocytosed by cancer cells and immediately dissociate at acidic early endosome to activate fluorescent signals and photoactivity. Subsequently, the activated TPPa quickly translocates from early endosome to mitochondria. Under laser irradiation, singlet oxygen could be generated in mitochondria, inducing intrinsic apoptosis in human HO8910 ovarian cancer cells. M-TPPa also exhibits high tumor imaging contrast and remarkable inhibition on tumor progression without obvious toxicity in HO8910-tumor bearing mice. Therefore, the rationally designed nanoparticles, with precise dual-targeting of distinct organelles and theranostic signal amplification, provides a promising strategy for efficient cancer treatment.

Quick-Responsive Polymer-Based Thermosensitive Liposomes for Controlled Doxorubicin Release and Chemotherapy.

Thermosensitive liposomes (TSLs) have been widely investigated for controlled drug release at specific pathophysiological sites. Although excellent thermo-sensitivity under hyperthermia (HT) was already realized for TSLs, their in vivo stability under physiological temperature still remains challenging. To overcome this limitation, optimized polymer-based thermosensitive liposomes (P-TSLs) with good thermo-sensitivity as well as satisfactory in vivo stability were developed in this study for tumor-specific controlled delivery of doxorubicin (DOX). In particular, polymers including p(NIPAM-r-HPMA) and p(HPMA-r-APMA) were successfully synthesized based on a reversible addition-fragmentation chain transfer (RAFT) technique. Next, thermosensitive polymer p(NIPAM-r-HPMA) was first proposed to be inserted into the lipid bilayer of TTSL by a postinsertion method. The resulting P-TTSL had a phase transition temperature (Tm) of around 42 °C and displayed excellent thermo-sensitivity under HT: nearly 70% of DOX was released within 1 min when only 1% p(NIPAM-r-HPMA) was incorporated. Moreover, its stability was maintained at 37 °C. Compared with TTSL, significantly higher cellular uptake of DOX under HT was noticed in P-TTSL, indicating a burst release of DOX at 42 °C. In addition, both in vitro tumor spheroid experiments and in vivo tumor slices demonstrated an enhanced DOX deep penetration when treated by P-TTSL under HT. To achieve in vivo imaging and local HT under NIR, p (HPMA-r-APMA) was labeled by Cy7.5 and coinserted into TTSL, and the best drug efficacy was observed in CY-P-TTSL with HT along with prolonged blood circulation time. We have further investigated the biocompatibility of the developed CY-P-TTSL, and reduced cardiotoxicity was observed even under HT in comparison with free DOX, demonstrating it is a reliable thermosensitive drug carrier for improving drug stability and therapeutic efficacy.

Redox/enzyme sensitive chondroitin sulfate-based self-assembled nanoparticles loading docetaxel for the inhibition of metastasis and growth of melanoma.

In this report, redox/enzyme responsive chondroitin sulfate-ss-deoxycholic acid (CSCD) conjugates were synthesized using cystamine as the linkage which could self-assemble to form self-assembled nanoparticles (175.6 + 5.2 nm) in the aqueous environment. Docetaxel (DTX) was loaded in nanoparticles with desired loading efficiency for the inhibition of tumor growth and metastasis of melanoma. Interestingly, nanoparticles were demonstrated to respond to hyaluronidase-1 (Hyal-1) which could degrade chondroitin sulfate (CS) backbones. In this case, we designed dual-sensitive nanoparticles with enhanced drug release pattern under the presence of glutathione (GSH)/Hyal-1. Compared with Taxotere®, CSCD nanoparticles significantly improved the DTX distribution in tumors and lungs with about 4.4-fold higher area-under-the-curve (AUC) value. In situ tumor volume and pulmonary metastatic formation were reduced upon the administration of DTX-loaded CSCD nanoparticles via DTX-induced apoptosis and decreased metastasis-promotion protein expression. With only minor cytotoxicity, CSCD nanoparticles could be promising nano-drug delivery systems for successful management of melanoma.

Insight into the role of dual-ligand modification in low molecular weight heparin based nanocarrier for targeted delivery of doxorubicin.

Low molecular weight heparin nanoparticles (LMWH) modified by glycyrrhetinic acid (GA) (LMWH-GA) and further decorated by lactobionic acid (LA) (LA-LMWH-GA) were reported as novel hepatocellular carcinoma (HPC)-targeted carriers to overcome multidrug resistance (MDR) of doxorubicin (DOX). The drug-loaded nanoparticles had negative charge of around -25mV and average size range of 70-170nm. These nanoparticles performed sustained drug release in vitro and prolonged DOX residence time in blood circulation in vivo. Compared to free DOX, DOX-loaded nanoparticles demonstrated increased DOX accumulation in drug-resistance HepG2/ADR cells and enhanced in vitro therapeutic efficacy. However, DOX/LA-LMWH-GA with dual ligands didn't show higher cellular uptake and cytotoxicity than single GA modified DOX/LMWH-GA, although both GA-mediated and LA-mediated endocytosis were involved in their cell internalization. Uptake pathway inhibition study revealed the less efficacy of DOX/LA-LMWH-GA in cellular level could be attributed to the reduced effect of micropinocytosis and caveolae-mediated endocytosis in cellular uptake. Interestingly, the DOX-loaded nanoparticles developed from lower drug/carrier feeding ratio possessed higher performance in cell internalization and in vitro efficacy compared to those developed from higher drug/carrier feeding ratio, which could highlight the role of carrier in drug delivery process.

Internal stimuli-responsive nanocarriers for drug delivery: Design strategies and applications.

The design of internal stimuli-responsive nanocarriers has been extensively used for delivery of various active compounds including drugs, peptides and genes. These nanosystems are not only designed for improved solubility, enhanced bioavailability, and prolonged blood circulation time, furthermore, they can be tailored chemically to achieve selective drug release at the desired sites of action, which can enable them to bypass physiological or pathological obstacles and achieve enhanced therapeutic efficacy. This review presents current functional moieties responsive to a variety of internal stimuli, including pH, redox, enzyme, temperature. Their design strategies and biomedical applications are also highlighted in detail. It is expected that this review can provide inspiration and impetus for exploiting more promising internal stimuli-responsive nano-systems for drug delivery.