Regenerating Chemotherapeutics through Copper-Based Nanomedicine: Disrupting Protein Homeostasis for Enhanced Tumor Therapy.

The bis-(diethyldithiocarbamate)-copper (CuET), the disulfiram (DSF)-Cu complex, has exhibited noteworthy anti-tumor property. However, its efficacy is compromised due to the inadequate oxidative conditions and the limitation of bioavailable copper. Because CuET can inactivate valosin-containing protein (VCP), a bioinformatic pan-cancer analysis of VCP is first conducted in this study to identify CuET as a promising anticancer drug for diverse cancer types. Then, based on the drug action mechanism, a nanocomposite of CuET and copper oxide (CuO) is designed and fabricated utilizing bovine serum albumin (BSA) as the template (denoted as CuET-CuO@BSA, CCB). CCB manifests peroxidase (POD)-mimicking activity to oxidize the tumor endogenous H2O2 to generate reactive oxygen species (ROS), enhancing the chemotherapy effect of CuET. Furthermore, the cupric ions released after enzymatic reaction can regenerate CuET, which markedly perturbs intracellular protein homeostasis and induces apoptosis of tumor cells. Meanwhile, CCB triggers cuproptosis by inducing the aggregation of lipoylated proteins. The multifaceted action of CCB effectively inhibits tumor progression. Therefore, this study presents an innovative CuET therapeutic strategy that creates an oxidative microenvironment in situ and simultaneously self-supply copper source for CuET regeneration through the combination of CuO nanozyme with CuET, which holds promise for application of CuET for effective tumor therapy.

Concentration-QTc Modeling of the DPP-4 Inhibitor HSK7653 in a First-in-Human Study of Chinese Healthy Volunteers.

Cofrogliptin (HSK7653) is a long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus with a twice-monthly dosing regimen. This study included 62 participants (48 without food effect, 14 with food effect) receiving single doses of HSK7653 (5, 10, 25, 50, 100, and 150 mg) or placebo. Pharmacokinetic samples were collected over 24 hours postdosing and sampling times are aligned with 12-lead electrocardiograms (ECGs) which were derived from continuous ECG recordings. For the concentration-QT interval corrected for heart rate (C-QTc) analysis, we used linear mixed-effects modeling to characterize the correlation between plasma concentrations of HSK7653 and the change from baseline in the QT interval which was corrected by Fridericia's formula (ΔQTcF). The result showed that a placebo-corrected Fridericia corrected QT interval (ΔΔQTcF) prolongation higher than 10 milliseconds is unlikely at the mean maximum observed concentration (Cmax) (411 ng/mL) associated with the recommended therapeutic doses (25 mg twice-monthly), even at the highest supratherapeutic concentration (2425 ng/mL). Thus, HSK7653 does not significantly affect QT prolongation at either recommended doses or the highest supratherapeutic concentration.

Biotransformation and disposition characteristics of HSK7653, a novel long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.

AIM: To investigate the metabolism and disposition characteristics of HSK7653 in healthy male Chinese participants. METHODS: A single oral dose of 80 µCi (25 mg) [14C]HSK7653 capsules was administered to six healthy participants, and blood, plasma, urine and faeces were collected. Quantitative and qualitative analysis was conducted to investigate the pharmacokinetics, blood-to-plasma ratio, mass balance and metabolism of HSK7653. RESULTS: The drug was well absorbed and reached a maximum concentration at 1.25 h. The drug-related components (HSK7653 and its metabolites) were eliminated slowly, with a half-life (t1/2) of 111 h. Unchanged HSK7653 contributed to more than 97% of the total radioactivity in all plasma samples. The blood-to-plasma ratio (0.573-0.845) indicated that HSK7653 did not tend to distribute into blood cells. At 504 h postdose, up to 95.9% of the dose was excreted, including 79.8% in urine and 16.1% in faeces. Most of the radioactivity (75.5% dose) in excreta was unchanged HSK7653. In addition, nine metabolites were detected in urine and faeces. The most abundant metabolite was M6-2, a dioxidation product of HSK7653, which accounted for 4.73% and 2.63% of the dose in urine and faeces, respectively. The main metabolic pathways of HSK7653 in vivo included oxidation, pyrrole ring opening and sulphonamide hydrolysation. CONCLUSION: HSK7653 was well absorbed, slightly metabolized and slowly excreted in humans. The high plasma exposure and long t1/2 of HSK7653 may contribute to its long-lasting efficacy as a long-acting dipeptidyl peptidase-4 inhibitor.

pH/GSH dual responsive nanosystem for nitric oxide generation enhanced type I photodynamic therapy.

Tumor hypoxia diminishes the effectiveness of traditional type II photodynamic therapy (PDT) due to oxygen consumption. Type I PDT, which can operate independently of oxygen, is a viable option for treating hypoxic tumors. In this study, we have designed and synthesized JSK@PEG-IR820 NPs that are responsive to the tumor microenvironment (TME) to enhance type I PDT through glutathione (GSH) depletion. Our approach aims to expand the sources of therapeutic benefits by promoting the generation of superoxide radicals (O2-.) while minimizing their consumption. The diisopropyl group within PEG-IR820 serves a dual purpose: it functions as a pH sensor for the disassembly of the NPs to release JSK and enhances intermolecular electron transfer to IR820, facilitating efficient O2-. generation. Simultaneously, the release of JSK leads to GSH depletion, resulting in the generation of nitric oxide (NO). This, in turn, contributes to the formation of highly cytotoxic peroxynitrite (ONOO-.), thereby enhancing the therapeutic efficacy of these NPs. NIR-II fluorescence imaging guided therapy has achieved successful tumor eradication with the assistance of laser therapy.

A model-informed approach to accelerate the clinical development of cofrogliptin (HSK7653), a novel ultralong-acting dipeptidyl peptidase-4 inhibitor.

AIM: To employ a model-informed drug development approach in facilitating decision making and expediting the clinical progress of cofrogliptin (HSK7653), a novel ultralong-acting dipeptidyl peptidase-4 (DPP-4) inhibitor, for the treatment of type 2 diabetes (T2D) via a biweekly dosing regimen. METHODS: Firstly, a population pharmacokinetics and pharmacodynamics (PopPKPD) model was developed using PK and PD data from a single ascending dose study to simulate the PK and PD time profiles of HSK7653 after multiple doses. Secondly, model-based meta-analysis (MBMA) was performed on published clinical studies of Eastern Asian subjects for all DPP-4 inhibitors. We hypothesized a consistent relationship between PK and DPP-4 inhibition in both healthy individuals and in those with T2D, establishing a quantitative correlation between DPP-4 inhibition and HbA1c. Finally, the predicted PK/DPP-4 inhibition/HbA1c profiles were validated by T2D patients in late clinical trials. RESULTS: The PK/DPP-4 inhibition/HbA1c profiles of T2D patients treated with HSK7653 matched the modelled data. Our PopPKPD and MBMA models predict multiple ascending dosing PK and PD characteristics from single ascending dosing data, as well as the long-term efficacy in T2D patients, based on healthy subjects. CONCLUSIONS: Successful waiver approval for the phase 2b dose-finding study was achieved through model-informed recommendations, facilitating the clinical development of HSK7653 and other DPP-4 inhibitors.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, and Dose-Increasing Study on the Safety, Tolerability and PK/PD of Multiple Doses of HSK7653 by Oral Administration in Patients with Type 2 Diabetes Mellitus in China.

INTRODUCTION: This study assessed the safety, tolerability, and PK/PD of HSK7653 tablets in Chinese patients with type 2 diabetes mellitus (T2DM). METHODS: This was a Phase IIa, multicenter, randomized, double-blind, placebo-controlled, and dose-increasing study with 48 Chinese diabetes patients. Subjects were randomly assigned to placebo and 10/25/50 mg dose groups, and they received oral administration once every two weeks for a total of six times. Safety and tolerability were assessed throughout this study, and PK/PD parameters were analyzed using non-compartment model with WinNonlin. RESULTS: The three doses of HSK7653 were well tolerated, and the incidence of TEAE and ADR was not significantly increased compared with the placebo group. Cmax increased linearly with the increasing dose, and the mean t1/2 was 64.0-87.0 h. The first dose and last dose PK parameters were similar. After oral administration of 10-50 mg HSK7653 every two weeks, the average Rac_Cmax and Rac_AUC were 0.9-1.0 and 1.0-1.1 respectively; therefore, HSK7653 was not accumulated in vivo. All three doses significantly inhibited DPP-4 activity and increased plasma GLP-1 level and serum insulin levels. When the plasma concentration of HSK7653 was ≥ 20.0 ng/mL, the DPP-4 inhibition rate in all subjects was maintained at > 80.0%. In 10 and 25 mg dose groups, the HbA1c levels maintained a downward trend compared with the placebo group. DISCUSSION: HSK7653 showed desirable pharmacokinetic and pharmacodynamic properties with good safety and tolerability in Chinese T2DM patients. DPP-4 inhibition rate and plasma GLP-1 levels were higher in each dose group than in placebo group. TRIAL REGISTRATION NUMBER: CTR20182505 (Drug Clinical Trial Registration and Information Disclosure Platform, www.chinadrugtrials.org.cn ).

Fluorinated Polymer Donors for Nonfullerene Organic Solar Cells.

The rapid development of narrow-bandgap nonfullerene acceptors (NFAs) has boosted the efficiency of organic solar cells (OSCs) over 19 %. The new features of high-performance NFAs, such as visible-NIR light absorption, moderate the highest occupied molecular orbitals (HOMO), and high crystallinity, require polymer donors with matching physical properties. This emphasizes the importance of methods that can effectively tune the physical properties of polymers. Owning to very small atom size and strongest electronegativity, the fluorination has been proved the most efficient strategy to regulate the physical properties of polymer donors, including frontier energy level, absorption coefficient, dielectric constant, crystallinity and charge transport. Owing to the success of fluorination strategy, the vast majority of high-performance polymer donors possess one or more fluorine atoms. In this review, the fluorination synthetic methods, the synthetic route of well-known fluorinated building blocks, the fluorinated polymers which are categorized by the type of donor or acceptor units, and the relationships between the polymer structures, properties, and photovoltaic performances are comprehensively surveyed. We hope this review could provide the readers a deeper insight into fluorination strategy and lay a strong foundation for future innovation of fluorinated polymers.

Black Phosphorus/MnO2 Nanocomposite Disrupting Bacterial Thermotolerance for Efficient Mild-Temperature Photothermal Therapy.

The emergence of multi-drug resistant (MDR) pathogens is a major public health concern, posing a substantial global economic burden. Photothermal therapy (PTT) at mild temperature presents a promising alternative to traditional antibiotics due to its biological safety and ability to circumvent drug resistance. However, the efficacy of mild PTT is limited by bacterial thermotolerance. Herein, a nanocomposite, BP@Mn-NC, comprising black phosphorus nanosheets and a manganese-based nanozyme (Mn-NZ) is developed, which possesses both photothermal and catalytic properties. Mn-NZ imparts glucose oxidase- and peroxidase-like properties to BP@Mn-NC, generating reactive oxygen species (ROS) that induce lipid peroxidation and malondialdehyde accumulation across the bacterial cell membrane. This process disrupts unprotected respiratory chain complexes exposed on the bacterial cell membrane, leading to a reduction in the intracellular adenosine triphosphate (ATP) content. Consequently, mild PTT mediated by BP@Mn-NC effectively eliminates MDR infections by specifically impairing bacterial thermotolerance because of the dependence of bacterial heat shock proteins (HSPs) on ATP molecules for their proper functioning. This study paves the way for the development of a novel photothermal strategy to eradicate MDR pathogens, which targets bacterial HSPs through ROS-mediated inhibition of bacterial respiratory chain activity.

Manipulating the Alkyl Chains of Naphthodithiophene Imide-Based Polymers to Concurrently Boost the Efficiency and Stability of Organic Solar Cells.

Morphology instability holds the major responsibility for efficiency degradation of organic solar cells (OSCs). However, how to develop polymer donors simultaneously with high efficiency and excellent morphology stability remains challenging. Herein, we reported naphtho[2,1-b:3,4-b']dithiophene-5,6-imide (NDTI)-based new polymers PNDT1 and PNDT2. The alkyl chain engineering leads to high crystallinity, high hole mobility (>10-3 cm2 V-1 S-1), and nanofibrous film morphology, which enable PNDT2 to exhibit an efficiency of 18.13% and a remarkable FF value of 0.80. Moreover, the NDTIs have short π-π stacking and abundant short interactions, and their polymers exhibit superior morphological stability. Therefore, the PNDT2-based OSCs exhibit much better device stability than that of PNDT1, PAB-α, and benchmark polymers PM6 and D18. This work suggests the great importance of the large conjugated backbone of the monomer and alkyl chain engineering to develop high-performance and morphology-stable polymers for OSCs.

pH-sensitive gold nanoclusters labeling with radiometallic nuclides for diagnosis and treatment of tumor.

The acidic microenvironment is one of the remarkable features of tumor and is also a reliable target for tumor theranostics. Ultrasmall gold nanoclusters (AuNCs) have good in vivo behaviors, such as non-retention in liver and spleen, renal clearance, and high tumor permeability, and held great potential for developing novel radiopharmaceuticals. Herein, we developed pH-sensitive ultrasmall gold nanoclusters by introducing quaternary ammonium group (TMA) or tertiary amine motifs (C6A) onto glutathione-coated AuNCs (TMA/GSH@AuNCs, C6A-GSH@AuNCs). Density functional theory simulation revealed that radiometal 89Sr, 223Ra, 44Sc, 90Y, 177Lu, 89Zr, 99mTc, 188Re, 106Rh, 64Cu, 68Ga, and 113Sn could stably dope into AuNCs. Both TMA/GSH@AuNCs and C6A-GSH@AuNCs could assemble into large clusters responding to mild acid condition, with C6A-GSH@AuNCs being more effective. To assess their performance for tumor detection and therapy, TMA/GSH@AuNCs and C6A-GSH@AuNCs were labeled with 68Ga, 64Cu, 89Zr and 89Sr, respectively. PET imaging of 4T1 tumor-bearing mice revealed TMA/GSH@AuNCs and C6A-GSH@AuNCs were mainly cleared through kidney, and C6A-GSH@AuNCs accumulated in tumors more efficiently. As a result, 89Sr-labeled C6A-GSH@AuNCs eradicated both the primary tumors and their lung metastases. Therefore, our study suggested that GSH-coated AuNCs held great promise for developing novel radiopharmaceuticals that specifically target the tumor acidic microenvironment for tumor diagnosis and treatments.

A Multifluorination Strategy Toward Wide Bandgap Polymers for Highly Efficient Organic Solar Cells.

Creating new electron-deficient unit is highly demanded to develop high-performance polymer donors for non-fullerene organic solar cells (OSCs). Herein, we reported a multifluorinated unit 4,5,6,7-tetrafluoronaphtho[2,1-b : 3,4-b']dithio-phene (FNT) and its polymers PFNT-F and PFNT-Cl. The advantages of multifluorination: (1) it enables the polymers to exhibit low-lying HOMO (≈-5.5 eV) and wide band gap (≈2.0 eV); (2) the short interactions (F⋅⋅⋅H, F⋅⋅⋅F) endow the polymers with properties of high film crystallinity and efficient hole transport; (3) well miscibility with NFAs that leads to a more well-defined nanofibrous morphology and face-on orientation in the blend films. Therefore, the PFNT-F/Cl : N3 based OSCs exhibit impressive FF values of 0.80, and remarkable PCEs of 17.53 % and 18.10 %, which make them ranked the best donor materials in OSCs. This work offers new insights into the rational design of high-performance polymers by multifluorination strategy.

High Performance Polarization-Resolved Photodetectors Based on Intrinsically Stretchable Organic Semiconductors.

Polarization-sensitive photodetectors based on anisotropic semiconductors sense both the intensity and polarization state information without extra optical components. Here, a self-powered organic photodetector (OPD) composed of intrinsically stretchable polymer donor PNTB6-Cl and non-fullerene acceptor Y6 is reported. The PNTB6-Cl:Y6 photoactive film accommodates a remarkable 100% strain without fracture, exhibiting a high optical anisotropy of 1.8 after strain alignment. The resulting OPD not only shows an impressive faint-light detection capability (high spectral responsivity of 0.45 A W-1 and high specific detectivity of 1012 Jones), but also has a high anisotropic responsivity ratio of 1.42 under the illumination of parallel and traversed polarized light. To the best of the authors' knowledge, both the detector performance and polarization features are among the best-performing OPDs and polarization-sensitive photodetectors. As a proof-of-concept, polarization-sensitive OPDs are also utilized to set up a polarimetric imaging system and full-Stokes polarimeter. This work explores the potential of highly stretchable organic semiconductors for state-of-art polarization imaging and spectroscopy applications.

Corrigendum: Combination effect of three main constituents from Sarcandra glabra inhibits oxidative stress in the mice following acute lung injury: a role of MAPK-NF-κB pathway.

[This corrects the article DOI: 10.3389/fphar.2020.580064.].

Tumor microenvironment-responsive nanohybrid for hypoxia amelioration with photodynamic and near-infrared II photothermal combination therapy.

Phototherapy, particularly photothermal therapy (PTT) and photodynamic therapy (PDT), has been widely investigated for tumor treatment. However, the limited tissue penetration depth of light in the near-infrared I (NIR-I) region and the hypoxic tumor microenvironment (TME) severely constrain their clinical applications. To address these challenges, in the present study, we developed a chlorin e6 (Ce6) and MnO2-coloaded, hyaluronic acid (HA)-coated single-walled carbon nanohorns (SWNHs) nanohybrid (HA-Ce6-MnO2@SWNHs) for PDT and PTT combination therapy of tumor. HA-Ce6-MnO2@SWNHs responded to the mild acidic TME to ameliorate tumor hypoxia, thus enhancing tumor PDT. Moreover, HA-Ce6-MnO2@SWNHs had a high photothermal conversion efficiency at 1064 nm (55.48%), which enabled deep tissue penetration (3.05 cm) and allowed for highly efficient tumor PTT in near-infrared II (NIR-II) window. PDT and PTT combination therapy with HA-Ce6-MnO2@SWNHs achieved a good therapeutic efficacy on 4T1 tumor-bearing mice, eradicating the primary tumors and suppressing cancer recurrence. Our study provides a promising strategy for developing a hypoxia relief and deep tissue penetration phototherapy platform by using SWNHs for highly effective tumor PDT and NIR-II PTT combination therapy. STATEMENT OF SIGNIFICANCE: The hypoxic tumor microenvironment (TME) and the limited penetration of the NIR-I light in biological tissues compromise the efficacy of photothermal therapy (PTT) and photodynamic therapy (PDT) on tumors. Here, we developed a chlorin e6 (Ce6) and MnO2-coloaded, hyaluronic acid (HA)-coated single-walled carbon nanohorns (SWNHs) nanohybrid (HA-Ce6-MnO2@SWNHs) for PDT and PTT combination therapy of tumors. The nanohybrid could efficiently accumulate in tumors through CD44-mediated active targeting. The sequential MnO2-enhanced PDT and efficient NIR-II PTT had a remarkable therapeutic effect by eliminating the primary tumor and simultaneously inhibiting tumor recurrence.

A Frequency-Adjustable Tuning Fork Electromagnetic Energy Harvester.

In this paper, a frequency-adjustable tuning fork electromagnetic energy harvester is introduced. The electromagnetic vibration energy harvester can adjust its natural frequency according to a change in the environmental excitation frequency without any change to the structure. In the frequency-adjustable range, it can make the energy harvester resonant with the environment excitation, and the output frequency stays the same. The frequency-adjustable tuning fork electromagnetic energy harvester significantly increases the range of frequencies used. The operating frequency of the centre can be easily switched from 9.2 to 20 Hz, enabling the application of multiple excitation frequencies. In addition, the output power and power density are significantly increased compared to a piezoelectric tuning fork energy harvester of the same size. The peak power is 23.59 mW at 9.2 Hz, the power increases by 14.85 mW, and the power density increases by 169.88%. The experimental results show that the electromagnetic tuning fork frequency-adjustable conversion energy harvester can make the LED lamp work.

A Tuning Fork Frequency Up-Conversion Energy Harvester.

In this paper, a novel tuning fork structure for self-frequency up-conversion is proposed. The structure has an in-phase vibration mode and an anti-phase vibration mode. The in-phase vibration mode is used to sense the environment vibration, and the anti-phase vibration mode is used for energy conversion and power generation. The low-frequency energy collection and the high-frequency energy conversion can be achieved simultaneously. Theoretical and experimental results show that the tuning fork frequency up-conversion energy harvester has excellent performance. This structure provides the energy harvester with excellent output power in a low-frequency vibration environment. At the resonant frequency of 7.3 Hz under 0.7 g acceleration, the peak voltage is 41.8 V and the peak power is 8.74 mW. The tuning fork frequency up-conversion energy harvester causes the humidity sensor to work stably. The structure has the potential to power wireless sensor nodes or to be used as a small portable vibration storage device, especially suitable for the monitoring of the environment related to human movement.

One-pot synthesis of 68Ga-doped ultrasmall gold nanoclusters for PET/CT imaging of tumors.

Gold nanoclusters (AuNCs) have attracted much attention for tumor theranostics in recent years because of their ability of renal clearance and to escape the reticuloendothelial system (RES) sequestration. In this study, we presented a novel method to synthesize 68Ga-doped (labeled) AuNCs by simultaneous reduction of 68GaCl3 and HAuCl4 by glutathione. As synthesized 68Ga-doped, glutathione-coated AuNCs (68Ga-GSH@AuNCs) were ultrasmall in size (<2 nm), highly stable under physiological conditions and renally clearable, and had high efficiency for tumor targeting. To demonstrate the universality of this 68Ga labeling method and further enhance tumor targeting efficiency, arginine-glycine-aspartate (RGD)-containing peptide was introduced as co-reductant to synthesize RGD peptide and glutathione co-coated, 68Ga-labeled AuNCs (68Ga-RGD-GSH@AuNCs). Introduction of RGD peptide did not interfere the synthesis process but significantly enhanced the tumor targeting efficiency of the AuNCs. Our study demonstrated that it was feasible to label AuNCs with gallium-68 by direct reduction of the radioisotope and HAuCl4 with reductant peptides, holding a great potential for clinical translation for PET/CT detection of tumors.

The Role of the Core Attachment Positioning in Triggering Intramolecular Singlet Exciton Fission in Perylene Diimide Tetramers.

Previous studies have proposed that the presence of a flexible π-bridge linker is crucial in activating intramolecular singlet exciton fission (iSEF) in multichromophoric systems. In this study, we report the photophysical properties of three analogous perylene diimide (PDI) dendritic tetramers showing flexible/twisted π-bridged structures with α- and ß-substitutions and a rigid/planar structure with a ß-fused ring (ßC) connection to a benzodithiophene-thiophene (BDT-Th) core. The rigidity and enhanced planarity of ßC lead to significant intramolecular charge transfer and triplet formation via an intersystem crossing pathway. Steady-state spectroscopic measurements reveal similar absorption and emission spectra for the α-tetramer and the parent PDI monomer. However, their fluorescence quantum yield is significantly different. The negligible fluorescence yield of the α-tetramer (0.04%) is associated with a competitive nonradiative decay pathway. Indeed, for this twisted compound in a high polar environment, a fast and efficient iSEF with a triplet quantum yield of 124% is observed. Our results show that the α-single-bond connections in the α compound are capable of interrupting the coupling among the PDI units, favoring iSEF. We propose that the formation of the double triplet (1[TT]) state is through a superposition of singlet states known as [S1S0][TT]CT, which has been suggested previously for pentacene derivatives. Using steady-state and time-resolved spectroscopic experiments, we demonstrate that the conformational flexibility of the linker itself is necessary but not sufficient to allow iSEF. For the case of the other twisted tetramer, ß, the strong π-π co-facial interactions between the adjacent PDI units in its structure lead to excimer formation. These excimer states trap the singlet excitons preventing the formation of the 1[TT] state, thus inhibiting iSEF.

Sequential PDT and PTT Using Dual-Modal Single-Walled Carbon Nanohorns Synergistically Promote Systemic Immune Responses against Tumor Metastasis and Relapse.

Immune responses stimulated by photodynamic therapy (PDT) and photothermal therapy (PTT) are a promising strategy for the treatment of advanced cancer. However, the antitumor efficacy by PDT or PTT alone is less potent and unsustainable against cancer metastasis and relapse. In this study, Gd3+ and chlorin e6 loaded single-walled carbon nanohorns (Gd-Ce6@SWNHs) are developed, and it is demonstrated that they are a strong immune adjuvant, and have high tumor targeting and penetration efficiency. Then, three in vivo mouse cancer models are established, and it is found that sequential PDT and PTT using Gd-Ce6@SWNHs synergistically promotes systemic antitumor immune responses, where PTT stimulates dendritic cells (DCs) to secrete IL-6 and TNF-α, while PDT triggers upregulation of IFN-γ and CD80. Moreover, migration of Gd-Ce6@SWNHs from the targeted tumors to tumor-draining lymph nodes sustainably activates the DCs to generate a durable immune response, which eventually eliminates the distant metastases without using additional therapeutics. Gd-Ce6@SWNHs intervened phototherapies also generate durable and long-term memory immune responses to tolerate and prevent cancer rechallenge. Therefore, this study demonstrates that sequential PDT and PTT using Gd-Ce6@SWNHs under moderate conditions elicits cooperative and long-lasting antitumor immune responses, which are promising for the treatment of patients with advanced metastatic cancers.

Output of MEMS Piezoelectric Energy Harvester of Double-Clamped Beams with Different Width Shapes.

For a microelectromechanical system (MEMS) piezoelectric energy harvester consisting of double-clamped beams, the effects of both beam shape and electrode arrangement on the voltage outputs are analyzed. For two kinds of harvester structures including millimeter-scale and micro-scale, and different shapes including rectangular, segmentally trapezoidal and concave parabolic are taken into account. Corresponding electric outputs are calculated and tested. Their results are in good agreement with each other. The experimental results validate the theoretical analysis.