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Antimicrobial photodynamic therapy (aPDT) has emerged as an appealing therapeutic option against biofilm infections. However, effectively penetrating the dense barrier of biofilm and anchoring bacteria to achieve biofilm elimination and wound healing under hypoxic environments remains a challenge for aPDT. Herein, three type I/II Hypocrellin B (HB)‐cationic photosensitizers (HB‐P, HB‐TP, and HB‐TTP) are designed based on a multi‐cationic long chains molecular engineering strategy. With an increasing number of introduced cations, the reactive oxygen species (ROS) production and bacterial‐anchoring abilities of HB‐cationic photosensitizers are greatly enhanced. Notably, HB‐TTP demonstrates higher type I/II aPDT activity and broad‐spectrum antibacterial properties. Furthermore, to effectively address the conundrum of healing biofilm‐infected wounds, a ROS‐responsive core‐shell microneedle (HB‐TTP&EGF@MN) is designed by biphasically integrating HB‐TTP and growth factor. When the microneedle penetrates biofilm, the shell quickly dissolves and releases HB‐TTP to achieve biofilm removal under laser irradiation. The core is subsequently degraded slowly in the presence of endogenous ROS within the wound, facilitating a sustained release of growth factor to promote wound tissue regeneration. This work not only provides an effective strategy for the rational design of efficient antimicrobial agents but also proposes innovative ideas for the development of controlled‐release pharmaceutical materials to synergize against biofilm infections. [ABSTRACT FROM AUTHOR]

Background: Gastroesophageal junction adenocarcinoma (GEJA) is a malignant tumor located at the junction of the esophagus and stomach, the incidence of which is increasing year by year, while screening for early biomarkers is limited. Tandem mass tagging (TMT) coupled with liquid chromatography–tandem mass spectrometry (LC/MS/MS) has been used to screen for differential proteins in various cancers. Methods: Differential proteins in GEJA and precancerous lesions were screened using TMT–LC/MS/MS, and then proteins that met expectations were selected for trend clustering analysis, combined with GO and KEGG analysis for functional annotation of differential proteins in GEJA. Then, parallel reaction monitoring and immunohistochemistry techniques were used to validate the accuracy of the proteomics data. Results: Our group screened the differential proteins during GEJA progression using proteomics technology, analyzed the expression trends and functional regions involved in the differential proteins during carcinogenesis, and validated the accuracy of the experimental results. Conclusions: The screening of differential proteins in GEJA carcinogenesis based on TMT–LC/MS/MS technology provides detailed information for the elucidation of GEJA progression process, pathogenesis, early screening and screening of candidate markers. [ABSTRACT FROM AUTHOR]

Purpose: The detection rate of colorectal neuroendocrine tumours (CR-NETs) is increasing, but their treatment is still controversial. Lymph node metastasis is an important reference index for the selection of treatment. The aim of our study was to investigate the factors associated with lymph node metastasis and prognosis of CR-NETs. Methods: The case characteristics of patients with colorectal neuroendocrine tumours from January 2011 to December 2020 were retrospectively analysed, including age, gender, tumour size, tumour location, lymph node metastasis, pathological grade and follow-up. Results: A total of 195 cases of CR-NETs were included in this study. When 15 mm was used as the cut-off value, the sensitivity, specificity and area under the curve (AUC) of lymph node metastases were 95.9%, 95.2% and 0.986, respectively. Multivariate analysis suggested that tumour size ≥ 15 mm (OR: 30.517, 95% CI: 1.250 ~ 744.996, p = 0.036) and lymphovascular invasion (OR: 42.796, 95% CI: 2.882 ~ 635.571, p = 0.006) were independent risk factors for lymph node metastasis. Age ≥ 56 (HR: 7.434, 95% CI: 1.334 ~ 41.443, p = 0.022) and distant metastasis (HR: 24.487, 95% CI: 5.357 ~ 111.940, p < 0.001) were independent prognostic factors in multivariable analyses. Conclusions: When the size of a CR-NET is ≥ 15 mm, the risk of lymph node metastasis is higher, and it is recommended to choose the surgical method carefully. Tumour size and lymphovascular invasion were independent risk factors for lymph node metastasis. Age ≥ 56 and distant metastasis were independent prognostic factors. [ABSTRACT FROM AUTHOR]

Supramolecular self‐assemblies of dendritic peptides with well‐organized nanostructures have great potential as multifunctional biomaterials, yet the complex self‐assembly mechanism hampers their wide exploration. Herein, a self‐stabilized supramolecular assembly (SSA) constructed from a PEGylated dendritic peptide conjugate (PEG‐dendritic peptide‐pyropheophorbide a, PDPP), for augmenting tumor retention and therapy, is reported. The supramolecular self‐assembly process of PDPP is concentration‐dependent with multiple morphologies. By tailoring the concentration of PDPP, the supramolecular self‐assembly is driven by noncovalent interactions to form a variety of SSAs (unimolecular micelles, oligomeric aggregates, and multi‐aggregates) with different sizes from nanometer to micrometer. SSAs at 100 nm with a spherical shape possess extremely high stability to prolong blood circulation about 4.8‐fold higher than pyropheophorbide a (Ppa), and enhance tumor retention about eight‐fold higher than Ppa on day 5 after injection, which leads to greatly boosting the in vivo photodynamic therapeutic efficiency. RNA‐seq demonstrates that these effects of SSAs are related to the inhibition of MET‐PI3K‐Akt pathway. Overall, the supramolecular self‐assembly mechanism for the synthetic PEGylated dendritic peptide conjugate sheds new light on the development of supramolecular assemblies for tumor therapy. [ABSTRACT FROM AUTHOR]

Developing nanoplatforms integrating superior fluorescence imaging ability in second near-infrared (NIR-II) window and tumor microenvironment responsive multi-modal therapy holds great potential for real-time feedback of therapeutic efficacy and optimizing tumor inhibition. Herein, we developed a pH-sensitive pyrrolopyrrole aza-BODIPY-based amphiphilic molecule (PTG), which has a balanced NIR-II fluorescence brightness and photothermal effect. PTG is further co-assembled with a vascular disrupting agent (known as DMXAA) to prepare PTDG nanoparticles for combined anti-vascular/photothermal therapy and real-time monitoring of the tumor vascular disruption. Each PTG molecule has an active PT-3 core which is linked to two PEG chains via pH-sensitive ester bonds. The cleavage of ester bonds in the acidic tumor environment would tricker releases of DMXAA for anti-vascular therapy and further assemble PT-3 cores into micrometer particles for long term monitoring of the tumor progression. Furthermore, benefiting from the high brightness in the NIR-II region (119.61 M−1 cm−1) and long blood circulation time (t 1/2 = 235.6 min) of PTDG nanoparticles, the tumor vascular disrupting process can be in situ visualized in real time during treatment. Overall, this study demonstrates a self-assembly strategy to build a pH-responsive NIR-II nanoplatform for real-time monitoring of tumor vascular disruption, long-term tracking tumor progression and combined anti-vascular/photothermal therapy. [ABSTRACT FROM AUTHOR]

A GGT-activated two-photon fluorescent probe (4F-2CN–GSH) was developed based on a cascade reaction. 4F-2CN–GSH could selectivily detect GGT with low detection limit and distinguish ovarian cancer cells from normal cells using both one-photon and two-photon fluorescence imaging. [ABSTRACT FROM AUTHOR]

Abstract Photoactive agents based on natural products have attracted substantial attention in clinical applications because of their distinct biological activity, molecular structure multiformity, and low biotoxicity. Herein, we initially modify hypocrellin B (HB) with 1,2-diamino-2-methyl propane to form near-infrared (NIR) light (>700 nm)-responsive amino-substituted HB derivative (DPAHB). The DPAHB exhibit broad absorption (400–800 nm), NIR emission (maximum emission peak at 710 nm), and high singlet oxygen (1O 2) quantum yield (∼0.33) under NIR light (721 nm) irradiation. After self-assembly by using DPAHB with PEG-PLGA, the as-prepared nanovesicles (DPAHB NVs) retain efficient 1O 2 generation, more interestingly, show high photothermal conversion efficiency (∼0.24) under NIR light (721 nm) irradiation for synergistic photodynamic therapy (PDT) and photothermal therapy toward hypoxic tumor. The DPAHB NVs can not only be as a fluorescence/photoacoustic imaging agent but also exhibit an even stronger PDT efficiency than that of chlorin e6 (a widely used classic photosensitizer). In vitro and in vivo studies demonstrate that DPAHB NVs possess high photothermal stability, enhanced tumor accumulation, and suitable biodegradation rate, thus, show a highly promising clinical potential as a new photoactive agent for cancer therapy. [ABSTRACT FROM AUTHOR]

As phototheranostic agents, carbon dots (CDs), have recently drawn considerable attention due to their excellent physicochemical properties. However, the complex synthetic route and high-cost of CDs greatly limit their practical application. To address this issue, given their nearly infinite supply from nature, Hypocrella bambusae is used as the precursor for the preparation of CDs in this study. The obtained Hypocrella bambusae CDs (HBCDs) possess good water solubility, broad absorption (350–800 nm), red-light emission (maximum peak at 610 nm), and low biotoxicity. Moreover, HBCDs can highly generate 1 O 2 (0.38) and heat (27.6%) under 635 nm laser irradiation. These excellent properties of HBCDs capacitate them to be utilized for bimodal fluorescence/photoacoustic imaging-guided synergistic photodynamic therapy (PDT)/photothermal therapy (PTT). This work provides a new candidate for tumor treatment with the combination of PDT and PTT, and explores a novel approach for the preparation of CD-based phototheranostic agents with natural biomass as raw carbon sources. [ABSTRACT FROM AUTHOR]

Real-time monitoring vascular responses is crucial for evaluating the therapeutic effects of vascular-targeted photodynamic therapy (V-PDT). Herein, we developed a highly-stable and bright aggregation induced emission (AIE) fluorophore (PTPE3 NP) for dynamic fluorescence (FL) imaging of vascular dysfunction beyond 1300 nm window during V-PDT. The superior brightness (ϵ max Φ f>1000 nm ≈ 180.05 M−1 cm−1) and high resolution of PTPE3 NP affords not only high-clarity images of whole-body and local vasculature (hindlimbs, mesentery, and tumor) but also high-speed video imaging for tracking blood circulation process. By virtue of the NPs' prolonged blood circulation time (t 1/2 ≈ 86.5 min) and excellent photo/chemical (pH, RONS) stability, mesenteric and tumor vascular dysfunction (thrombosis formation, vessel occlusion, and hemorrhage) can be successfully visualized during V-PDT by FL imaging for the first time. Furthermore, the reduction of blood flow velocity (BFV) can be monitored in real time for precisely evaluating efficacy of V-PDT. These provide a powerful approach for assessing vascular responses during V-PDT and promote the development of advanced fluorophores for biological imaging. [ABSTRACT FROM AUTHOR]

As a class of highly dynamic organelles, lipid droplets (LDs) are involved in numerous physiological functions, and the changes in polarity of LDs are closely related to a variety of diseases. In this work, we developed two polarity-sensitive fluorescent probes (CC-CH and CC-Cl) based on curcumin analogs. CC-CH and CC-Cl with a donor–acceptor–donor (D–A–D) structure exhibited the property of intramolecular charge transfer (ICT); thus, their fluorescence emissions were significantly attenuated with increasing ambient polarity. Cell experiments indicated that CC-CH and CC-Cl showed excellent photostability, a low cytotoxicity, and a superior targeting ability regarding LDs. After treatment with oleic acid (OA) and methyl-β-cyclodextrin (M-β-CD), the polarity changes of LDs in living cells could be visualized by using CC-CH and CC-Cl. In addition, CC-CH and CC-Cl could monitor polarity changes of LDs in different pathological processes, including inflammatory responses, nutrient deprivation, and H2O2-induced oxidative stress. Therefore, CC-CH and CC-Cl are promising potential fluorescent probes for tracking intracellular LD polarity changes. [ABSTRACT FROM AUTHOR]

Two photosensitizers (CCOH and CCN) were designed and synthesized by introducing coumarin into the curcumin (CUR) structure. Compared with CUR, more reactive oxygen species (ROS) were generated by CCOH and CCN in type I and II synergy upon light irradiation. Cell experiments indicated that CCN with an excellent LD-targeting effect could be used to monitor the changes in the morphology and number of LDs in tumor cells during PDT. [ABSTRACT FROM AUTHOR]

Placenta is a temporary critical organ related to fetal development and pregnancy outcomes. And epidemiologic data demonstrate an increased risk of placental abnormality after in vitro fertilization and embryo transfer (IVF-ET). This study aims to explore the molecular mechanism for PPAR signaling pathway in placenta subjected to IVF-ET in the first trimester. Four first trimester placenta samples from double chorionic twins to single reduction in IVF-ET only because of oviducts factors. The other four control placenta samples from double chorionic twin were derived from those unplanned spontaneously conceived pregnancy after the legal termination. Affymetrix HG-U133 Plus 2.0 Array was performed to evaluate the global gene expressions. We confirmed microarray results from 10 significant differential genes using RT-qPCR. And 10 deregulated gene products were stained in the first trimester placenta by immunohistochemistry. These differentially expressed genes in IVF-ET placentas were submitted to functional annotation of clustering tools of bioinformatics resources and gene ontology enrichment analysis. Schematic representation of placental PPAR signaling pathway was labelled by Kyoto Encyclopedia of Genes and Genomes (KEGG). Analysis results of early placental PPAR signaling pathway gene expression from 8 women demonstrated 34 genes with a significant change in expression between IVF-ET and control group, 25 up-regulated; 9 down-regulated. KEGG pathway analysis indicated that IVF-ET manipulation extensively over-activated PPAR signaling pathway. Immune tolerance, trophoblast invasion, syncytia formation, lipid and glucose metabolism, inflammatory response and other complex biological functions were disturbed. RT-qPCR results and proteins staining intensity were consisted with microarray. Placental gene expressions and functions in PPAR signaling pathway were affected by IVF-ET treatment in the first trimester, which may offer a potential mechanism for the pathogenesis of various adverse outcomes during the perinatal period. [ABSTRACT FROM AUTHOR]

Background: The placenta is a highly specialized temporary organ that is related to fetal development and pregnancy outcomes, and epidemiological data demonstrate an increased risk of placental abnormality after in vitro fertilization and embryo transfer (IVF-ET). Methods: This study examines alterations in the transcriptome profile of first-trimester placentas from IVF-ET pregnancies and analyzes the potential mechanisms that play a role in the adverse perinatal outcomes associated with IVF-ET procedures. Four human placental villi from first-trimester samples were obtained through fetal bud aspiration from patients subjected to IVF-ET due to oviductal factors. An additional four control human placental villi were derived from a group of subjects who spontaneously conceived a twin pregnancy. We analyzed their transcriptomes by microarray. Then, RT-qPCR and immunohistochemistry were utilized to analyze several dysregulated genes to validate the microarray results. Biological functions and pathways were analyzed with bioinformatics tools. Results: A total of 3405 differentially regulated genes were identified as significantly dysregulated (> 2-fold change; P < 0.05) in the IVF-ET placenta in the first trimester: 1910 upregulated and 1495 downregulated genes. Functional enrichment analysis of the differentially regulated genes demonstrated that the genes were involved in more than 50 biological processes and pathways that have been shown to play important roles in the first trimester in vivo. These pathways can be clustered into coagulation cascades, immune response, transmembrane signaling, metabolism, cell cycle, stress control, invasion and vascularization. Nearly the same number of up- and downregulated genes participate in the same biological processes related to placental development and maintenance. Procedures utilized in IVF-ET altered the expression of first-trimester placental genes that are critical to these biological processes and triggered a compensatory mechanism during early implantation in vivo. Conclusion: These data provide a potential basis for further analysis of the higher frequency of adverse perinatal outcomes following IVF-ET, with the ultimate goal of developing safer IVF-ET protocols. [ABSTRACT FROM AUTHOR]

Combined chemotherapy and targeted therapy holds immense potential in the management of advanced gastric cancer (GC). GC tissues exhibit an elevated expression level of protein kinase B (AKT), which contributes to disease progression and poor chemotherapeutic responsiveness. Inhibition of AKT expression through an AKT inhibitor, capivasertib (CAP), to enhance cytotoxicity of paclitaxel (PTX) toward GC cells is demonstrated in this study. A cathepsin B‐responsive polymeric nanoparticle prodrug system is employed for co‐delivery of PTX and CAP, resulting in a polymeric nano‐drug BPGP@CAP. The release of PTX and CAP is triggered in an environment with overexpressed cathepsin B upon lysosomal uptake of BPGP@CAP. A synergistic therapeutic effect of PTX and CAP on killing GC cells is confirmed by in vitro and in vivo experiments. Mechanistic investigations suggested that CAP may inhibit AKT expression, leading to suppression of the phosphoinositide 3‐kinase (PI3K)/AKT signaling pathway. Encouragingly, CAP can synergize with PTX to exert potent antitumor effects against GC after they are co‐delivered via a polymeric drug delivery system, and this delivery system helped reduce their toxic side effects, which provides an effective therapeutic strategy for treating GC. [ABSTRACT FROM AUTHOR]

Background: By investigating the knowledge, medication, occurrence of complications, and risks among elderly non-valvular atrial fibrillation (NVAF) patients in Shanghai communities, and providing standardized comprehensive management and follow-up, we aim to explore the impact of standardized community management on improving disease awareness, standardizing atrial fibrillation (AF) treatment, reducing the risk of complications occurrence, and addressing risk factors for AF patients. Methods: This research selected elderly atrial fibrillation patients from Zhuanqiao Community Health Service Center, Minhang District, Shanghai from July 2020 to October 2022. Their personal health records and examination results were reviewed, and the incidence of AF, awareness, medication, and complications were investigated. Age-adjusted Charlson Comorbidity Index (aCCI), CHA2DS2-VASc score, and HAS-BLED score were used to evaluate disease burden, thromboembolic risk, and bleeding risk, respectively. The patients were subjected to standardized community management, and the compliance rate of disease awareness, treatment, resting heart rate, blood pressure, fasting blood glucose, and body mass index (BMI) were assessed at the baseline, 6 months and 1 year after management. Results: A total of 243 NVAF patients were included, with an average aCCI score of (4.5 ± 1.1). Among them, 28% of the patients were aware of their AF, and 18.1% of the patients were aware of the hazards of AF. Of the patients, 11.9% used anticoagulant drugs, including 6.6% and 5.3% for warfarin and non-vitamin K antagonist oral anticoagulants (NOACs), respectively. 7% of patients used antiplatelet drugs. 26.7% of the patients used heart rate control drugs. 10.3% of the patients experienced thromboembolic events, and 0.8% of the patients experienced bleeding events. 93.0% of the patients were at high risk of thromboembolism, and 24.7% of the patients were at high risk of bleeding. Compared with the baseline, there were significant statistical differences (P < 0.001) in disease awareness, awareness of the hazards of AF, use of anticoagulant drugs and heart rate control drugs, and control of risk factors among NVAF patients after standardized community management. Moreover, with the extension of management time, there was a linear increase in the awareness of NVAF, awareness of the hazards of AF, utilization rate of anticoagulant drugs, utilization rate of heart rate control drugs, blood pressure, blood glucose, and BMI compliance rate (P < 0.001). Conclusion: Currently, the awareness, treatment, and control of risk factors for AF in elderly NVAF patients in Shanghai community are not satisfactory. Standardized community management helps to improve the diagnosis, treatment, and control of risk factors in AF. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) have been demonstrated to be involved in tumor initiation and relapse, and the presence of CSCs in the tumor tissue often leads to therapeutic failure. BBI608 has been identified to eliminate CSCs by inhibiting signal transducer and activator of transcription 3 (STAT3). In this study, we confirm that BBI608 can efficiently suppress the proliferation and migration of non-small cell lung cancer (NSCLC) cells, and specifically kill the stemness-high population in chemoresistant NSCLC cells. To improve its bioavailability and tumor accumulation, BBI608 is successfully encapsulated into redox-responsive PEGylated branched N-(2-hydroxypropyl) methacrylamide (HPMA)-deoxy cholic acid (DA) polymeric nanoparticles (BBI608-SS-NPs). The BBI608-SS-NPs can release the drug in response to high concentrations of intracellular glutathione, and exhibit cytotoxicity against lung cancer cells and CSCs comparable to the free drug BBI608. Furthermore, the BBI608-SS-NPs preferentially accumulate in tumor sites, resulting in a superior anti-tumor efficacy in both cisplatin-resistant cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of NSCLC. Mechanistic studies demonstrate that BBI608-SS-NPs not only directly inhibit the downstream genes of the STAT3 pathway, but also indirectly inhibit the Wnt pathway. Overall, this stimuli-responsive polymeric nanoformulation of BBI608 shows great potential in the treatment of chemoresistant NSCLC by targeting CSCs. A BBI608-loaded, redox-responsive nanoformulation is fabricated, exhibiting superior anti-tumor efficacy in drug-resistant CDX and PDX models of NSCLC through "dual inhibition" of the JAK-STAT and Wnt pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

The mechanism underlying the potential risk associated with in vitro fertilization and embryo transfer (IVF-ET) has been previously investigated but remains to be fully elucidated. As the placenta is a critical organ that sustains and protects the fetus, this is an important area of research. The aim of the present study was to determine the difference in trophoblast cell function in the first trimester between naturally conceived pregnancies and pregnancies achieved via IVF-ET therapy. A total of 20 placental villi in first trimester samples were obtained through fetal bud aspiration from patients undergoing IVF-ET due to oviductal factors between January 2016 and August 2018. In addition, a further 20 placental villi were obtained from those who naturally conceived and had normal pregnancies but were undergoing artificial abortion; these patients were recruited as the controls. Reverse transcription-quantitative (RT-q)PCR and semi-quantitative immunohistochemical methods were used to detect the mRNA and protein expression of α-fetoprotein (AFP), vascular endothelial growth factor (VEGF), transferrin (TF), tubulin β1 class VI (TUBB1), metallothionein 1G (MT1G), BCL2, glial cells missing transcription factor 1 (GCM1), epidermal growth factor (EGF) receptor (EGFR), PTEN and leukocyte associated immunoglobulin like receptor 2 (LAIR2) in villi from both groups. Differentially expressed genes were analyzed using Search Tool for the Retrieval of Interacting Genes, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was conducted. The RT-qPCR data revealed that the mRNA expression levels of AFP, VEGF and TF were significantly higher in the IVF-ET group than in the control group (P<0.05), and those of TUBB1, MT1G, BCL2, GCM1, EGFR, PTEN and LAIR2 were significantly lower (P<0.05). These gene products were expressed in the placental villus tissues, either in the cytoplasm, or in the membrane of syncytiotrophoblast and cytotrophoblast cells. The immunohistochemistry results were in line with those observed using RT-qPCR. KEGG pathway analysis indicated that the trophoblast cell function of the IVF-ET group in the first trimester was different from naturally conceived pregnancies with regard to proliferation, invasion, apoptosis and vascular development. The IVF-ET process may trigger adaptive placental responses, and these compensatory mechanisms could be a risk for certain diseases later in life. [ABSTRACT FROM AUTHOR]

Interaction between carcinoma-associated fibroblasts (CAFs) and tumor cells leads to the invasion and metastasis of breast cancer. Herein, we prepared a redox-responsive chondroitin sulfate (CS)-based nanomedicine, in which hydrophobic cabazitaxel (CTX) was conjugated to the backbone of CS via glutathione (GSH)-sensitive dithiomaleimide (DTM) to form an amphipathic CS-DTM-CTX (CDC) conjugate, and dasatinib (DAS) co-assembled with the CDC conjugate to obtain DAS@CDC. After CD44 receptor-mediated internalization by CAFs, the nanomedicine could reverse CAFs to normal fibroblasts, blocking their crosstalk with tumor cells and reducing synthesis of major tumor extracellular matrix proteins, including collagen and fibronectin. Meanwhile, the nanomedicine internalized by tumor cells could effectively inhibit tumor proliferation and metastasis, leading to shrinkage of the tumor volume and inhibition of lung metastasis in a subcutaneous 4T1 tumor model with low side effects. Collectively, the nanomedicine showed a remarkably synergistic therapy effect against breast cancer by modulating tumor-stromal crosstalk. A redox-responsive chondroitin sulfate/cabazitaxel/dasatinib nanomedicine (DAS@CDC) could block crosstalk between tumor cells and carcinoma-associated fibroblasts (CAFs) to inhibit tumor metastasis via the DDR2/p-ERK1/2/Snail1 signaling pathway, curb tumor cell proliferation, and induce cell death. [Display omitted] • To achieve synergistic anticancer, a redox-responsive nanomedicine was prepared. • CAFs were reversed to normal fibroblasts to block their crosstalk with tumor cells. • Reducing the synthesis of major tumor extracellular matrix proteins was achieved. • Synergistic therapy against breast cancer, inhibiting metastasis, but low side effects. [ABSTRACT FROM AUTHOR]

[Display omitted] • A ratiometric fluorescent probe (Probe 1) was designed for GGT detection. • Probe 1 can sensitively and selectively detect GGT in complex biological systems. • Probe 1 can be successfully applied for ratiometric imaging of GGT in living cells. γ-Glutamyl transpeptidase (GGT) is one of the biomarker of cancer, hepatitis, and numerous other diseases. The accurate analysis of GGT is useful for the early diagnosis of these diseases. In this work, Probe 1 , a ratiometric fluorescent probe based on 2,3,5,6-tetrafluoroterephthalonitrile, was designed for GGT detection. The results indicated that Probe 1 can sensitively and selectively detect GGT in phosphate buffered solution and complex biological systems (e.g., blood serum). Furthermore, Probe 1 has been successfully applied for ratiometric imaging of GGT in cancer cells and normal cells. [ABSTRACT FROM AUTHOR]

Facile tailoring of photosensitizers (PSs) with advanced and synergetic properties is highly expected to broaden and deepen photodynamic therapy (PDT) applications. Herein, a catalyst‐free thiol–yne click reaction was employed to develop the sulfur atom‐based PSs by using the in situ formed sulfur "heavy atom effect" to enhance the intersystem crossing (ISC), while such an effect can be remarkably magnified by the polymerization. The introduction of a tetraphenylpyrazine‐based aggregation‐induced emission (AIE) unit was also advantageous in PS design by suppressing their non‐radiative decay to facilitate the ISC in the aggregated state. Besides, the resulting sulfur atom electron donor, together with a double‐bond π bridge and AIE electron acceptor, created a donor‐π‐acceptor (D‐π‐A) molecular system with good two‐photon excitation properties. Combined with the high singlet oxygen generation efficiency, the fabricated polymer nanoparticles exhibited an excellent in vitro two‐photon‐excited PDT towards cancer cells, therefore possessing a huge potential for the deep‐tissue disease therapy. [ABSTRACT FROM AUTHOR]

Facile tailoring of photosensitizers (PSs) with advanced and synergetic properties is highly expected to broaden and deepen photodynamic therapy (PDT) applications. Herein, a catalyst‐free thiol–yne click reaction was employed to develop the sulfur atom‐based PSs by using the in situ formed sulfur "heavy atom effect" to enhance the intersystem crossing (ISC), while such an effect can be remarkably magnified by the polymerization. The introduction of a tetraphenylpyrazine‐based aggregation‐induced emission (AIE) unit was also advantageous in PS design by suppressing their non‐radiative decay to facilitate the ISC in the aggregated state. Besides, the resulting sulfur atom electron donor, together with a double‐bond π bridge and AIE electron acceptor, created a donor‐π‐acceptor (D‐π‐A) molecular system with good two‐photon excitation properties. Combined with the high singlet oxygen generation efficiency, the fabricated polymer nanoparticles exhibited an excellent in vitro two‐photon‐excited PDT towards cancer cells, therefore possessing a huge potential for the deep‐tissue disease therapy. [ABSTRACT FROM AUTHOR]

Abstract: Luminescent quantum dots (QDs)-semiconductor nanocrystals are a promising alternative to organic dyes for fluorescence-based applications. We have developed procedures to use CdS to encapsulate CdTe and synthesize a new kind of functionalized CdTe/CdS QDs for the quantitative and selective determination of bovine serum albumin (BSA). Maximum fluorescence intensity was produced at pH 6.83, with excitation and emission wavelengths at 336 and 524nm, respectively. Under optimal conditions, the straight line equation: ΔF =6.84+62.29C (10−6 moldm−3) was found between the relative fluorescence intensity and the concentration of BSA in the range of 0–1.2×10−6 moldm−3, and the limit of detection was 5.4×10−8 moldm−3. Based on this approach, a novel quantitative method for the determination of BSA is presented in this paper. [Copyright &y& Elsevier]

A bromine-substituted thermally activated delayed fluorescent (TADF) molecule AQCzBr2 is designed with both small singlet–triplet splitting (ΔEST) and increased spin–orbit coupling (SOC) to boost intersystem crossing (ISC) for singlet oxygen generation. AQCzBr2 nanoparticles (NPs) demonstrate high productivity of singlet oxygen generation (ΦΔ = 0.91) which allows highly efficient photodynamic therapy toward cancer cells. [ABSTRACT FROM AUTHOR]

Peroxalate CL as an energy source to excite photosensitizers has attracted tremendous attention in photodynamic therapy (PDT). In this work, peroxyoxalate CPPO and hypocrellin B (HB)‐based nanoparticles (CBNPs) for ultrasound (US)‐enhanced self‐exciting PDT were designed and prepared. CBNPs showed an excellent therapeutic effect against cancer cells with the assistance of US. This US‐enhanced‐chemiluminescence system avoids the dependence on external light and provides an example for inspiring more effective and precise strategies for cancer treatment. [ABSTRACT FROM AUTHOR]

Hypocrellin B (HB) derived from naturally produced hypocrellins has attracted considerable attention in photodynamic therapy (PDT) because of its excellent photosensitive properties. However, the weak absorption within a "phototherapy window" (600–900 nm) and poor water solubility of HB have limited its clinical application. In this study, two HB derivatives (i. e., HE and HF) were designed and synthesized for the first time by introducing two different substituent groups into the HB structure. The obtained derivatives showed a broad absorption band covering the near‐infrared (NIR) region, NIR emission (peaked at 805 nm), and singlet oxygen quantum yields of 0.27/0.31. HE‐PEG‐NPs were also prepared using 2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐N‐[methoxy(polyethyleneglycol)‐2000] (DSPE‐mPEG2000) to achieve excellent dispersion in water and further explored their practical applications. HE‐PEG‐NPs not only retained their 1O2‐generating ability, but also exhibited a photothermal conversion efficiency of 25.9%. In vitro and in vivo therapeutic results revealed that the synergetic effect of HE‐PEG‐NPs on PDT and photothermal therapy (PTT) could achieve a good performance. Therefore, HE‐PEG‐NPs could be regarded as a promising phototheranostic agent. [ABSTRACT FROM AUTHOR]

Herein, two water‐soluble PROXYL‐based magnetic resonance imaging (MRI) macromolecular organic contrast agents (mORCAs) are designed and synthesized: linear and cross‐linked PCE‐mPEG‐Ppa‐PROXYL. They are prepared by conjugating linear and cross‐linked poly(carboxylate ester) (PCE) with poly(ethylene glycol) (mPEG2000)‐modified nitroxides (PROXYL), respectively. Both mORCAs form self‐assembled aggregates in an aqueous phase and PROXYL is protected inside a hydrophobic core to achieve great resistance to reduction in the physiological environment, and they have low toxicity. Since cross‐linked PCE‐mPEG‐Ppa‐PROXYL possess a branched architecture, its self‐assembled aggregate is more stable and compact with a greater particle size. Cross‐linked PCE‐mPEG‐Ppa‐PROXYL outperform the linear one in the following aspects: 1) its longitudinal relaxivity (r1 = 0.79 mm−1 s−1) is higher than that of the linear one (r1 = 0.64 mm−1 s−1) and both excel the best mORCA reported so far (r1 = 0.42 mm−1 s−1); 2) its blood retention time (≈48 h) is longer than that of its linear counterpart (≈10 h); 3) cross‐linked PCE‐mPEG‐Ppa‐PROXYL provided better MR imaging contrast resolution in normal organs (liver and kidney) and tumor of mice than the linear one. Overall, cross‐linked PCE‐mPEG‐Ppa‐PROXYL may have great potential to be a novel metal‐free macromolecular contrast agent for MR imaging. [ABSTRACT FROM AUTHOR]

A stimuli‐responsive polymeric prodrug‐based nanotheranostic system with imaging agents (cyanine5.5 and gadolinium‐chelates) and a therapeutic agent paclitaxel (PTX) is prepared via polymerization and conjugating chemistry. The branched polymeric PTX‐Gd‐based nanoparticles (BP‐PTX‐Gd NPs) demonstrate excellent biocompatibility, and high stability under physiological conditions, but they stimuli‐responsively degrade and release PTX rapidly in a tumor microenvironment. The in vitro behavior of NPs labeled with fluorescent dyes is effectively monitored, and the NPs display high cytotoxicity to 4T1 cells similar to free PTX by impairing the function of microtubules, downregulating anti‐apoptotic protein Bcl‐2, and upregulating the expression of Bax, cleaved caspase‐3, cleaved caspase‐9, cleaved‐PARP, and p53 proteins. Great improvement in magnetic resonance imaging (MRI) is demonstrated by these NPs, and MRI accurately maps the temporal change profile of the tumor volume after injection of NPs and the tumor treatment process is also closely correlated with the T1 values measured from MRI, demonstrating the capability of providing real‐time feedback to the chemotherapeutic treatment effectiveness. The imaging‐guided chemotherapy to the 4T1 tumor in the mice model achieves an excellent anti‐tumor effect. This stimuli‐responsive polymeric nano‐agent opens a new door for efficient breast cancer treatment under the guidance of fluorescence/MRI. [ABSTRACT FROM AUTHOR]

Carbon dots (CDs), a kind of phototheranostic agent with the capability of simultaneous bioimaging and phototherapy [i.e. photodynamic therapy (PDT) or photothermal therapy (PTT)], have received considerable attention because of their remarkable properties, including flexibility for surface modification, high biocompatibility, low toxicity and photo‐induced activity for malignant tumor cells. Among numerous carbon sources, it has been found that natural biomass are good candidates for the preparation of CD phototheranostic agents. In this study, pheophytin, a type of Mg‐free chlorophyll derivative and also a natural product with low toxicity, was used as a raw carbon source for the synthesis of CDs by using a microwave method. The obtained hydrophobic CDs exhibited a maximum near‐infrared (NIR) emission peak at approximately 680 nm, and high singlet oxygen (1O2) generation with a quantum yield of 0.62. The self‐assembled CDs from the as‐prepared CDs with DSPE‐mPEG2000 retained efficient 1O2 generation. The obtained carbon dot assembly was not only an efficient fluorescence (FL) imaging agent but also a smart PDT agent. Our studies indicated that the obtained hydrophilic CD assembly holds great potential as a new phototheranostic agent for cancer therapy. This work provides a new route for synthesis of CDs and proposes a readily available candidate for tumor treatment. [ABSTRACT FROM AUTHOR]

Hydrogen peroxide (H 2 O 2) as an important reactive oxygen species (ROS) is correlated in various oxidative stress and cell signaling processes. Thus, developing an effective method that can monitor H 2 O 2 in the Golgi apparatus is of great importance. Herein, a Golgi-targeting two-photon fluorescent probe (GT-H 2 O 2) that can be excited by a femto-second pulse (760 nm) is designed. GT-H 2 O 2 utilized aminoquinoline as a fluorophore / Golgi-targetable unit and borate ester as a H 2 O 2 -responsive unit with an intramolecular charge transfer strategy. The borate ester of GT-H 2 O 2 was oxidized by H 2 O 2 selectively to afford a new fluorescent molecule GT-NH 2 , thereby realizing a ratiometric detection of H 2 O 2. The probe exhibited a high sensitivity and selectivity to H 2 O 2 with a linear range from 5 to 60 μM. In addition, endogenous / exogenous H 2 O 2 could be directly visualized utilizing GT-H 2 O 2 in vitro and in vivo by one/two-photon microscopy. • A two-photon fluorescent probe (GT-H 2 O 2) is presented to sense H 2 O 2 levels. • GT-H 2 O 2 exhibited a rapid and notable ratiometric fluorescent response for H 2 O 2. • GT-H 2 O 2 can achieve Golgi localization. • GT-H 2 O 2 was visualized to monitor endogenous/exogenous H 2 O 2 by two-photon imaging. [ABSTRACT FROM AUTHOR]

Two asymmetrical benzoxanthene dyes (BP-1 and BP-2) were designed and synthesized by a convenient one-step procedure from naphthaldehyde and m -aminophenol precursors. These dyes showed long-wavelength absorption, near-infrared emission (>650 nm), and large Stokes shifts (>90 nm) because of the asymmetrical introduction of the benzene ring into the xanthene structure. BP-1 exhibited high fluorescence quantum yield in organic solvents, whereas BP-2 showed very weak fluorescence due to the photoinduced electron transfer of 9-substituted groups. Cell experiments indicated that BP-1 with crescent-shape structure showed lower cytotoxicity and higher photostability than BP-2 and could rapidly stain RNA in nucleoli at low concentration. [Display omitted] • Two asymmetrical benzoxanthene dyes were synthesized by a convenient one-step procedure. • The dyes showed long-wavelength absorption, near-infrared emission and large Stokes shifts. • BP-1 could stained RNA in nucleoli rapidly with low cytotoxicity and good photostability. • BP-2 showed a very weak fluorescence and cytotoxicity due to 9-substituted groups. [ABSTRACT FROM AUTHOR]

An A-D-A structured AIEgen based nanoparticles was designed for long-term imaging, and effective photodynamic therapy. The small ΔE ST of 0.227 eV make BTZPP NPs possess excellent 1O 2 generation ability, and the lysosome-targeted property further assist the treatment effect of PDT. [Display omitted] • A-D-A structured AIE photosensitizer (BTZPP) with small ΔE ST was designed. • BTZPP has large Stokes shift, deep red fluorescence and high 1O 2 quantum yield. • The lysosome targeted ability make BTZPP NPs kill cancer cells more effectively. • Imaging guided PDT of cancer was demonstrated. Photosensitizers (PSs) with aggregation-induced emission (AIE) feature show promising applications in fluorescence imaging-guided photodynamic therapy (PDT) in virtue of their enhanced fluorescence and phototoxicity in aggregate state. Seeking the ideal AIE luminogens (AIEgens) with good capability of generating reactive oxygen species is still urgent. Here we rationally synthesized an acceptor-donor-acceptor (A-D-A) structured AIEgen (BTZPP) and then prepared it into nanoparticles (NPs) through a simple re-precipitation procedure. The obtained BTZPP NPs show a deep-red emission peaked at 635 nm, a large Stokes shift of 195 nm, and a high 1O 2 generation quantum yield of 72.3%. Moreover, these NPs can selectively target lysosomes in live cells and image mouse tumor with a high contrast and long-term tracking (up to 14 days) capability. The high-efficiency imaging-guided PDT against cancer cells and tumors is successfully demonstrated in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) has emerged as a promising minimally invasive and selective approach for the treatment of deep tumors. In this review, SDT-associated mechanisms include reactive oxygen species (ROS) and shear force. Organic sonosensitizers was systematically classify into porphyrins, phthalocyanines, xanthenes, indocyanines, natural products, and quinolones etc. The combination of SDT with phototherapy, chemodynamical therapy, chemotherapy, starvation therapy, gas therapy and immunotherapy, improves its therapeutic efficiency. [Display omitted] • The mechanisms of SDT are discussed. • The advantages and limitations of organic sonosensitizers for SDT are reviewed. • Strategies to improve the SDT efficacy are provided. • Guidelines are offered for the design of effective sonosensitizers. Sonodynamic therapy (SDT), which involves a combination of low-intensity ultrasound (US) and a chemical sonosensitizer, has emerged as a promising minimally invasive and selective approach for the treatment of deep tumors. US not only increases cell membrane permeability, thereby enhancing the cellular uptake efficiency of chemical sonosensitizers, but also excites chemical sonosensitizers in deep tissues to generate reactive oxygen species (ROS), which in turn kill cancer cells. As compared with inorganic materials, organic sonosensitizers exhibit a defined chemical structure, controlled synthesis process, excellent biodegradability, and high ROS generation. However, they frequently exhibit poor water solubility, strong phototoxicity, and low tumor tissue targeting capacity. In this review, we address the currently accepted mechanisms in SDT and the recent progresses in organic sonosensitizers, discuss the strategies to improve the water solubility, tumor targeting capacity, biocompatibility, and therapeutic effects of organic sonosensitizers. The advantages of combining SDT with other cancer treatments, including phototherapy, chemodynamic therapy, chemotherapy, starvation therapy, gas therapy, and immune therapy are also demonstrated. Finally, the existing challenges and future perspectives on clinical SDT of tumor are discussed. [ABSTRACT FROM AUTHOR]

• The GSH-responsive PEGylated heparin-pyropheophorbide-a nanoconjugates were prepared. • Heparin PEGylation enhanced cellular uptake, ROS production and apoptosis ratio. • The PEG-cleavable heparin achieved deep penetration and the highest PDT efficiency. To deliver photosensitizers with PEGylated heparin (HP) into tumor cells for photodynamic therapy, we prepared two polyethylene glycol (PEG)-functionalized HP-based polymers conjugated with pyropheophorbide-a (Ppa): a non-GSH-responsive nanoagent (HP-Ppa-mPEG) with the mPEG moiety chemically attached to HP directly; and a GSH-responsive nanoagent (HP-Ppa-SS-mPEG) with the mPEG moiety conjugated to HP via a disulfide linkage. The Ppa-functionalized HP without PEGylation (HP-Ppa) was designed as another control. These amphiphilic polymers could aggregate into nanoparticles. Cellular uptake of three nanoparticles by 4T1 cells led to abundant production of reactive oxygen species after irradiation by a 660 nm laser, inducing cell apoptosis. HP-Ppa-SS-mPEG was found to achieve the highest tumor accumulation, the longest retention time and the best penetration into tumor tissues, resulting in the highest in vivo anticancer efficacy with 94.3 % tumor growth inhibition rate, suggesting that tumor microenvironment-responsive PEGylated HP-based nanomedicines may act as efficient anticancer agents. [ABSTRACT FROM AUTHOR]

Molecular structure of pDHPMA-DOX-SS-mPEG, and schematic illustration of its self-aggregation into nano-aggregate for blood circulation and accumulation into tumors via the EPR effect. • Two functional polymer-DOX bioconjugates based nano-aggregates (NAs) were prepared. • NAs displayed pH and enzyme-responsive features and had excellent biocompatibility. • NAs entered into 4T1 cells through multiple endocytosis pathways. • NAs induced apoptosis by disrupting mitochondria function and actin cytoskeletons. • PEGylation for NA improved anti-tumor efficacy on 4T1 tumor bearing mice. Biocompatible, stimuli-responsive, intelligent and efficient drug delivery systems are essential for effectively suppressing cancer and reducing toxic side effects of chemotherapeutic drugs. Herein, two strategies have been employed to develop a N -(1,3-dihydroxypropan-2-yl) methacrylamide (DHPMA)-derived polymer carrier for doxorubicin (DOX) with a long circulation time: increasing molecular weight (MW) of the DHPMA polymer through an enzyme-responsive oligopeptide linker; and further grafting poly(ethylene glycol) (PEG) onto the polymer chain via a disulfide bond (pDHPMA-DOX-SS-mPEG), resulting in nano-aggregate. The nano-aggregate enters into 4T1 cells through multiple endocytosis pathways and DOX released in the presence of a low pH and reductive enzymes contribute to significant apoptosis by decreasing mitochondria membrane potential and disrupting actin cytoskeletons. Significantly enhanced tumor accumulation of the nano-aggregate is evidenced from ex vivo fluorescence imaging in comparison with the bioconjugate (pDHPMA-DOX) with no PEGylation. This is supported with a much longer terminal half-life time up to 16.9 h for pDHPMA-DOX-SS-mPEG, significantly higher than 10.4 h for pDHPMA-DOX and 2.7 h for free drug DOX. Accordingly, the best tumor inhibitive effect has been achieved by pDHPMA-DOX-SS-mPEG confirmed by significant reduction in tumor volumes and undetectable active proliferative cells and positive endotheliocytes from immunohistochemical staining of CD31 and Ki-67 in the 4T1 tumor tissue. The results demonstrate that increased MW through biodegradable linkers and grafted PEG significantly contribute to an extended circulation time, reduced systemic toxicity and an enhanced therapeutic efficacy. Tumor microenvironment-responsive PEGylated DHPMA-derived polymeric bioconjugate-based nano-aggregate offers the promising anti-tumor effect. [ABSTRACT FROM AUTHOR]