Homodimeric peptide radiotracer [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 imaging of cervical cancer patients.

PURPOSE: Vascular endothelial growth factor receptor 3 (VEGFR-3) plays a critical role in tumor lymphangiogenesis and metastasis, holding promise as a promising therapeutic target for solid tumors. TMVP1 (LARGR) is a 5-amino acid peptide previously identified in our laboratory from bacterial peptide display system that specifically targets VEGFR-3. Radiolabeled TMVP1 can be used for non-invasive imaging of VEGFR-3 expressing tumors. Homodimeric peptides have better targeting ability than monomeric peptides, and it is worth exploring whether homodimers of TMVP1 ((TMVP1)2) can achieve better imaging effects. This study aimed to explore the peptide properties and tumor assessment value of [68Ga]Ga-labeled (TMVP1)2. METHODS: In this study, we developed a TMVP1 homodimer that was conjugated with 1,4,7-triazacyclononane-N, N', N″-triacetic acid (NOTA) via tetraethyleneglycol (PEG4) and triglyicine (Gly3) spacer, and labeled with 68Ga, to construct [68Ga]Ga-NOTA-(TMVP1)2. Binding of VEGFR-3 by TMVP1 and (TMVP1)2, respectively, was modeled by molecular docking. The affinity of [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 and its ability to bind to cells were evaluated. MicroPET imaging and biodistribution studies of [68Ga]Ga-NOTA-(TMVP1)2 were performed in subcutaneous C33A cervical cancer xenografts. Five healthy volunteers and eight patients with cervical cancer underwent whole-body PET/CT acquisition 30-45 min after intravenous injection of [68Ga]Ga-NOTA-(TMVP1)2. RESULTS: Both molecular docking and cellular experiments showed that homodimeric TMVP1 had a higher affinity for VEGFR-3 than monomeric TMVP1. [68Ga]Ga-NOTA-(TMVP1)2 was excreted mainly through the renal route and partly through the liver route. In mice bearing C33A xenografts, [68Ga]Ga-NOTA-(TMVP1)2 specifically localized in the tumor (2.32 ± 0.10% ID/g). Pretreatment of C33A xenograft mice with the unlabeled peptide NOTA-(TMVP1)2 reduced the enrichment of [68Ga]Ga-NOTA-(TMVP1)2 in tumors (0.58 ± 0.01% ID/g). [68Ga]Ga-NOTA-(TMVP1)2 proved to be safe in all healthy volunteers and recruited patients, with no side effects or allergies noted. In cervical cancer patients, a majority of the [18F]-FDG identified lesions (18/22, 81.8%) showed moderate to high signal intensity on [68Ga]Ga-NOTA-(TMVP1)2. SUVmax and SUVmean were 2.32 ± 0.77 and 1.61 ± 0.48, respectively. With normal muscle (gluteus maximus) as background, tumor-to-background ratios were 3.49 ± 1.32 and 3.95 ± 1.64 based on SUVmax and SUVmean, respectively. CONCLUSION: The favorable characterizations of [68Ga]Ga-NOTA-(TMVP1)2 such as convenient synthesis, high specific activity, and high tumor uptake enable the evaluation of VEGFR-3 in cervical cancer patients and warrant further clinical studies. TRIAL REGISTRATION: ChiCTR-DOD-17012458. Registered August 23, 2017 (retrospectively registered).

Recent Advancements in Continuous-Flow Suzuki-Miyaura Coupling Utilizing Immobilized Molecular Palladium Complexes.

Immobilized Pd-catalyzed Suzuki-Miyaura coupling under continuous-flow conditions using a packed-bed reactor, representing an efficient, automated, practical, and safe technology compared to conventional batch-type reactions. The core objective of this study is the development of an active and durable catalyst. In contrast to supported Pd nanoparticles, the attachment of Pd complexes onto solid supports through well-defined coordination sites is considered a favorable approach for preparing highly dispersed and stabilized Pd species. These species can be directly employed in various flow reactions without the need for pre-treatment. This concept paper explores recent achievements involving the application of immobilized Pd complexes as precatalysts for continuous-flow Suzuki-Miyaura coupling. Our focus is to elucidate the significance of the designed catalyst structures in relation to their catalytic performance under flow conditions. Additionally, we highlight various reaction systems and catalyst packing methods, emphasizing their crucial roles in establishing a practical synthesis process.

Continuous-Flow Suzuki-Miyaura Coupling in Water and Organic Solvents Promoted by Blends of Stabilized Convoluted Polymeric Palladium Catalysts and Polymeric Auxiliary Materials.

Given that heterogeneous palladium-catalyzed C-C bond formation reactions under continuous-flow conditions are well suited for the efficient and safe production of pharmaceuticals and functional materials, the development of active and durable catalysts for this purpose is a matter of high practical significance. Here, a previously established molecular convolution methodology was used to synthesize catalysts for Suzuki-Miyaura coupling under flow conditions by blending convoluted polymeric palladium catalysts (prepared from copolymers of 4-vinylpyridine and 4-tert-butylstyrene) and crosslinked polymeric auxiliary materials (prepared from copolymers of divinylbenzene and 4-tert-butylstyrene). The optimal catalyst exhibited high performance and durability and allowed numerous biaryl products such as liquid-crystalline materials, organic electroluminescent materials, and pharmaceuticals to be continuously synthesized with turnover frequencies of up to 238 h-1 . In a demonstration of practical utility, the developed catalytic system was used for the continuous synthesis of two pharmaceuticals (felbinac and fenbufen) in water as the sole solvent.

A multifunctional integrated biomimetic spore nanoplatform for successively overcoming oral biological barriers.

The biological barriers have seriously restricted the efficacious responses of oral delivery system in diseases treatment. Utilizing a carrier based on the single construction means is hard to overcome these obstacles simultaneously because the complex gastrointestinal tract environment requires carrier to have different or even contradictory properties. Interestingly, spore capsid (SC) integrates many unique biological characteristics, such as high resistance, good stability etc. This fact offers a boundless source of inspiration for the construction of multi-functional oral nanoplatform based on SC without further modification. Herein, we develop a type of biomimetic spore nanoplatform (SC@DS NPs) to successively overcome oral biological barriers. Firstly, doxorubicin (DOX) and sorafenib (SOR) are self-assembled to form carrier-free nanoparticles (DS NPs). Subsequently, SC is effectively separated from probiotic spores and served as a functional vehicle for delivering DS NPs. As expect, SC@DS NPs can efficaciously pass through the rugged stomach environment after oral administration and further be transported to the intestine. Surprisingly, we find that SC@DS NPs exhibit a significant improvement in the aspects of mucus penetration and transepithelial transport, which is related to the protein species of SC. This study demonstrates that SC@DS NPs can efficiently overcome multiple biological barriers and improve the therapeutic effect.

In Vivo Activation of T-Cell Proliferation by Regulating Cell Surface Receptor Clustering Using a pH-Driven Interlocked DNA Nano-Spring.

Activation of T-cell proliferation specifically in a tumor is crucial for reducing the autoimmune side effects of antitumor immunotherapy. Herein, we developed a pH-driven interlocked DNA nano-spring (iDNS) to stimulate T-cell activation in vivo in response to the low pH value in a tumor microenvironment. The interlocked structure of iDNS provide a more rigid scaffold in comparison to double-stranded DNA for ligand assembly, which can help to control the spatial distribution of ligands with more accuracy. We have demonstrated that the pH-driven reversible reconfiguration of iDNS provides a powerful way to regulate the nanoscale distribution of T-cell receptors (CD3) on the cell surface. The relatively low pH value (pH 6.5) in a solid tumor was able to drive the springlike shrinking of iDNS and induce significant T-cell proliferation, leading to an enhanced antitumor effect, thus providing a tool for specifically inducing an immune response in a tumor for immunotherapy.

Experiments and Numerical Simulation of N-decane/Ethanol Bi-Component Droplet Evaporation.

The evaporation characteristics of n-decane-based bi-component or multi-component droplets have been veiled for application in advanced combustion. This paper proposes to experimentally investigate the evaporation of n-decane/ethanol bi-component droplets settled in the convective hot air, and numerically simulate the key parameters affecting the evaporation charactersitics. It was found that the evaporation behavior was interactively affected by the mass fraction of ethanol and the ambient temperature. For mono-component n-decane droplets, the evaporation process included the transient heating (non-isothermal) and steady evaporation (isothermal) stages. In the isothermal stage, the evaporation rate followed d2-law. The evaporation rate constant linearly increased as the ambient temperature enhanced (573~873 K). For n-decane/ethanol bi-component droplets, at low mass fractions (≤0.2), the isothermal evaporation processes were steady due to the good miscibility between n-decane and ethanol, like mono-component n-decane, whereas at high mass fractions (≥0.4), the evaporation process experienced ultrashort heating and fluctuating evaporation stages. During the fluctuating evaporation, the bubbles formed inside the bi-component droplets and expanded, resulting in the occurrence of the microspray (secondary atomization) and the microexplosion. The evaporation rate constant of bi-component droplets increased as the ambient temperature enhanced, and showed a "V-shaped" trend with the increase of the mass fraction, and the evaporation rate constant was the smallest at 0.4. The evaporation rate constants based on the numerical simulation by using the multiphase flow model and Lee model showed reasonable agreement with the experimental ones, suggesting a potential of application in practical engineering.

Visualizing Single-Nucleotide Variations in a Nuclear Genome Using Colocalization of Dual-Engineered CRISPR Probes.

Direct visualization of single-nucleotide variation (SNV) in single cells is of great importance for understanding the spatial organization of genomes and their relationship with cell phenotypes. Herein, we developed a new strategy for visualizing SNVs in a nuclear genome using colocalization of dual-engineered CRISPR probes (CoDEC). By engineering the structure of sgRNA, we incorporated a hairpin in the spacer domain for improving SNV recognition specificity and a loop in the nonfunctional domain for localized signal amplification. Using guide probe-based colocalization strategy, we can successfully distinguish on-target true positive signals from the off-target false positives with high accuracy. Comparing with a proximity ligation-based assay (CasPLA), the probe colocalization strategy extended applicable target gene sites (the distance between two designed probes can be extended to around 200nt) and improved detection efficiency. This newly developed method provides a facile way for studying in situ information on SNVs in individual cells for basic research and clinical applications with single-molecule and single-nucleotide resolutions.

Giant moiré trapping of excitons in twisted hBN.

Excitons in van der Waals (vdW) stacking interfaces can be trapped in ordered moiré potential arrays giving rise to the attractive phenomena of quantum optics and bosonic many-body effects. Compared to the prevalent transition metal dichalcogenides (TMDs) systems, due to the wide bandgap and low dielectric constant, excitons in twist-stacked hexagonal boron nitride (hBN) are anticipated trapped in deeper moiré potential, which enhances the strength of interactions. However, constrained by the common low detectivity of weak light-emitting in the deep-ultraviolet (DUV) bands, the moiré excitons in twist-hBN remain elusive. Here, we report that a remarkable DUV emitting band (peak located at ∼260 nm) only emerges at the twisted stacking area of hBN, which is performed by a high collection efficiency and spatially-resolved cathodoluminescence (CL) at room temperature. Significant peak red shifting contrast to defect-bound excitons of bulk hBN indicates the giant trapping effects of moiré potential for excitons. The observation of deeply trapped excitons motivates further studies of bosonic strongly correlation physics based on the twist-hBN system.

TRIM37 promotes the aggressiveness of ovarian cancer cells and increases c-Myc expression by binding to HUWE1.

Tripartite motif containing 37 (TRIM37) was reported to function as a tumor promoter in the development of various cancers. However, the biological role of TRIM37 in ovarian cancer (OC) was still unclear. Expressions of TRIM37 and HUWE1 were detected by qRT-PCR and western blotting in OC cells. Cell proliferation was evaluated by CCK-8 assay and colony formation assay. Cell migration and invasion capabilities were examined by wound healing and transwell assay. Flow cytometry and western blotting were performed to measure cell apoptosis. Wnt/ß-catenin pathway and the expression of c-Myc were identified by qRT-PCR and western blotting. The binding of TRIM37 and HUWE1 was predicted by STRING database and verified by co-immunoprecipitation. In addition, a xenograft mouse model was established to evaluate the effects of TRIM37 and HUWE1 on tumor growth and c-MYC expression in vivo. The present study revealed that TRIM37 expression was upregulated in OC tissues and cells. TRIM37 silencing inhibited OC cell migration and invasion, promoted OC cell apoptosis, and blocked Wnt/ß-catenin signaling pathway, as well as suppressing c-MYC protein expression. Mechanistic studies suggested that TRIM37 binds to HUWE1. HUWE1 was upregulated in OC cells and TRIM37 promoted the c-MYC expression through targeting HUWE1. Animal experiments showed that TRIM37 silencing significantly repressed the tumor growth and c-MYC protein level, but HUWE1 overexpression reversed the effects of TRIM37 knockdown on mice with OC. Our findings revealed that TRIM37 accelerated the progression of OC and promoted c-MYC expression by binding to HUWE1, which provides therapeutic targets for OC treatment.

Biomimetic micelles to accurately regulate the inflammatory microenvironment for glomerulonephritis treatment.

Glomerulonephritis is a key factor in leading to end-stage renal disease. Mesangial cell proliferation and macrophage infiltration are two prominent features linked in a vicious circle mechanism for glomerulonephritis progression. Herein, a novel biomimetic pH-sensitive nanomicelle (MM/HA-DXM) was constructed to synergize hyaluronic acid (HA)-activated macrophage phenotypic remodeling and dexamethasone (DXM)-mediated mesangial cell killing for precise treatment of glomerulonephritis. Owing to the camouflaged coating with endogenous macrophage membrane (MM), MM/HA-DXM could escape from RES phagocytosis and then be recruited to inflammatory glomerulus by active homing effect. Afterwards, HA-DXM nanomicelles ruptured in response to the weakly acidic glomerulonephritis microenvironment, to locally release HA and DXM. On the one hand, DXM can inhibit the abnormal proliferation of mesangial cells. On the other hand, HA transformed pro-inflammatory M1 macrophages into anti-inflammatory M2 phenotype to improve the glomerular inflammatory microenvironment. In doxorubicin-induced glomerulonephritis models, results revealed that MM/HA-DXM could specifically "homing" to inflammatory renal tissue with 4.33-fold improvement in targeting performance. In addition, in vivo pharmacodynamic results proved that after treatment with MM/HA-DXM, the proteinuria level decreased to 2.33 times, as compared with that of control group, demonstrating a superior therapeutic effect on glomerulonephritis via this collaborative two-pronged anti-inflammatory therapy strategy.

A rare case report of primary Sjögren's syndrome with clinical characteristics similar to those of CLIPPERS.

BACKGROUND: Primary Sjögren's syndrome (pSS) is an autoimmune inflammatory disease characterized by dryness of the eyes, mouth and other mucous membranes. Patients with pSS can also present with extraglandular manifestations, such as pulmonary, kidney and nervous system involvement. Central nervous system (CNS) manifestations have rarely been described in pSS. CASE PRESENTATION: A 33-year-old man was admitted with a one-month history of dizziness, speech disturbance, and walking instability. His brain enhanced magnetic resonance imaging (MRI) showed symmetrical, enhanced "salt-and-pepper-like" speckled lesions in the brainstem, basal ganglia, and subcortical regions, and his diagnosis was considered possible chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Further examination revealed that anti-SSA antibody was positive, and the Schirmer test and labial salivary gland histopathology were abnormal, which supported the diagnosis of pSS. CONCLUSION: pSS is a chronic systemic autoimmune disease that involves neurological complications. This case suggests that CNS lesions of pSS can present with clinical and MRI findings similar to those of CLIPPERS.

Copper-based metal-organic framework impedes triple-negative breast cancer metastasis via local estrogen deprivation and platelets blockade.

Metastasis is one of the main causes of failure in the treatment of triple-negative breast cancer (TNBC). Abnormally estrogen level and activated platelets are the key driving forces for TNBC metastasis. Herein, an "ion/gas" bioactive nanogenerator (termed as IGBN), comprising a copper-based MOF and loaded cisplatin-arginine (Pt-Arg) prodrug is developed for metastasis-promoting tumor microenvironment reprogramming and TNBC therapy. The copper-based MOF not only serves as a drug carrier, but also specifically produces Cu2+ in tumors, which catalytic oxidizing estrogen to reduce estrogen levels in situ. Meanwhile, the rationally designed Pt-Arg prodrug reduced into cisplatin to significantly promote the generation of H2O2 in the tumor, then permitting self-augmented cascade NO gas generation by oxidizing Arg through a H2O2 self-supplied way, thus blocking platelet activation in tumor. We clarified that IGBN inhibited TNBC metastasis through local estrogen deprivation and platelets blockade, affording 88.4% inhibition of pulmonary metastasis in a 4T1 mammary adenocarcinoma model. Notably, the locally copper ion interference, NO gas therapy and cisplatin chemotherapy together resulted in an enhanced therapeutic efficacy in primary tumor ablation without significant toxicity. This "ion/gas" bioactive nanogenerator offers a robust and safe strategy for TNBC therapy.

Boosting cisplatin chemotherapy by nanomotor-enhanced tumor penetration and DNA adducts formation.

Despite many nano-based strategies devoted to delivering cisplatin for tumor therapy, its clinical benefits are compromised by poor tissue penetration and limited DNA adducts formation of the drug. Herein, a cisplatin loading nanomotor based janus structured Ag-polymer is developed for cisplatin delivery of deeper tissue and increased DNA adducts formation. The nanomotor displayed a self-propelled tumor penetration fueled by hydrogen peroxide (H2O2) in tumor tissues, which is catalytically decomposed into a large amount of oxygen bubbles by Ag nanoparticles (NPs). Notably, cisplatin could elevate the intracellular H2O2 level through cascade reactions, further promote the degradation of Ag NPs accompanied with the Ag+ release, which could downregulate intracellular Cl- through the formation of AgCl precipitate, thereby enhancing cisplatin dechlorination and Pt-DNA formation. Moreover, polymer can also inhibit the activity of ALKBH2 (a Fe2+-dependent DNA repair enzyme) by chelating intracellular Fe2+ to increase the proportion of irreparable Pt-DNA cross-links. It is found that deep tissue penetration, as well as the increased formation and maintenance of Pt-DNA adducts induced by the nanomotor afford 80% of tumor growth inhibition with negligible toxicity. This work provides an important perspective of resolving chemotherapeutic barriers for boosting cisplatin therapy.

Cardiorespiratory fitness and mortality from all causes, cardiovascular disease and cancer: dose-response meta-analysis of cohort studies.

OBJECTIVE: Current evidence of the associations between cardiorespiratory fitness (CRF) and mortality is limited. We performed a meta-analysis to assess the dose-response association of CRF with mortality from all causes, cardiovascular disease (CVD) and cancer in healthy population. METHODS: PubMed, EMBASE and Web of Science were searched up to 26 December 2019 for reports of cohort studies giving risk estimates for all-cause, CVD and cancer mortality by level of CRF. Cohort studies were included if CRF was assessed by an exercise stress test and reported as at least three levels or per incremental increase, and the association of CRF with all-cause, CVD and cancer mortality was evaluated. Generalised least-squares regression models were used to assess the quantitative relation of CRF with all-cause, CVD and cancer mortality. RESULTS: 34 cohort studies were eligible for the meta-analysis. The pooled relative risks (RRs) for all-cause, CVD and cancer mortality per one-metabolic equivalent increase in CRF were 0.88 (95% CI 0.83 to 0.93), 0.87 (95% CI0.83 to 0.91) and 0.93 (95% CI 0.91 to 0.96), respectively. As compared with lowest CRF, with intermediate CRF, the summary RRs for all-cause, CVD and cancer mortality were 0.67 (95% CI 0.61 to 0.74), 0.60 (95% CI 0.51 to 0.69) and 0.76 (95% CI 0.69 to 0.84), respectively, and with highest CRF were 0.47 (95% CI 0.39 to 0.56), 0.49 (95% CI 0.42 to 0.56) and 0.57 (95% CI 0.46 to 0.70), respectively. CONCLUSION: Our analysis showed inverse dose-response associations of CRF with all-cause, CVD and cancer mortality, which provides evidence for public health recommendations for preventing all-cause, CVD and cancer mortality. PROSPERO REGISTRATION NUMBER: CRD42020208883.

Long noncoding RNA ARRDC1-AS1 is activated by STAT1 and exerts oncogenic properties by sponging miR-432-5p/PRMT5 axis in glioma.

Dysfunction of long noncoding RNA (lncRNA) is associated with tumorigenesis of various malignancies, including glioma. Previously, lncRNA ARRDC1 antisense RNA 1(ARRDC1-AS1) has been reported to be dysregulated in several tumors. However, the roles of ARRDC1-AS1 in glioma have not been investigated. In this study, we firstly reported that ARRDC1-AS1 expression was distinctly increased in both glioma specimens and cell lines, and high ARRDC1-AS1 expression was associated with advanced clinical progression and poor prognosis of glioma patients. Additionally, STAT1 could activate the transcription of ARRDC1-AS1. Functional studies revealed that knockdown of ARRDC1-AS1 suppressed the proliferation, migration and invasion of glioma cells. Mechanisms exploration indicated ARRDC1-AS1 served as a sponge of miR-432-5p to upregulate PRMT5 expressions. Rescue experiments indicated that knockdown of miR-432-5p reversed the inhibiting effects of ARRDC1-AS1 knockdown on glioma cells. Overall, our findings highlighted the importance of STAT1/ARRDC1-AS1/miR-432-5p/PRMT5 axis in glioma progression and offered novel strategies for glioma treatments.

Photoactivated Self-Disassembly of Multifunctional DNA Nanoflower Enables Amplified Autophagy Suppression for Low-Dose Photodynamic Therapy.

Low-dose photodynamic therapy (PDT) holds great promise for reducing undesired patient photosensitivity in cancer treatment. Yet, its therapeutic effect is significantly affected by intracellular cytoprotective processes, such as autophagy. Here, an efficient autophagy suppressor is developed, which is a multifunctional DNA nanoflower (DNF) consisted of tumor-targeting aptamers and DNAzymes for silencing autophagy-related genes, with surface modification of low-dose photosensitizer (Ce6). It is found that the multifunctional DNF can specifically target tumor cells and generate reactive oxygen species (ROS) under light irradiation to trigger self-disassembly of DNF, enhancing the bioavailability of encoded DNAzymes, leading to amplified autophagy suppression. As a facile spatiotemporally programmable photogene therapy platform, the designed DNF is able to suppress tumor growth in vivo with a very low injection dose of Ce6 (18 µg kg-1 , around 100 times lower than the generally applied dose), representing a promising strategy for cancer therapy with safely low-dose PDT.

Artemisinin co-delivery system based on manganese oxide for precise diagnosis and treatment of breast cancer.

Tumor microenvironment (TME) responsive intelligent system can realize the specific release and uniform distribution of chemotherapy drugs in tumor tissues, to achieve high-efficiency and low-toxic treatment of tumors. In this paper, drug delivery system TKD@RBCm-Mn2O3-ART with the above characteristics was constructed. We synthesized hollow mesoporous manganese trioxide (Mn2O3) nanoparticles and firstly found that they owned time-dependent size transformation feature in simulated TME. The particle size decreased from 318 nm to 50 nm and 6 nm at 1 h and 4 h in simulated TME, respectively. Then artemisinin (ART) was loaded into Mn2O3to realize the co-delivery of Mn2+and ART. The modification of homologous red cell membrane (RBCm) and TKD peptide was aimed at long circulation and tumor targeting in the body.In vitroresults demonstrated that in the presence of GSH, the cumulative drug release percentage could achieve 97.5%. Meanwhile, Mn2O3exhibited a good imaging capability in tumor, with the relaxation rate of 6.3113 mM-1s-1. After entering into MCF-7 cells, TKD@RBCm-Mn2O3/ART synchronously released Mn2+and ART to generate large amount of ROS and induce DNA damage.In vivoresults proved TKD@RBCm-Mn2O3/ART could arrive the deep area of solid tumors and achieve accurate diagnosis and treatment of breast cancer.

Limiting tumor cells comprehensively at micro and macro levels to improve the therapeutic effect of chemotherapy.

Clinical data shows that antitumor treatments are often ineffective if tumor cells have metastasized. To gain an effective antitumor therapeutic effect, in this report, the tumor cell was limited to the primary site and simultaneously ablated by chemotherapy. Considering the extremely complicated process of cancer metastasis, we seek to comprehensively suppress tumor metastases at both micro and macro levels, which closely link to migration and interact with each other. At the micro level, the motility of the tumor cell was decreased via accelerating mitochondria fusion. At the macro level, the unfavorable hypoxia environment was improved. A liposome-based multifunctional nanomedicine was designed by coloading latrunculin B (LAT-B), an inhibitor of actin polymerization, and doxorubicin (DOX) into the hydrophobic bilayers and aqueous cavity, respectively. Meanwhile, an oxygen reservoir named perfluoropentane (PFP) was encapsulated into the liposome core to fulfill synergistic treatment of metastatic tumors. In this paper, we demonstrated that the metastasis of the tumor cell could be effectively inhibited by LAT-B through promoting mitochondria fusion without affecting its function, making it as an encouraging candidate for effective anti-metastasis therapy. Meanwhile, we found that the combination of LAT-B and DOX shows a synergistic effect against tumors because the combined effect of these two drugs cover the entire cell proliferation process. In a word, this report presents a potential improvement in the treatment of metastatic cancer.

Nanoenabled Intracellular Calcium Bursting for Safe and Efficient Reversal of Drug Resistance in Tumor Cells.

Multidrug resistance (MDR) of a tumor is the main cause of failure of clinical chemotherapy. Herein, we report a simple, yet versatile, tumor-targeting "calcium ion nanogenerator" (TCaNG) to reverse drug resistance by inducing intracellular Ca2+ bursting. Consequently, the TCaNG could induce Ca2+ bursting in acidic lysosomes of tumor cells and then reverse drug resistance according to the following mechanisms: (i) Ca2+ specifically accumulates in mitochondria, suppressing cellular respiration and relieving tumor hypoxia, thus inhibiting P-glycoprotein biosynthesis by downregulating HIF-1α expression. (ii) Ca2+-bursting-induced respiratory depression blocks intracellular ATP production, which further leads to the P-gp incompetence. As a result, the TCaNG could decrease the IC50 of DOX to MCF-7/ADR cells by approximately 30 times and reduce the proliferation of drug-resistant tumors by approximately 13 times without obvious side effects. This simple, safe, and effective "Ca2+ bursting" strategy holds the potential for clinical application in tumor treatment.

Bioinspired Nanosponge for Salvaging Ischemic Stroke via Free Radical Scavenging and Self-Adapted Oxygen Regulating.

Either hypoxia in an acute ischemic stroke before thrombolysis or the oxygen-boost after thrombolysis cause a high level of free radicals, resulting in successive injuries to neurocytes. To treat an ischemic stroke, it is needed to scavenge free radicals, combining sequentially regulating hypoxia and oxygen-boost microenvironment. Here, we report an engineered nanosponge (Mn3O4@nanoerythrocyte-T7, MNET) that could remodel the microenvironment of a stroke by self-adapted oxygen regulating and free radical scavenging. With a long circulation time in blood due to the stealth effect of the erythrocyte and preferential accumulation in the infarct site by the assisting of T7 peptide, MNET exerts a distinct therapeutic effect in two stages of an ischemic stroke: (i) before thrombolysis, rescue neurocyte via rapid free radical scavenging and timely oxygen supply; (ii) after thrombolysis, suppress oxygen-boost via oxygen storage, as well as scavenge free radical to avoid reperfusion injury. MNET holds an attractive potential for ischemic stroke treatment via phased regulation of pathological microenvironment.