Activating Single-Atom Ni Site via First-Shell Si Modulation Boosts Oxygen Reduction Reaction.

Atomically dispersed nitrogen-coordinated 3d transition-metal site on carbon support (M-NC) are promising alternatives to Pt group metal-based catalysts toward oxygen reduction reaction (ORR). However, despite the excellent activities of most of M-NC catalysts, such as Fe-NC, Co-NC et al., their durability is far from satisfactory due to Fenton reaction. Herein, this work reports a novel Si-doped Ni-NC catalyst (Ni-SiNC) that possesses high activity and excellent stability. X-ray absorption fine structure and aberration-corrected transmission electron microscopy uncover that the single-atom Ni site is coordinated with one Si atom and three N atoms, constructing Ni-Si1 N3  moiety. The Ni-SiNC catalyst exhibits a half-wave potential (E1/2 ) of 0.866 V versus RHE, with a distinguished long-term durability in alkaline media of only 10 mV negative shift in E1/2  after 35 000 cycles, which is also validated in Zn-air battery. Density functional theory calculations reveal that the Ni-Si1 N3  moiety facilitates ORR kinetics through optimizing the adsorption of intermediates.

Boron Coordination Effect in Ni-Nx Doped Graphene Catalysts on the ORR Performance Based on DFT Calculations.

The coordination atoms of metal active site in transition metal N-doped carbon single atom electrocatalysts play a vital role in dominating the catalytic performance of oxygen reduction reaction (ORR) at the cathode of fuel cells or metal-air cells. In view of weak adsorption ability of Ni active site in NiN4 -C catalysts to oxygen intermediate states, herein we introduce boron atoms with smaller electronegativity than N and C atoms to modulate the local coordination environment and electronic structures of Ni site. First-principles density functional calculations reveal that both B substitution for N atoms (NiN2 B2 -C) and B coordinating with N and C (NiN4 B8 -C) can effectively optimize the Gibbs free energy of oxygen intermediate states and hence improve the catalytic activity of the materials. In addition, we propose that the trend change in catalytic activity is mainly governed by the filling of antibonding orbitals between Ni-3d and O-2p states near the Fermi level.

Irinotecan/scFv co-loaded liposomes coaction on tumor cells and CAFs for enhanced colorectal cancer therapy.

BACKGROUND: Cancer-associated fibroblasts (CAFs), as an important component of stroma, not only supply the "soils" to promote tumor invasion and metastasis, but also form a physical barrier to hinder the penetration of therapeutic agents. Based on this, the combinational strategy that action on both tumor cells and CAFs simultaneously would be a promising approach for improving the antitumor effect. RESULTS: In this study, the novel multifunctional liposomes (IRI-RGD/R9-sLip) were designed, which integrated the advantages including IRI and scFv co-loading, different targets, RGD mediated active targeting, R9 promoting cell efficient permeation and lysosomal escape. As expected, IRI-RGD/R9-sLip showed enhanced cytotoxicity in different cell models, effectively increased the accumulation in tumor sites, as well as exhibited deep permeation ability both in vitro and in vivo. Notably, IRI-RGD/R9-sLip not only exhibited superior in vivo anti-tumor effect in both CAFs-free and CAFs-abundant bearing mice models, but also presented excellent anti-metastasis efficiency in lung metastasis model. CONCLUSION: In a word, the novel combinational strategy by coaction on both "seeds" and "soils" of the tumor provides a new approach for cancer therapy, and the prepared liposomes could efficiently improve the antitumor effect with promising clinical application prospects.

Boron carbon nitride as efficient oxygen reduction reaction support.

The electrocatalytic oxygen reduction reaction (ORR) is crucial for energy conversion systems such as fuel cells and metal-air batteries. Boron carbon nitrogen (BCN) is a novel functional material with a high specific surface area, excellent corrosion resistance, and outstanding electrochemical stability. These properties make BCN an effective ORR catalyst and a promising support for metal catalysts. This study leveraged the strong interaction between BCN and metals to anchor platinum nanoparticles (Pt NPs) onto the BCN surface (Pt/BCN), significantly enhancing the durability of traditional Pt/C catalysts in ORR. The half-wave potential of Pt/BCN is 0.927 V, higher than Pt/XC-72R (0.857 V) and commercial Pt/C (0.879 V). Notably, after 10,000 durability test cycles, the mass activity (MA) of Pt/XC-72R and commercial Pt/C decreased by 67 % and 75 %, respectively. Even after 50,000 cycles, Pt/BCN exhibited only a 54 % decrease in MA. Experimental data and density functional theory calculations confirmed increased electron transfer from Pt to the BCN support, indicating a strong electronic metal-support interaction (EMSI) between Pt and BCN. This strong EMSI effectively anchored the Pt NPs, preventing migration and aggregation during the ORR process. Consequently, our research introduces a novel electrocatalyst support material with significant potential for ORR and broader applications.

Comparison of left ventricular global and segmental strain parameters by cardiovascular magnetic resonance tissue tracking in light-chain cardiac amyloidosis and hypertrophic cardiomyopathy.

Background: Apical sparing of left ventricular (LV) strain can occur in light-chain cardiac amyloidosis (AL-CA). We employed indicators of the strain ratio of the apex to base (RAB) and the relative apical sparing of strain (RAS) on the basis of LV global and segmental strain to distinguish AL-CA from hypertrophic cardiomyopathy (HCM). Methods: In all, 36 AL-CA patients, 37 HCM patients, and 36 healthy controls underwent 3.0 T cardiac magnetic resonance (CMR) examination. We compared LV strain parameters from CMR tissue tracking (CMR-TT), including global and segmental peak radial strain (PRS), peak circumferential strain (PCS), and peak longitudinal strain (PLS); the peak systolic strain rate in radial, circumferential, and longitudinal directions (PSSR_R, PSSR_C, PSSR_L); and the peak diastolic strain rate in radial, circumferential, and longitudinal directions (PDSR_R, PDSR_C, PDSR_L). We also assessed the values of RAB and RAS. Differences in all groups were compared using an independent t-test and a nonparametric rank sum test. Results: In the comparison of global strain parameters, all the peak strain, systolic, and diastolic peak strain rates of the AL-CA group significantly decreased compared with those of the HCM and healthy control groups (all P<0.001). The values of PSSR in all directions were lower in the AL-CA than in the HCM patients (PSSR_R, P<0.001; PSSR_C, P=0.004; PSSR_L, P=0.010) . In the analysis of segmental strain parameters, all peak strains in the basal segment showed significant differences between the AL-CA and HCM groups (all P<0.001). Some strain rate parameters in the basal segment were also noted to be significantly different (PSSR_R, P<0.001; PSSR_L, P<0.001; PDSR_R, P=0.015; PDSR_C, P=0.020). Both the RAB and RAS of peak strain in all directions showed significant differences between the AL-CA and HCM groups (all P<0.001). The RAB of the radial and circumferential PSSR showed statistical differences between the 2 groups (P<0.001 and P=0.001). The RAS in the radial direction of both the PSSR and PDSR was statistically different (P=0.003 and P=0.012). Conclusions: The CMR-TT technique can be used to quantitatively compare global and segmental strain differences between AL-CA and HCM. In addition, RAB and RAS are reliable parameters for assessing the apical sparing pattern and thus, for distinguishing AL-CA from HCM.

Correlation of four-phase CT findings of rectal neuroendocrine neoplasms with different World Health Organization grades.

PURPOSE: To investigate the four-phase computed tomography (CT) features of rectal neuroendocrine neoplasms (R-NENs) as they relate to different World Health Organization pathological grades. METHODS: A total of 42 patients who underwent pre-operative four-phase CT for evaluation of neoplasms confirmed as different pathological grades of R-NENs by surgery were included. The CT features were retrospectively analyzed by two radiologists in consensus including the tumor location, shape, long diameter, necrosis, boundary, transmural invasion, CT attenuation values of noncontrast and different enhancement phases, intra mesenteric metastasis, lateral lymph node metastasis, and distant metastasis. The differences among R-NENs of different pathological grades were analyzed using T-test, analysis of variance, and non-parametric rank sum test. RESULTS: Among 42 cases (23 males, 19 females, aged 57 ± 10.48 years) of R-NENs, neuroendocrine tumors G1, G2, and G3 (NET G1, NET G2, NET G3) and neuroendocrine carcinoma (NEC) were 13, 13, 3 and 13 cases, respectively. There were statistically significant differences in tumor long diameter, shape, necrosis, boundary, transmural invasion, CT values in delayed phase, intra mesenteric metastasis, lateral lymph node metastasis, and liver metastasis of different pathological grades (P < 0.001, P = 0.014, P = 0.004, P < 0.001, P < 0.001, P = 0.038, P = 0.006, P = 0.022, and P = 0.020, respectively). CONCLUSION: Features on four-phase CT can correlate with WHO pathological grades of R-NENs; this may be helpful for preoperative diagnosis and prognosis evaluation.

The value of enhanced CT features and texture-signatures in assessing the inflammatory infiltration of pancreatic ductal adenocarcinoma.

Purpose: To explore the predictive value of computed tomography (CT) imaging features and CT-based texture analysis in assessing inflammatory infiltration in pancreatic ductal adenocarcinoma (PDAC). Methods: A total of 43 patients with PDAC confirmed by surgical pathology were included in the study. The clinical, radiological, surgical, and pathological features of the patients were analyzed retrospectively using the chi-square test or Spearman's correlation. Receiver operating characteristic (ROC) curves were utilized to assess the overall predictive ability of the tumor enhancement degree on triphasic contrast-enhanced CT images for the inflammatory infiltration degree in PDAC. Furthermore, all CT data were uploaded to the RadCloud platform for region of interest (ROI) delineation and feature extraction. Then, the Variance Threshold and SelectKBest algorithms were used to find the optimal CT features. Binary logistic regression was employed to analyze the selected features in all three contrast-enhanced CT phases, and regression equations were formulated. ROC analysis was performed to evaluate the predictive effectiveness of each equation. Results: The analysis revealed a statistically significant correlation between the degree of differentiation and radiological findings such as necrosis and cystic degeneration, vascular invasion, and the presence of ascites (P < 0.05). The enhancement degree of the tumor in both the arterial and venous phases was significantly correlated with the inflammatory infiltration degree (P < 0.05); however, the areas under the ROC curve (AUCs) of arterial and venous enhancement were 0.570 and 0.542, respectively. Regression equations based on the texture features of triphasic contrast-enhanced tumors were formulated, and their AUCs were 0.982, 0.643, and 0.849. Conclusion: Conventional radiological features are not significantly correlated with the degree of inflammatory infiltration in PDAC. The enhancement degrees in both the arterial phase and venous phase were statistically correlated with the inflammatory infiltration level but had poor predictive value. The texture features of PDAC on contrast-enhanced CT may show a better assessment value, especially in the arterial phase.

A Multifunctional, Highly Biocompatible, and Double-Triggering Caramelized Nanotheranostic System Loaded with Fe3O4 and DOX for Combined Chemo-Photothermal Therapy and Real-Time Magnetic Resonance Imaging Monitoring of Triple Negative Breast Cancer.

Purpose: Owing to lack of specific molecular targets, the current clinical therapeutic strategy for triple negative breast cancer (TNBC) is still limited. In recent years, some nanosystems for malignancy treatment have received considerable attention. In this study, we prepared caramelized nanospheres (CNSs) loaded with doxorubicin (DOX) and Fe3O4 to achieve the synergistic effect of combined therapy and real-time magnetic resonance imaging (MRI) monitoring, so as to improve the diagnosis and therapeutic effect of TNBC. Methods: CNSs with biocompatibility and unique optical properties were prepared by hydrothermal method, DOX and Fe3O4 were loaded on it to obtain Fe3O4/DOX@CNSs nanosystem. Characteristics including morphology, hydrodynamic size, zeta potentials and magnetic properties of Fe3O4/DOX@CNSs were evaluated. The DOX release was evaluated by different pH/near-infrared (NIR) light energy. Biosafety, pharmacokinetics, MRI and therapeutic treatment of Fe3O4@CNSs, DOX and Fe3O4/DOX@CNSs were examined in vitro or in vivo. Results: Fe3O4/DOX@CNSs has an average particle size of 160 nm and a zeta potential of 27.5mV, it demonstrated that Fe3O4/DOX@CNSs is a stable and homogeneous dispersed system. The hemolysis experiment of Fe3O4/DOX@CNSs proved that it can be used in vivo. Fe3O4/DOX@CNSs displayed high photothermal conversion efficiency, extensive pH/heat-induced DOX release. 70.3% DOX release is observed under the 808 nm laser in the pH = 5 PBS solution, obviously higher than pH = 5 (50.9%) and pH = 7.4 (less than 10%). Pharmacokinetic experiments indicated the t1/2ß, and AUC0-t of Fe3O4/DOX@CNSs were 1.96 and 1.31 -fold higher than those of DOX solution, respectively. Additionally, Fe3O4/DOX@CNSs with NIR had the greatest tumor suppression in vitro and in vivo. Moreover, this nanosystem demonstrated distinct contrast enhancement on T2 MRI to achieve real-time imaging monitoring during treatment. Conclusion: Fe3O4/DOX@CNSs is a highly biocompatible, double-triggering and improved DOX bioavailability nanosystem that combines chemo-PTT and real-time MRI monitoring to achieve integration of diagnosis and treatment of TNBC.

Engineering cation vacancies in high-entropy layered double hydroxides for boosting the oxygen evolution reaction.

High-entropy layered double hydroxides (HE-LDHs) are emerging as promising electrocatalysts towards the OER due to their high-entropy effect and the cocktail effect. However, the catalytic activity and stability of HE-LDHs is, as yet, unsatisfactory. Herein, we designed FeCoNiCuZn LDHs with rich cation vacancies, which need only low overpotentials of 227, 275 and 293 mV to reach 10, 100 and 200 mA cm-2, respectively, and show almost no decay up to 200 h at 200 mA cm-2. DFT calculations validate that the cation vacancies can boost the intrinsic activity of HE-LDHs through optimizing the adsorption energy of OER intermediates.

In-situ surface reconstruction of single-crystal (NiFe)3Se4 nano-pyramid arrays for efficient oxygen evolution.

Transition metal-based selenides (TMSe) are considered as efficient pre-electrocatalysts towards oxygen evolution reaction (OER). However, the key factor in determining the surface reconstruction of TMSe under OER condition is not yet clear. Herein, we uncover that the crystallinity of TMSe will obviously impact the conversion degree from TMSe to transition metal oxyhydroxides (TMOOH) during OER. A novel single-crystal (NiFe)3Se4 nano-pyramid array grown on NiFe foam is fabricated by a facile one-step polyol process, which exhibits an excellent OER activity and stability, only requiring 170 mV to reach a current density of 10 mA cm-2 and can sustain for more than 300 h. In situ Raman spectrum studies reveals that the single-crystal (NiFe)3Se4 is partially oxidized on its surface during OER, generating a dense heterostructure of (NiFe)OOH/(NiFe)3Se4. Benefiting from the in situ formed heterointerface, the adsorption of OER intermediates on Ni active sites calculated by density functional theory (DFT) analysis is optimized, leading to the reduced energy barrier, which accounts for the enhanced intrinsic activity. This work not only reports a novel single-crystal (NiFe)3Se4 nano-pyramid array electrocatalyst with high-efficient OER performance, but also gains a deep insight into the role of the crystallinity of TMSe on the surface reconstruction during OER.

CMR left ventricular strains beyond global longitudinal strain in differentiating light-chain cardiac amyloidosis from hypertrophic cardiomyopathy.

Background: The clinical value of left ventricular (LV) global longitudinal strain (GLS) in the differential diagnosis of light-chain cardiac amyloidosis (AL-CA) and hypertrophic cardiomyopathy (HCM) has been previously reported. In this study, we analyzed the potential clinical value of the LV long-axis strain (LAS) to discriminate AL-CA from HCM. Furthermore, we analyzed the association between all the LV global strain parameters derived from cardiac magnetic resonance (CMR) feature tracking and LAS in both the AL-CA and HCM patients to assess the differential diagnostic efficacies of these global peak systolic strains. Materials and methods: Thus, this study enrolled 89 participants who underwent cardiac MRI (CMRI), consisting of 30 AL-CA patients, 30 HCM patients, and 29 healthy controls. The intra- and inter-observer reproducibility of the LV strain parameters including GLS, global circumferential strain (GCS), global radial strain (GRS), and LAS were assessed in all the groups and compared. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic performances of the CMR strain parameters in discriminating AL-CA from HCM. Results: The intra- and inter-observer reproducibility of the LV global strains and LAS were excellent (range of interclass correlation coefficients: 0.907-0.965). ROC curve analyses showed that the differential diagnostic performances of the global strains in discriminating AL-CA from HCM were good to excellent (GRS, AUC = 0.921; GCS, AUC = 0.914; GLS, AUC = 0.832). Furthermore, among all the strain parameters analyzed, LAS showed the highest diagnostic efficacy in differentiating between AL-CA and HCM (AUC = 0.962). Conclusion: CMRI-derived strain parameters such as GLS, LAS, GRS, and GCS are promising diagnostic indicators that distinguish AL-CA from HCM with high accuracy. LAS showed the highest diagnostic accuracy among all the strain parameters.

nc-RNA-mediated high expression of CDK6 correlates with poor prognosis and immune infiltration in pancreatic cancer.

BACKGROUND: Emerging evidence manifests that cyclin-dependent kinase 6 (CDK6) plays an essential part in the initiation and progression of several types of human cancer, and its descending expression is correlated with an adverse prognosis. However, the precise role of CDK6 in Pancreatic cancer (PC) remains obscure. AIMS: To identify the potential ceRNA regulatory axis of CDK6 in PC and explore its relationship with immune cells and immune checkpoints. MATERIALS & METHODS: Using The Cancer Genome Atlas TCGA and GTEx data analyze the expression and survival of CDK6 in patients in pan-cancer, and cellular experiments were performed to verify the effect of CDK6 on cell function. Using GEPIA and STARBASE databases to analyze prognosis, expression and survival, and identify non coding RNA (ncRNA) that mediates CDK6 overexpression. The TIMER 2.0 database was used for immune correlation analysis. RESULTS: We revealed CDK6 might be an oncogene in PC, and the HOXA11-AS /NR2F1-AS1- miR-454-3p axis was identified as the possible upstream ncRNA-associated pathway of CDK6 in PC. In addition, CDK6 show significant association with three immune checkpoints (PD-L1, PD-L2, and HAVCR2), the infiltration level of immune cells, and immunity biomarkers. DISCUSSION: We discussed some applications of CDK6 in breast cancer, melanoma, and hemorrhagic malignancies. The role of miR-15a-5p, HOXA11-AS and NR2F1-AS1 in tumor development was also discussed based on existing studies. The potential mechanism of CDK6 affecting immune cells in pancreatic cancer was discussed. CONCLUSIONS: Overall, these results established that nc-RNA-mediated high expression of CDK6 is associated with patient outcomes and immune invasion in pancreatic cancer.

Activating lattice oxygen in high-entropy LDH for robust and durable water oxidation.

The oxygen evolution reaction is known to be a kinetic bottleneck for water splitting. Triggering the lattice oxygen oxidation mechanism (LOM) can break the theoretical limit of the conventional adsorbate evolution mechanism and enhance the oxygen evolution reaction kinetics, yet the unsatisfied stability remains a grand challenge. Here, we report a high-entropy MnFeCoNiCu layered double hydroxide decorated with Au single atoms and O vacancies (AuSA-MnFeCoNiCu LDH), which not only displays a low overpotential of 213 mV at 10 mA cm-2 and high mass activity of 732.925 A g-1 at 250 mV overpotential in 1.0 M KOH, but also delivers good stability with 700 h of continuous operation at ~100 mA cm-2. Combining the advanced spectroscopic techniques and density functional theory calculations, it is demonstrated that the synergistic interaction between the incorporated Au single atoms and O vacancies leads to an upshift in the O 2p band and weakens the metal-O bond, thus triggering the LOM, reducing the energy barrier, and boosting the intrinsic activity.

Development and external validation of a radiomics combined with clinical nomogram for preoperative prediction prognosis of resectable pancreatic ductal adenocarcinoma patients.

Purpose: To develop and externally validate a prognosis nomogram based on contrast-enhanced computed tomography (CECT) combined clinical for preoperative prognosis prediction of patients with pancreatic ductal adenocarcinoma (PDAC). Methods: 184 patients from Center A with histopathologically confirmed PDAC who underwent CECT were included and allocated to training cohort (n=111) and internal validation cohort (n=28). The radiomic score (Rad - score) for predicting overall survival (OS) was constructed by using the least absolute shrinkage and selection operator (LASSO). Univariate and multivariable Cox regression analysis was used to construct clinic-pathologic features. Finally, a radiomics nomogram incorporating the Rad - score and clinical features was established. External validation was performed using Center B dataset (n = 45). The validation of nomogram was evaluated by calibration curve, Harrell's concordance index (C-index) and decision curve analysis (DCA). The Kaplan-Meier (K-M) method was used for OS analysis. Results: Univariate and multivariate analysis indicated that Rad - score, preoperative CA 19-9 and postoperative American Joint Committee on Cancer (AJCC) TNM stage were significant prognostic factors. The nomogram based on Rad - score and preoperative CA19-9 was found to exhibit excellent prediction ability: in the training cohort, C-index was superior to that of the preoperative CA19-9 (0.713 vs 0.616, P< 0.001) and AJCC TNM stage (0.713 vs 0.614, P< 0.001); the C-index was also had good performance in the validation cohort compared with CA19-9 (internal validation cohort: 0.694 vs 0.555, P< 0.001; external validation cohort: 0.684 vs 0.607, P< 0.001) and AJCC TNM stage (internal validation cohort: 0.694 vs 0.563, P< 0.001; external validation cohort: 0.684 vs 0.596, P< 0.001). The calibration plot and DCA showed excellent predictive accuracy in the validation cohort. Conclusion: We established a well-designed nomogram to accurately predict OS of PDAC preoperatively. The nomogram showed a satisfactory prediction effect and was worthy of further evaluation in the future.

HPLC Coupled with Chemical Fingerprinting for Multi-Pattern Recognition for Identifying the Authenticity of Clematidis Armandii Caulis.

A method for identifying Chinese medicinal materials and their related adulterants was constructed by taking Clematidis Armandii Caulis (Chuanmutong, a universally used traditional Chinese medicine) as an example. Ten batches of genuine Chuanmutong varieties and five batches of related adulterants were analyzed and compared based on the high-performance liquid chromatography (HPLC) fingerprints combined with chemometrics, including cluster analysis (CA), principal component analysis (PCA), and orthogonal partial least-squares discrimination analysis (OPLS-DA). In addition, the content of ß-sitosterol was determined. The control chemical fingerprint of Chuanmutong was established, and 12 common peaks were identified. The similarity between the fingerprint of 10 batches of genuine Chuanmutong varieties and the control fingerprint was 0.910-0.989, while the similarity of five batches of adulterants was only 0.133-0.720. Based on the common peaks in the chromatogram, 15 batches of samples were classified into three content levels by PCA, and were aggregated into four categories by CA, achieving a clear distinction between authentic Chuanmutong and adulterants of Chuanmutong. Further, seven differential components that can effectively identify authentic Chuanmutong and adulterants of Chuanmutong were found through OPLS-DA. The ß-sitosterol content of 10 batches of genuine Chuanmutong varieties was 97.53-161.56 µg/g, while the ß-sitosterol content of the five batches of adulterants varied greatly, among which the ß-sitosterol content of Clematis peterae Hand.-Mazz. and Clematis gouriana Roxb. Var. finetii Rehd. et Wils. was significantly lower than that of authentic varieties of Chuanmutong. The HPLC index component content and chemical fingerprint multi-pattern recognition method established in this study provide a new strategy for effectively identifying authentic Chinese medicinal materials and related adulterants.

Therapeutic Response of Multifunctional Lipid and Micelle Formulation in Hepatocellular Carcinoma.

Hepatic stellate cells (HSCs), as an important part of the tumor microenvironment (TME), could be activated by tumor cells as cancer-associated fibroblasts (CAFs), thereby promoting the production of extracellular matrix (ECM) and favoring the development of tumors. Therefore, blocking the "CAFs-ECM" axis is a promising pathway to improve antitumor efficacy. Based on this, we developed a multifunctional nanosized delivery system composed of hyaluronic acid-modified pH-sensitive liposomes (CTHLs) and glycyrrheic acid-modified nanomicelles (DGNs), which combines the advantages of targeted delivery, pH-sensitivity, and deep drug penetration. To mimic actual TME, a novel HSCs+BEL-7402 cocultured cell model and a m-HSCs+H22 coimplanted mice model were established. As expected, CTHLs and DGNs could target CAFs and tumor cells, respectively, and promote the drug penetration and retention in tumor regions. Notably, CTHLs+DGNs not only exhibited a superior antitumor effect in three-level tumor-bearing mice but also presented excellent antimetastasis efficiency in lung-metastatic mice. The antitumor mechanism revealed that the lipid&micelle mixed formulations effectively inhibited the activation of CAFs, reduced the deposition of ECM, and reversed the epithelial-mesenchymal transition (EMT) of tumor cells. In brief, the nanosized delivery system composed of CTHLs and DGNs could effectively improve the therapeutic effect of liver cancer by blocking the "CAFs-ECM" axis, which has a good clinical application prospect.

Acidic tumor microenvironment-sensitive liposomes enhance colorectal cancer therapy by acting on both tumor cells and cancer-associated fibroblasts.

Cancer-associated fibroblasts (CAFs) play a crucial role in facilitating tumor invasion and metastasis, which act as the "soil" in the tumor microenvironment (TME). Accordingly, it would be a promising strategy to enhance the antitumor effect by killing both tumor cells and CAFs simultaneously. Herein, novel TME acid-responsive liposomes for co-delivery of IRI and 398 (IRI&398-s-LPs) were developed, in which the rapid release of both drugs could be triggered under acidic conditions. Notably, a CT-26/3T3 cell co-culture system was used to mimic the real TME both in vitro and in vivo. Cellular immunofluorescence revealed that IRI&398-s-LPs could efficiently decrease the activation of CAFs. In vitro cytotoxicity evaluation demonstrated that IRI&398-s-LPs exhibited higher cytotoxicity than the other liposomal formulations in the CT-26 and CT-26/3T3 cell co-culture system. In vivo NIRF imaging showed that the IRI&398-s-LPs could increase drug accumulation in the tumor sites. Furthermore, IRI&398-s-LPs not only presented superior in vivo anti-tumor activity in CT-26 bearing BALB/c mice, but also enhanced the effect in CT-26/3T3 cell bearing mice with decreased collagen and CAF biomarker expression. Furthermore, IRI&398-s-LPs also presented superior anti-metastatic efficiency in a lung metastasis model. These results indicated that this combinational strategy for eliminating both tumor cells and CAFs provides a new approach for cancer therapy, and the prepared TME-responsive liposomes for co-delivery of drugs hold promising clinical application prospects.

Dual-Ligand-Modified Liposomes Co-Loaded with Anti-Angiogenic and Chemotherapeutic Drugs for Inhibiting Tumor Angiogenesis and Metastasis.

BACKGROUND: Tumor angiogenesis has been proven to potentiate tumor growth and metastasis; therefore, the strategies targeting tumor-related angiogenesis have great potentials in antitumor therapy. METHODS: Here, the GA&Gal dual-ligand-modified liposomes co-loaded with curcumin and combretastatin A-4 phosphate (CUCA/GA&Gal-Lip) were prepared and characterized. A novel "BEL-7402+HUVEC" co-cultured cell model was established to mimic tumor microenvironment. The cytotoxicity and migration assays were performed against the novel co-cultured model. Angiogenesis ability was evaluated by tube formation test, and in vivo metastatic ability was evaluated by lung metastasis test. RESULTS: The result demonstrated that dual-ligand-modified liposomes showed greater inhibition of tumor angiogenesis and metastasis in comparison with other combined groups. Significantly, the mechanism analysis revealed that curcumin and combretastatin A-4 phosphate could inhibit tumor angiogenesis and metastasis via down-regulation of VEGF and VEGFR2 expression, respectively, and that GA&Gal-Lip could improve antitumor effect by GA/Gal-mediated active-targeting delivery. CONCLUSION: CUCA/GA&Gal-Lip hold great potentials in hepatoma-targeting delivery of antitumor drugs and can achieve anti-angiogenic and anti-metastatic effects by simultaneously blocking VEGF/VEGFR2 signal pathway, therefore exhibiting superior anti-hepatoma efficacy.

Combined anti-hepatocellular carcinoma therapy inhibit drug-resistance and metastasis via targeting "substance P-hepatic stellate cells-hepatocellular carcinoma" axis.

Peripheral nerves have emerged as the important components in tumor microenvironment (TME), which could activate hepatic stellate cells (HSCs) by secreting substance P (SP), leading to hepatocellular carcinoma (HCC) invasion and metastasis. Herein, we proposed a novel anti-HCC concept of blocking "SP-HSCs-HCC" axis for omnidirectional inhibition of HCC development. To pursue this aim, the novel CAP/GA-sHA-DOX NPs were developed for targeted co-delivery of capsaicin (CAP) and doxorubicin (DOX) using glycyrrhetinic acid (GA) modified sulfated-HA (sHA) as nanocarriers. Among that, CAP could inhibit the activation of HSCs as an inhibitor of SP. Notably, to real mimic "SP-HSCs-HCC" axis for in vitro and in vivo evaluation, both "SP + LX-2+BEL-7402" co-cultured cell model and "SP + m-HSC + H22" co-implantation mice model were attempted for the first time. Furthermore, in vivo anti-HCC effects were performed in three different tumor-bearing models: subcutaneous implantation of H22 or "SP + m-HSC + H22", intravenous injection of H22 for lung metastasis, and orthotopic implantation of H22 for primary HCC. Our results showed that CAP/GA-sHA-DOX NPs could be efficiently taken up by tumor cells and activated HSCs (aHSCs) simultaneously, and effectively inhibit tumor drug-resistance and migration by blocking SP-induced HSCs activation. In addition, CAP/GA-sHA-DOX NPs exhibited low ECM deposition, less tumor angiogenesis, and superior in vivo anti-HCC effects. The anti-HCC mechanisms revealed that CAP/GA-sHA-DOX NPs could down-regulate the expression level of Vimentin and P-gp, reverse epithelial-mesenchymal transition (EMT) of tumor cells. In brief, the nano-sized combination therapy based on GA-sHA-DOX polymers could effectively inhibit drug-resistance and metastasis of HCC by blocking "SP-HSCs-HCC" axis, which provides a promising approach for cancer therapy.

Study on different particle sizes of DOX-loaded mixed micelles for cancer therapy.

Nano-based drug delivery systems have been widely applied in cancer therapy, among that, particle sizes may affect the delivery efficiency of nanocarriers. The purpose of this study was to evaluate the potential impacts of particle size on tumor therapy, in consideration of this, lipid/glycocholic acid mixed micelles (LGs) were designed as the model nanocarriers. Doxorubicin (DOX) loaded LGs with two different particle sizes at around 10 nm and 100 nm, respectively, were successfully prepared by controlling the ratio of EPC to GAH. In vitro release study showed that the release behaviors of DOX in mixed micelles with two different particle sizes was basically consistent and showed sustained release. DOX-LGs at 10 nm exhibited higher cellular uptake capacity, compared with DOX-LGs at 100 nm. Besides, in vivo NIFR imaging also demonstrated that DOX-LGs at 10 nm had more accumulation in tumor site. Furthermore, DOX-LGs at 10 nm presented both higher in vitro cytotoxicity and superior in vivo antitumor activity than that of 100 nm. In vivo safety evaluations showed that the mixed micelles had lower toxicities than free DOX solution formulations. These results indicated that the nanoparticles with smaller particle size could improve the profiles in cellular uptake, tumor accumulation as well as anti-tumor efficacy, which would provide a theoretical principle for the design of nanoparticles.