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Objective: Medication-related osteonecrosis of the jaw bones (MRONJ) is a well-known complication of antiresorptive and antiangiogenic drugs. Since the first report, more occurrences of MRONJ have been described worldwide. Dental extraction has been described by many studies as one of the risk factors for MRONJ. Comprehensive dental care (CDC) is a preventive dental method provided to patients prior to drug commencement. This study aims to determine the association between CDC and MRONJ. Patients and methods. A retrospective analysis was performed on 75 medical records of patients on antiresorptive and/or antiangiogenic drugs between February 2018 and May 2021. Demographics and clinical and radiographic data were collected. Univariate and multivariate analyses were performed to determine the factors associated with MRONJ. Results: Of the 75 patients who met the inclusion criteria, 11 (14.7%) developed MRONJ. Three out of 11 patients (27.2%) developed MRONJ spontaneously, while eight patients (72.8%) developed it after trauma from dentures or dental extractions. Following a binary logistic regression analysis, the lack of CDC was identified as a significant predictor of MRONJ. Patients who did not receive CDC had an odds ratio of 8.64 (95% confidence interval (CI): 1.27–58.62, p = 0.03). However, dental extraction did not show a statistically significant association with MRONJ in both the univariate and multivariate analyses. Conclusion: CDC before treatment with antiresorptive and antiangiogenic drugs is a potentially effective preventive method for reducing MRONJ. Dental extraction was not a significant factor in relation to MRONJ. [ABSTRACT FROM AUTHOR]

Background: The anti-angiogenic agent anlotinib offers a new treatment option for triple-negative breast cancer (TNBC) patients with brain metastases. This study aimed to evaluate the efficacy and safety of anlotinib in the treatment of TNBC patients with brain metastases. Methods: Between October 2019 and April 2024, 29 TNBC patients with brain metastases who had failed prior therapy and were treated with anlotinib were retrospectively analyzed. The primary endpoint was central nervous system (CNS) progression-free survival (PFS), and secondary endpoints included overall survival (OS), intracranial disease control rate (iDCR), intracranial objective response rate (iORR), and safety. Results: The median CNS PFS of 29 patients was 7.2 months (95% confidence interval [CI], 3.5-10.9 months), and the median OS was 10.2 months (95% CI, 5.6-14.8 months). The iORR and iDCR were 31.0% and 86.2%, respectively. Five patients (17.2%) experienced grade 3-4 adverse events (AEs), with bone marrow suppression (2/29, 6.9%) being the most common. Most AEs were clinically manageable, and no treatment-related death was observed. Conclusion: Anlotinib demonstrated encouraging efficacy and manageable toxicity in the treatment of TNBC patients with brain metastases who had failed standard treatment. [ABSTRACT FROM AUTHOR]

Abstract Objective Medication-related osteonecrosis of the jaw bones (MRONJ) is a well-known complication of antiresorptive and antiangiogenic drugs. Since the first report, more occurrences of MRONJ have been described worldwide. Dental extraction has been described by many studies as one of the risk factors for MRONJ. Comprehensive dental care (CDC) is a preventive dental method provided to patients prior to drug commencement. This study aims to determine the association between CDC and MRONJ. Patients and methods. A retrospective analysis was performed on 75 medical records of patients on antiresorptive and/or antiangiogenic drugs between February 2018 and May 2021. Demographics and clinical and radiographic data were collected. Univariate and multivariate analyses were performed to determine the factors associated with MRONJ. Results Of the 75 patients who met the inclusion criteria, 11 (14.7%) developed MRONJ. Three out of 11 patients (27.2%) developed MRONJ spontaneously, while eight patients (72.8%) developed it after trauma from dentures or dental extractions. Following a binary logistic regression analysis, the lack of CDC was identified as a significant predictor of MRONJ. Patients who did not receive CDC had an odds ratio of 8.64 (95% confidence interval (CI): 1.27–58.62, p = 0.03). However, dental extraction did not show a statistically significant association with MRONJ in both the univariate and multivariate analyses. Conclusion CDC before treatment with antiresorptive and antiangiogenic drugs is a potentially effective preventive method for reducing MRONJ. Dental extraction was not a significant factor in relation to MRONJ.

Abstract As an emerging cancer treatment strategy, reactive oxygen species-based tumor catalytic therapies face enormous challenges due to hypoxia and the overexpression of glutathione (GSH) in the tumor microenvironment. Herein, a self-assembled copper-based nanoplatform, TCCHA, was designed for enzyme-like catalysis-enhanced chemodynamic/photodynamic/antiangiogenic tritherapy against hepatocellular carcinoma. TCCHA was fabricated from Cu2+, 3,3′-dithiobis (propionohydrazide), and photosensitizer chlorine e6 via a facile one-pot self-assembly strategy, after which an aldehyde hyaluronic acid was coated, followed by loading of the antivascular drug AL3818. The obtained TCCHA nanoparticles exhibited pH/GSH dual-responsive drug release behaviors and multienzymatic activities, including Fenton, glutathione peroxidase-, and catalase-like activities. TCCHA, a redox homeostasis disruptor, promotes ⋅OH generation and GSH depletion, thus increasing the efficacy of chemodynamic therapy. TCCHA, which has catalase-like activity, can also reinforce the efficacy of photodynamic therapy by amplifying O2 production. In vivo, TCCHA efficiently inhibited tumor angiogenesis and suppressed tumor growth without apparent systemic toxicity. Overall, this study presents a facile strategy for the preparation of multienzyme-like nanoparticles, and TCCHA nanoparticles display great potential for enzyme catalysis-enhanced chemodynamic/photodynamic/antiangiogenic triple therapy against cancer. Graphical Abstract

As an emerging cancer treatment strategy, reactive oxygen species-based tumor catalytic therapies face enormous challenges due to hypoxia and the overexpression of glutathione (GSH) in the tumor microenvironment. Herein, a self-assembled copper-based nanoplatform, TCCHA, was designed for enzyme-like catalysis-enhanced chemodynamic/photodynamic/antiangiogenic tritherapy against hepatocellular carcinoma. TCCHA was fabricated from Cu2+, 3,3′-dithiobis (propionohydrazide), and photosensitizer chlorine e6 via a facile one-pot self-assembly strategy, after which an aldehyde hyaluronic acid was coated, followed by loading of the antivascular drug AL3818. The obtained TCCHA nanoparticles exhibited pH/GSH dual-responsive drug release behaviors and multienzymatic activities, including Fenton, glutathione peroxidase-, and catalase-like activities. TCCHA, a redox homeostasis disruptor, promotes ⋅OH generation and GSH depletion, thus increasing the efficacy of chemodynamic therapy. TCCHA, which has catalase-like activity, can also reinforce the efficacy of photodynamic therapy by amplifying O2 production. In vivo, TCCHA efficiently inhibited tumor angiogenesis and suppressed tumor growth without apparent systemic toxicity. Overall, this study presents a facile strategy for the preparation of multienzyme-like nanoparticles, and TCCHA nanoparticles display great potential for enzyme catalysis-enhanced chemodynamic/photodynamic/antiangiogenic triple therapy against cancer. [ABSTRACT FROM AUTHOR]

Abstract Aims Neovascularization plays a crucial role in liver fibrosis (LF), and blocking vascular endothelial growth factor receptors (VEGFR) has been shown to improve fibrosis. The aim of our study was to investigate the role of dual neovascularization targets, VEGFR, and platelet‐derived growth factor receptor (PDGFR), in ameliorating fibrosis. Methods In vitro, we observed the effects of apatinib (APA) (a VEGFR inhibitor) and donafenib (DON) (a VEGFR and PDGFR inhibitor) on the activation, proliferation, and apoptosis of hepatic stellate cells (HSCs) from rats and humans. In vivo, we established a thioacetamide (TAA)‐induced liver fibrosis rat model to explore the antifibrosis effect of APA and DON. We used the method of random table to randomly divide the rats into 4 groups. We detected the expression of angiogenesis‐related proteins using Western blot and immunohistochemistry. Results APA and DON inhibited the proliferation and activation of HSCs, promoted apoptosis of HSCs, and arrested the S phase of the cell cycle in vitro. We also found that DON had a stronger inhibitory effect on HSCs. In vivo, APA and DON ameliorated liver fibrosis, reduced collagen deposition and α‐SMA expression in rats, and DON had a stronger improvement effect. APA and DON downregulated the expression of VEGFR2 while inhibiting the phosphorylation of Akt and ERK1/2. DON can act through both VEGF and PDGF pathways, whereas APA can only act through the VEGF pathway. Conclusion Antiangiogenesis is a promising approach for the treatment of fibrosis. Compared with a single‐target drug (APA), the dual‐target drug (DON) can achieve better therapeutic effects.

[Display omitted] Copper-based nanomaterials show considerable potential in the chemodynamic therapy of cancers. However, their clinical application is restricted by low catalytic activity in tumor microenvironment and copper-induced tumor angiogenesis. Herein, a novel copper-doxorubicin-anlotinib (CDA) nanoconjugate was constructed by the combination of copper-hydrazide coordination, hydrazone linkage and Schiff base bond. The CDA nanoconjugate consists of a copper-3,3′-dithiobis(propionohydrazide)-doxorubicin core and an anlotinib-hyaluronan shell. Benefiting from hyaluronan camouflage and abundant disulfide bonds and Cu2+, the CDA nanoconjugate possessed excellent tumor-targeting and glutathione-depleting abilities and enhanced chemodynamic efficacy. Released doxorubicin significantly improved copper-mediated chemodynamic therapy by upregulating nicotinamide adenine dinucleotide phosphate oxidase 4 expression to increase intracellular H 2 O 2 level. Furthermore, the nanoconjugate produced excessive •OH to induce lipid peroxidation and mitochondrial dysfunction, thus greatly elevating doxorubicin-mediated chemotherapy. Importantly, anlotinib effectively inhibited the angiogenic potential of copper ions. In a word, the CDA nanoconjugate is successfully constructed by combined coordination and pH-responsive linkages, and displays the great potential of copper-drug conjugate for targeted synergistic chemo/chemodynamic/antiangiogenic triple therapy against cancers. [ABSTRACT FROM AUTHOR]

This document provides a summary of the direct cytotoxic effects of bevacizumab, a cancer treatment drug, on various types of cancer cells. The summary includes information on the specific cell lines used in the studies, the dosage and time of exposure to bevacizumab, and whether direct cytotoxicity was observed. The document also discusses the limitations of using colorimetric assays to assess bevacizumab's direct cytotoxic effects and proposes a redefined framework for understanding its role in cancer therapy. The proposed framework emphasizes the drug's ability to target both tumor vasculature and tumor cells, and suggests that individual variances in VEGFA expression levels may influence therapeutic responses. Incorporating bevacizumab's direct cytotoxic effect enriches our understanding of its mechanism and may help prevent or overcome resistance to the drug. The article discusses the need to reassess drug administration protocols, therapeutic combinations, and predictive biomarkers for bevacizumab in order to optimize its therapeutic outcomes. The authors suggest that further research is required to validate the direct cytotoxic effects of bevacizumab on tumor cells and propose a multifaceted experimental approach to address gaps in understanding. They emphasize the importance of using advanced imaging technologies and appropriate control cell lines to accurately analyze the cytotoxic effects of bevacizumab. The article also highlights challenges and limitations in translating the direct cytotoxic effects of bevacizumab into clinical practice, including tumor heterogeneity, determining optimal [Extracted from the article]

This study aimed to screen differentially expressed genes (DEGs) involved in the influence of antiangiogenic therapy on myeloid-derived suppressor cell (MDSC) infiltration and investigate their mechanisms of action. Data on DEGs after the action of antiangiogenic drugs in a pan-cancer context were obtained from the Gene Expression Omnibus (GEO) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the clusterProfiler package in R software. Single-sample gene set enrichment analysis was performed using the gene set variation analysis package to evaluate the levels of immune cells and the activity of immune-related pathways. The relationships of DEGs with the infiltration levels of MDSCs and specific immune cell subpopulations were investigated via gene module analysis. The top 10 key genes were subsequently obtained from PPI network analysis using the cytoHubba plugin of the Cytoscape platform. When the DEGs of the four datasets were intersected, a DEG in the intersection of three datasets and 12 DEGs in the intersection of two datasets were upregulated, and 28 DEGs in the intersection of two datasets were downregulated. GO and KEGG pathway enrichment analyses revealed that the DEGs were associated with multiple important signaling pathways closely related to tumor onset and development, including cell differentiation, cell proliferation, the cell cycle, and immune responses. Most downregulated genes in lung adenocarcinoma (LUAD) were positively correlated with MDSC expression. Only MGP was negatively correlated; the correlation between CACNG6 and MDSC expression was statistically insignificant. In lung squamous cell carcinoma (LUSC), the relationships of PMEPA1, PCDH7, NEURL1B, and CACNG6 with MDSC expression were statistically insignificant; MGP was negatively correlated with MDSC expression. The top 10 key genes with the highest degree scores obtained using the cytoHubba plugin of Cytoscape were AURKB, RRM2, BUB1, NUSAP1, PRC1, TOP2A, NCAPH, CENPA, KIF2C, and CCNA2. Most of these genes were upregulated in LUAD and associated with immune cell infiltration and prognosis in tumors. An analysis of the relationships between DEGs and infiltration by other specific immune cells revealed the presence of consistent patterns in the downregulated genes, which exhibited positive correlations with the levels of Th2 cells, γδ T cells, and CD56dim NK cells, and negative correlations with other infiltrating immune cells. Antiangiogenic therapy may regulate MDSC infiltration through multiple important signaling pathways closely associated with tumor onset and development, such as cell differentiation, cell proliferation, the cell cycle, and immune responses. Antiangiogenic drugs may exert effects by affecting various types of infiltrating cells associated with immune suppression. [ABSTRACT FROM AUTHOR]

Background: This study aimed to examine the clinical characteristics of bone metastasis (BoM) in patients with non‐small cell lung cancer (NSCLC) who have an epidermal growth factor receptor (EGFR) mutation and to identify the most effective treatment strategy using EGFR–tyrosine kinase inhibitors (TKIs). Methods: The study included patients with stage IV EGFR‐mutated NSCLC who were receiving first‐line treatment with EGFR–TKIs between January 2014 and December 2020. These patients were divided into two groups based on the presence or absence of BoM at the time of initial diagnosis. The BoM group was further subdivided based on whether they received denosumab or not. Results: The final analysis included 247 patients. Those with BoM at initial diagnosis had shorter progression‐free survival (12.6 vs. 10.5 months, p = 0.002) and overall survival (OS) (49.7 vs. 30.9 months, p = 0.002) compared to those without BoM. There was a difference in the location of metastatic sites between the two groups, with a higher incidence of extrathoracic metastasis in the BoM group (p < 0.001). The incidence of T790M was higher in patients with BoM than in those without (47.4% vs. 33.9%, p = 0.042). Multivariate Cox regression analysis revealed that sequential osimertinib treatment and the addition of antiangiogenic therapy (AAT) and denosumab therapy improved OS in patients with BoM. Conclusions: The presence of BoM is a negative prognostic factor for NSCLC patients with an EGFR mutation, possibly due to the presence of extrathoracic metastases. However, adding AAT and denosumab, along with sequential osimertinib, to the treatment regimen for patients with BoM can improve survival outcomes. [ABSTRACT FROM AUTHOR]

Early vascular-targeted drugs represented by VEGF single-pathway inhibitors pioneered the idea of regulating the tumor growth microenvironment and enhanced the chemotherapy effect in a variety of tumors. However, their shortcomings of "only winning PFS but not OS" have gradually revealed and warned that drug-resistant growth of tumors is unavoidable after long-term use. The activation of intracellular bypass signaling after inhibiting a single target may be an important reason. In order to eliminate this problem, attempts have been made to expand the combination of drug types and increase the intensity of drug treatment. The possibility of replacing single-target anti-angiogenic therapeutic drugs with multiple targets has also be explored. A new generation of "dual-dimension, multi-pathway" drugs that simultaneously inhibit multiple targets both in tumors and microvascular endothelial cells can be used either as single drugs in multiple tumor types, or in combination with chemotherapy, EGFR-TKI, or even immunological drugs. It demonstrates good efficacy and great potential and hope for upgrading vascular targeted therapy. It also enlightens us that future treatment and new drug development strategies cannot rely solely on the most precise target inhibition, but should have a "dual-dimension, multi-pathway" integration concept that looks at the overall situation from one corner. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF) not only serves as an autocrine survival factor for tumor cells themselves, but also stimulates angiogenesis by paracrine pathway. Strategies targeting VEGF holds tremendous potential for tumor therapy, however, agents targeting VEGF are limited by intolerable side effects, together with incomplete and temporary blocking of VEGF, resulting in unsatisfactory and unsustained therapeutic outcomes. Herein, hierarchical-unlocking virus-esque NanoCRISPR (HUNGER) is constructed for complete, permanent and efficient intracellular disruption of autocrine and paracrine pathway of VEGF, thereby eliciting notable tumor inhibition and antiangiogenesis. After intravenous administration, HUNGER exhibits prolonged blood circulation and hyaluronic acid-CD44 mediated tumor-targeting capability. Subsequently, when matrix metalloproteinase-2 is overexpressed in the tumor microenvironment, the PEG layer will be removed. The cell-penetrating peptide R8 endows HUNGER deep tumor penetration and specific cellular uptake. Upon cellular internalization, HUNGER undergoes hyaluronidase-triggered deshielding in lysosome, lysosomal escape is realized swiftly, and then the loaded CRISPR/Cas9 plasmid (>8 kb) is transported to nucleus efficiently. Consequentially, complete, permanent and efficient intracellular disruption of autocrine and paracrine pathway of VEGF ensures inhibition of angiogenesis and tumor growth with inappreciable toxicity. Overall, this work opens a brand-new avenue for anti-VEGF therapy and presents a feasible strategy for in vivo delivery of CRISPR/Cas9 system. Hierarchical-unlocking virus-esque NanoCRISPR (HUNGER) is constructed for complete, permanent and efficient intracellular disruption of autocrine and paracrine pathway of VEGF, thereby eliciting notable tumor inhibition and antiangiogenesis. By hierarchical-unlocking, HUNGER could achieve prolonged blood circulation, tumor-targeting, deep tumor penetration, specific cellular uptake and fast lysosomal escape. Consequentially, complete, permanent and efficient intracellular disruption of autocrine and paracrine pathway of VEGF ensures inhibition of angiogenesis and tumor growth with inappreciable toxicity. [Display omitted] [ABSTRACT FROM AUTHOR]

Bevacizumab plays an important role in the first and second line treatment for metastatic colorectal cancer (CRC). And induction of hypoxia and the tumors response to it plays an important role in determining the efficacy of antiangiogenic therapy while the connection between them remains unclear. Here, we found that lactate accumulated in the tumor environment of CRC and acted as substrates for histone lactylation, and this process was further induced by cellular enhanced glycolysis in hypoxia. We determined that CRC patients resistant to bevacizumab treatment presented with elevated levels of histone lactylation and inhibition of histone lactylation efficiently suppressed CRC tumorigenesis, progression and survival in hypoxia. Histone lactylation promoted the transcription of RUBCNL/Pacer, facilitating autophagosome maturation through interacting with BECN1 (beclin 1) and mediating the recruitment and function of the class III phosphatidylinositol 3-kinase complex, which had a crucial role in hypoxic cancer cells proliferation and survival. Moreover, combining inhibition of histone lactylation and macroautophagy/autophagy with bevacizumab treatment demonstrated remarkable treatment efficacy in bevacizumab-resistance patients-derived pre-clinical models. These findings delivered a new exploration and important supplement of metabolic reprogramming-epigenetic regulation, and provided a new strategy for improving clinical efficacy of bevacizumab in CRC by inhibition of histone lactylation. Abbreviations: 2-DG: 2-deoxy-D-glucose; BECN1: beclin 1; CQ: chloroquine; CRC: colorectal cancer; DMOG: dimethyloxalylglycine; H3K18la: histone H3 lysine 18 lactylation; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Nala: sodium lactate; PDO: patient-derived orgnoid; PDX: patient-derived xenograft; RUBCNL/Pacer: rubicon like autophagy enhancer; SQSTM1/p62: sequestosome 1. [ABSTRACT FROM AUTHOR]

Abstract Background This study aimed to examine the clinical characteristics of bone metastasis (BoM) in patients with non‐small cell lung cancer (NSCLC) who have an epidermal growth factor receptor (EGFR) mutation and to identify the most effective treatment strategy using EGFR–tyrosine kinase inhibitors (TKIs). Methods The study included patients with stage IV EGFR‐mutated NSCLC who were receiving first‐line treatment with EGFR–TKIs between January 2014 and December 2020. These patients were divided into two groups based on the presence or absence of BoM at the time of initial diagnosis. The BoM group was further subdivided based on whether they received denosumab or not. Results The final analysis included 247 patients. Those with BoM at initial diagnosis had shorter progression‐free survival (12.6 vs. 10.5 months, p = 0.002) and overall survival (OS) (49.7 vs. 30.9 months, p = 0.002) compared to those without BoM. There was a difference in the location of metastatic sites between the two groups, with a higher incidence of extrathoracic metastasis in the BoM group (p

Surgical resection is still the main means for clinical treatments of breast cancer, but the postoperative immunosuppressive microenvironment and neoangiogenesis of the residual tumors easily lead to tumor metastasis and recurrence, which will further endanger patients' lives. The combination of antiangiogenic therapy and immunotherapy may promote the mutually reinforced cycle of immune reprogramming and vascular normalization to avoid tumor metastasis and recurrence. Herein, we prepared polydopamine nanoparticles for improving tissue adhesion and enriching tumor-associated antigens. This nanoregulator together with regorafenib (REG) was further incorporated into a hydrogel developed from grafting adipic acid dihydrazide onto 2,2,6,6-tetramethylpiperidine-1-oxyl radical oxidized chitin and oxidized hyaluronic acid, which was injectable at the cavity after subcutaneous tumor surgery with good mechanical properties and degradability. The system showed long-term release of REG. After combining with anti-PD-L1, the hydrogel applied to the surgical wound exhibited a reduction in tumor metastasis and recurrence. This effect was achieved by suppressing angiogenesis and enhancing antitumor immunity, characterized by increased levels of effector T lymphocytes and activation of dendritic cells within tumors, spleens, and draining lymph nodes. The injectable hydrogel offers a promising strategy for postoperative management aimed at preventing tumor metastasis and recurrence.

Multitarget tyrosine kinase inhibitors (TKIs) serve as first-line therapeutics in the systemic treatment of hepatocellular carcinoma (HCC), yet their clinical effectiveness is hampered by suboptimal pharmacokinetics and bioavailability. There is a critical need to enhance the circulation, tumor targeting, and infiltration of TKIs. In this context, we developed a silk fibroin (SF)-based nanomedicine that exploits the chemical versatility and conformation tunability of SF. Folic acid (FA) with affinity toward HCC cells is utilized to functionalize SF, simultaneously aiding in the pH-sensitive β-sheet transitions of SF. This dynamic conformation behavior is key to improving the nanomedicine's circulation, biological adhesion, and tumor localization. By encapsulating Lenvatinib (Leva) TKI, the nanomedicine exhibits tumor-targeted accumulation and potent inhibition on HCC cell survival and angiogenesis, thereby amplifying Leva's bioavailability and therapeutic impact. Owing to SF's low immunogenicity and high reproducibility, this SF-based approach for TKI delivery holds substantial promise for advancing HCC systemic therapy.

Background: The anti-angiogenic agent anlotinib offers a new treatment option for triple-negative breast cancer (TNBC) patients with brain metastases. This study aimed to evaluate the efficacy and safety of anlotinib in the treatment of TNBC patients with brain metastases., Methods: Between October 2019 and April 2024, 29 TNBC patients with brain metastases who had failed prior therapy and were treated with anlotinib were retrospectively analyzed. The primary endpoint was central nervous system (CNS) progression-free survival (PFS), and secondary endpoints included overall survival (OS), intracranial disease control rate (iDCR), intracranial objective response rate (iORR), and safety., Results: The median CNS PFS of 29 patients was 7.2 months (95% confidence interval [CI], 3.5-10.9 months), and the median OS was 10.2 months (95% CI, 5.6-14.8 months). The iORR and iDCR were 31.0% and 86.2%, respectively. Five patients (17.2%) experienced grade 3-4 adverse events (AEs), with bone marrow suppression (2/29, 6.9%) being the most common. Most AEs were clinically manageable, and no treatment-related death was observed., Conclusion: Anlotinib demonstrated encouraging efficacy and manageable toxicity in the treatment of TNBC patients with brain metastases who had failed standard treatment., Competing Interests: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Li, Zhao, Liu and Sun.)

Aim: Angiogenesis is the hallmark of cancer progression driven by VEGF/VEGFR-2 signalling pathway, inhibition of which could be a solution to tackle the progression of tumour cells and thus arresting their growth. Materials & methods: A novel class of pyrazoles was synthesized using arginine and dibromo ketones. Antiangiogenic activity was performed by in vivo yolk sac method. Antioxidant activity was evaluated by hydroxyl and superoxide radical scavenging assays. Docking studies were performed to determine the pyrazoles' binding potential with VEGFR-2 receptor and VEGF tyrosine kinase. ADMET properties were calculated using SwissADME and admetSAR for drug-likeness. Results: Compounds 5a-e showed significant antiangiogenic effects. Compound 5f exhibited effective hydroxyl and superoxide radical scavenging activities. Docking results confirmed the potential binding efficiency with VEGFR-2 receptor over VEGF tyrosine kinase, thus, functioning as competitive-inhibitors. ADMET studies revealed that the compounds possess favourable drug-like qualities. Conclusion: This study presents a novel class of pyrazoles as promising antioxidant and antiangiogenic agents with favourable drug-likeness properties.

Cancer presents a significant health threat, necessitating the development of more precise, efficient, and less damaging treatment approaches. To address this challenge, we employed the 1-ethyl-(3-dimethyl aminopropyl) carbodiimide/ N -hydroxy succinimide (EDC/NHS) catalytic system and utilized quaternized chitosan oligosaccharide (HTCOSC) as a drug carrier to construct a nanoparticle delivery system termed HTCOSC-cRGD-ES2-MTX (CREM). This system specifically targets integrin αvβ3 on tumor cell surfaces and enables simultaneous loading of the antiangiogenic agent ES2 (IVRRADRAAVP) and the chemotherapy drug methotrexate (MTX). Due to its amphiphilic properties, CREM self-assembles into nanoparticles in aqueous solution, exhibiting an average diameter of 179.47 nm. Comparative studies demonstrated that CREM, in contrast to free ES2 and MTX-free nanoparticles (CRE), significantly suppressed the proliferation of EAhy926 endothelial cells and B16 melanoma cells in vitro , resulting in inhibition rates of 71.18 and 82.25%, respectively. Furthermore, CREM exhibited a hemolysis rate below 2%, indicating excellent in vitro antiangiogenic and antitumor activity as well as favorable blood compatibility. Additionally, both CRE and CREM demonstrated favorable tumor targeting capabilities through the specific binding action of cyclic RGD (cRGD) to integrin αvβ3. Further in vivo investigations revealed that CREM induced apoptosis in tumor cells via the mitochondrial apoptotic pathway and reduced the expression of angiogenic factors such as vascular endothelial growth factor (VEGF), thereby inhibiting tumor angiogenesis. This potent antitumor effect was evident through a tumor suppression rate of 80.19%. Importantly, histopathological staining (HE staining) demonstrated the absence of significant toxic side effects of CREM on various organs compared to MTX. In conclusion, the CREM nano drug delivery system synergistically enhances the therapeutic efficacy of antiangiogenic drugs and chemotherapeutic agents, thus offering a novel targeted approach for cancer treatment.

Synergistic therapy has shown greater advantages compared with monotherapy. However, the complex multiple-administration plan and potential side effects limit its clinical application. A transformable specific-responsive peptide (TSRP) is utilized to one-step achieve synergistic therapy integrating anti-tumor, anti-angiogenesis and immune response. The TSRP is composed of: i) Recognition unit could specifically target and inhibit the biological function of FGFR-1; ii) Transformable unit could self-assembly and trigger nanofibers formation; iii) Reactive unit could specifically cleaved by MMP-2/9 in tumor micro-environment; iv) Immune unit, stimulate the release of immune cells when LTX-315 (Immune-associated oncolytic peptide) exposed. Once its binding to FGFR-1, the TSRP could cleaved by MMP-2/9 to form the nanofibers on the cell membrane, with a retention time of up to 12 h. Through suppressing the phosphorylation levels of ERK 1/2 and PI3K/AKT signaling pathways downstream of FGFR-1, the TSRP significant inhibit the growth of tumor cells and the formation of angioginesis. Furthermore, LTX-315 is exposed after TSRP cleavage, resulting in Calreticulin activation and CD8 + T cells infiltration. All above processes together contribute to the increasing survival rate of tumor-bearing mice by nearly 4-folds. This work presented a unique design for the biological application of one-step synergistic therapy of bladder cancer., (© 2024 Wiley‐VCH GmbH.)

High-risk (HR) corneal transplantation presents a formidable challenge, with over 50% of grafts experiencing rejection despite intensive postoperative care involving frequent topical eyedrop administration up to every 2 h, gradually tapering over 6-12 months, and ongoing maintenance dosing. While clinical evidence underscores the potential benefits of inhibiting postoperative angiogenesis, effective antiangiogenesis therapy remains elusive in this context. Here, we engineered controlled-release nanomedicine formulations comprising immunosuppressants (nanoparticles) and antiangiogenesis drugs (nanowafer) and demonstrated that these formulations can prevent HR corneal transplantation rejection for at least 6 months in a clinically relevant rat model. Unlike untreated corneal grafts, which universally faced rejection within 2 weeks postsurgery, a single subconjunctival injection of the long-acting immunosuppressant nanoparticle alone effectively averted graft rejection for 6 months, achieving a graft survival rate of ∼70%. Notably, the combination of an immunosuppressant nanoparticle and an anti-VEGF nanowafer yielded significantly better efficacy with a graft survival rate of >85%. The significantly enhanced efficacy demonstrated that a combination nanomedicine strategy incorporating immunosuppressants and antiangiogenesis drugs can greatly enhance the ocular drug delivery and benefit the outcome of HR corneal transplantation with increased survival rate, ensuring patient compliance and mitigating dosing frequency and toxicity concerns.

Neovascular age-related macular degeneration (AMD), a leading cause of blindness, requires frequent intravitreal injection of antivascular endothelial growth factor (anti-VEGF), which could generate a succession of complications with poor patient compliance. The current VEGF-targeting therapies often fail in half of patients due to the complex pathologic microenvironment of excessive reactive oxygen species (ROS) production, and increased levels of inflammation are accompanied by choroidal neovascularization (CNV). We herein reported multifunctional nanotherapeutics featuring superior antioxidant and anti-inflammation properties that aim to reverse the pathological condition, alongside its strong targeted antiangiogenesis to CNV and its ability to provide long-term sustained bioactive delivery via the minimally invasive subconjunctival injection, so as to achieve satisfactory wet AMD treatment effects. Concretely, the nanomedicine was designed by coencapsulation of astaxanthin (AST), a red pigmented carotenoid known for its antioxidative, anti-inflammatory and antiapoptotic properties, and axitinib (AXI), a small molecule tyrosine kinase inhibitor that selectively targets the vascular epidermal growth factor receptor for antiangiogenesis, into the Food and Drug Administration (FDA) approved poly(lactic- co -glycolic acid) (PLGA), which forms the nanodrug of PLGA@AST/AXI. Our results demonstrated that a single-dose subconjunctival administration of PLGA@AST/AXI showed a rational synergistic effect by targeting various prevailing risk factors associated with wet AMD, ensuring persistent drug release profiles, maintaining good ocular biocompatibility, and causing no obvious mechanical damage. Such attributes are vital and hold significant potential in treating ocular posterior segment diseases. Moreover, this nanotherapeutic strategy represents a versatile and broad-spectrum nanoplatform, offering a promising alternative for the complex pathological progression of other neovascular diseases.

Age-related macular degeneration (AMD) disease has become a worldwide senile disease, and frequent intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) is the mainstream treatment in the clinic, which is associated with sight-threatening complications. Herein, nintedanib, an inhibitor of angiogenesis, and lutein, a potent antioxidant, can co-assemble into nanoparticles through multiple noncovalent interactions. Interestingly, the co-assembled lutein/nintedanib nanoparticles (L/N NPs) exhibit significantly improved stability and achieve long-term sustained release of two drugs for at least two months in mice. Interestingly, in rabbit eyeball with a more complete barrier system, the L/N NPs still successfully distribute in the retina and choroid for a month. In the laser-induced mouse choroidal neovascularization model, the L/N NPs after a minimally invasive subconjunctival administration can successfully inhibit angiogenesis and achieve comparable and even better therapeutic results to that of standard intravitreal injection of anti-VEGF. Therefore, the subconjunctival injection of L/N NPs with long-term sustained drug release behavior represents a promising and innovative strategy for AMD treatment. Such minimally invasive administration together with the ability to effectively inhibit angiogenesis reduce inflammation and counteract oxidative stress and holds great potential for improving patient outcomes and quality of life in those suffering from this debilitating eye condition., (© 2024 Wiley‐VCH GmbH.)

Colorectal cancer (CRC) is a common digestive tract tumor with the third incidence and death in the world. There is still an urgent need for effective therapeutic targets and prognostic markers for CRC. Herein, we report a novel potential target and marker, Chordin like-1 (CHRDL1). The function of CHRDL1 has been reported in gastric cancer, breast cancer, and oral squamous cell carcinoma. However, the biological effect of CHRDL1 in CRC remains unrevealed. Transwell and tube formation experiments were used to determine the biological function of CHRDL1. Western blot and rescue experiments were used to determine the specific mechanisms of CHRDL1. Results showed CHRDL1 is significantly downregulated in CRC cell lines and tissues. In vitro, experiments confirmed that CHRDL1 can inhibit cell growth, migration, invasion, angiogenesis and reverse epithelial-mesenchymal transformation. In vivo, experiments proved that it can inhibit tumor growth and metastasis. Mechanistically, we newly find that CHRDL1 exerts biological functions through the transforming growth factor-beta (TGF-β)/vascular endothelial growth factor signaling axis in vitro and in vivo. Therefore, we concluded that CHRDL1 reduces the growth, migration, and angiogenesis of CRC cells by downregulating TGF-β signaling. Our new findings on CHRDL1 may provide a basis for clinical antiangiogenesis therapy and the prognosis of CRC., (© 2024 Wiley Periodicals LLC.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The first-line treatment for advanced hepatocellular carcinoma (HCC) combines immune checkpoint inhibitors and antiangiogenesis agents to prolong patient survival. Nonetheless, this approach has several limitations, including stringent inclusion criteria and suboptimal response rates that stem from the severe off-tumor side effects and the unfavorable pharmacodynamics and pharmacokinetics of different drugs delivered systemically. Herein, we propose a single-agent smart nanomedicine-based approach that mimics the therapeutic schedule in a targeted and biocompatible manner to elicit robust antitumor immunity in advanced HCC. Our strategy employed pH-responsive carriers, poly(ethylene glycol)-poly(β-amino esters) amphiphilic block copolymer (PEG-PAEs), for delivering apatinib (an angiogenesis inhibitor), that were surface-coated with plasma membrane derived from engineered cells overexpressing PD-1 proteins (an immune checkpoint inhibitor to block PD-L1). In an advanced HCC mouse model with metastasis, these biomimetic responsive nanoconverters induced significant tumor regression (5/9), liver function recovery, and complete suppression of lung metastasis. Examination of the tumor microenvironment revealed an increased infiltration of immune effector cells (CD8 + and CD4 + T cells) and reduced immunosuppressive cells (myeloid-derived suppressor cells and T regulatory cells) in treated tumors. Importantly, our nanomedicine selectively accumulated in both small and large HCC occupying >50% of the liver volume to exert therapeutic effects with minimal systemic side effects. Overall, these findings highlight the potential of such multifunctional nanoconverters to effectively reshape the tumor microenvironment for advanced HCC treatment.