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Tumor growth and metastasis heavily rely on angiogenesis, crucial for solid tumor development. Inhibiting angiogenesis associated with tumors emerges as a potent therapeutic approach. Our previous work synthesized the chondroitin sulfate-modified antiangiogenic peptide CS-ES2-AF (CS-EA), which exhibited better antiangiogenic activity, longer half-life, and more robust targeting. In this work, we further evaluated the stability in vitro, cellular uptake mechanism, cell apoptosis mechanism, antitumor activity in vivo, and safety of CS-EA. The stability of CS-EA was consistently superior to that of EA at different temperatures and in different pH ranges. Furthermore, CS-EA mainly entered EAhy926 cells through the clathrin-mediated endocytosis pathway. CS-EA inhibited endothelial cell proliferation, and induced cell apoptosis through downregulating the Bcl-2, reducing mitochondria membrane potential, upregulating cytochrome c, Caspase 3, and reactive oxygen species levels. CS-EA showed better antitumor activity in the B16 xenografted tumor model, with a tumor inhibition rate 1.92 times higher than EA. Simultaneously, it was observed that CS-EA did not cause any harmful effects on the vital organs of the mice. These findings indicate that CS-EA holds significant promise for the treatment of tumors., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cancer metastasis is the leading cause of cancer-related death. Metastasis occurs at all stages of tumor development, with unexplored changes occurring at the primary site and distant colonization sites. The growing understanding of the metastatic process of tumor cells has contributed to the emergence of better treatment options and strategies. This review summarizes a range of features related to tumor cell metastasis and nanobased drug delivery systems for inhibiting tumor metastasis. The mechanisms of tumor metastasis in the ideal order of metastatic progression were summarized. We focus on the prominent role of nanocarriers in the treatment of tumor metastasis, summarizing the latest applications of nanocarriers in combination with drugs to target important components and processes of tumor metastasis and providing ideas for more effective nanodrug delivery systems., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Chemotherapy is an important cancer treatment modality, but the clinical utility of chemotherapeutics is limited by their toxic side effects, inadequate distribution and insufficient intracellular concentrations. Nanodrug delivery systems (NDDSs) have shown significant advantages in cancer diagnosis and treatment. Variable NDDSs that respond to endogenous and exogenous triggers have attracted much research interest. Here, we summarized nanomaterials commonly used for tumor therapy, such as peptides, liposomes, and carbon nanotubes, as well as the responses of NDDSs to pH, enzymes, magnetic fields, light, and multiple stimuli. Specifically, well-designed NDDSs can change in size or morphology or rupture when induced by one or more stimuli. The varying responses of NDDSs to stimulation contribute to the molecular design and development of novel NDDSs, providing new ideas for improving drug penetration and accumulation, inhibiting tumor resistance and metastasis, and enhancing immunotherapy., (© 2024 IOP Publishing Ltd.)

The progression and metastasis of solid tumors rely strongly on neovascularization. However, angiogenesis inhibitors alone cannot meet the needs of tumor therapy. This study prepared a new drug conjugate (PTX-GSHP-CYS-ES2, PGCE) by combining polysaccharides (heparin without anticoagulant activity, GSHP), chemotherapeutic drugs (paclitaxel, PTX), and antiangiogenic drugs (ES2). Furthermore, a tumor-targeted prodrug nanoparticle delivery system is established. The nanoparticles appear to accumulate in the mitochondrial of tumor cells and achieve ES2 and PTX release under high glutathione and acidic environment. It has been confirmed that PGCE inhibited the expression of multiple metastasis-related proteins by targeting the tumor cell mitochondrial apparatus and disrupting their structure. Furthermore, PGCE nanoparticles inhibit migration, invasion, and angiogenesis in B16F10 tumor-bearing mice and suppress tumor growth and metastasis in vitro. Further in vitro and in vivo experiments show that PGCE has strong antitumor growth and metastatic effects and exhibits efficient anti-angiogenesis properties. This multi-targeted nanoparticle system potentially enhances the antitumor and anti-metastatic effects of combination chemotherapy and antiangiogenic drugs., (© 2023 Wiley-VCH GmbH.)

The growth, migration and spread of malignant tumors requires a large number of new blood vessels to supply nutrients. In our previous study, it was found that the hyaluronic acid (HA) modified novel antiangiogenic peptide ES2-AF has better solubility, longer half-life, stronger targeting than non-modified ES2-AF, and it significantly inhibited the formation of new blood vessels. In the current work, we studied the stability of ES2-AF after HA modification, including heat stability, longterm stability, and pH stability. After treatment with HA-ES2-AF, cell apoptosis and the cell cycle were analyzed using flow cytometry. The inhibitory effect of HA-ES2-AF on tumors was investigated in vivo in HepG2 tumor-bearing nude mice. All the above results showed that HA-ES2-AF significantly improved stability, effectively induced apoptosis of endothelial cells, caused G1 phase arrest of endothelial cells, and decreased the percentage of cells in G2 and S phases. In vivo , HA-ES2-AF exhibited an inhibitory effect on tumors growth. In addition, the results provide a reliable basis for studying the inhibition of neovascularization and anti-tumor drugs in the future.

Anti-flt1 peptide (GNQWFI, AF) specifically binds to Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), thereby inhibiting the interaction of VEGFR1 with a series of ligands. ES2 (IVRRADRAAVP) can effectively inhibit the proliferation and invasion of endothelial cells and play a key role in anti-angiogenesis. AF and ES2 peptides differ in their activity. To better exploit the advantages of both, we designed a new peptide called ES2-AF (IVRRADRAAVPGGGGGGNQWFI). Hyaluronic acid (HA) is widely used in the pharmaceutical industry because of its biodegradable and high load performance. The HA-specific cell surface receptor CD44 was highly expressed in the tumour site during the anti-tumour study. Therefore, we used HA as a modifier to chemically modify ES2-AF; it was expected that the modified compound would have preferable solubility, stronger targeting, longer half-life, and better anti-angiogenesis effects in vivo. In this study, the anti-proliferative, anti-migration and targeting activities of HA-ES2-AF in vitro were studied by MTT, ELISA, transwell and SPR assays. Meanwhile, the anti-neovascularization activity of HA-ES2-AF in vivo was studied by CAM assay, and the targeting of HA-ES2-AF to tumour tissue was studied by bioimaging techniques. Finally, we also studied the half-life of HA-ES2-AF in vivo. In short, the bioactivity of the new peptide ES2-AF was enhanced to a certain extent, and ES2-AF modified by HA had higher anti-neovascularization activity in vitro and in vivo, had stronger targeting to tumour tissue, and had a significantly prolonged half-life in vivo. These results laid the foundation for its further development into targeting anti-tumour drugs., (Copyright © 2018 Elsevier B.V. All rights reserved.)