Hepatocellular carcinoma (HCC) is a challenging cancer to treat due to its high malignancy, strong invasiveness, and high risk of metastasis. Inhibiting lymphatic metastasis in the early stages is crucial for HCC therapy. Active targeted drug delivery systems, imbued with tumor and lymphatic targeting capability via ligand–receptor mediation, represent a promising therapeutic strategy. Cantharidin (CTD), the primary effective component of poisonous traditional Chinese medicine (PTCM) Mylabris, has unique therapeutic effects on HCC. However, its high toxicity limits its clinical application. In this study, based on the high expression of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) in the peritumoral lymphatic vessels and glycyrrhetinic acid receptor (GA-R) in hepatocellular carcinoma cells, we developed CTD-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles modified with glycyrrhetinic acid (GA)–hyaluronic acid (HA) copolymers (GA-HA-PLGA/CTD NPs) through electrostatic interactions. This nanoparticle platform could preferentially accumulate cargo into the tumors and peritumoral lymphatic vessels, increasing drug accumulation in tumors and lymph nodes while decreasing drug accumulation in other organs, particularly the heart and kidney. As a result, it could enhance antitumor efficacy and inhibit lymphatic metastasis better than PLGA/CTD NPs while also reducing systemic toxicity. Furthermore, the variation of HA molecular weights and degrees of GA substitution could regulate the distribution of nanoparticles within tumors and lymph nodes. Overall, GA-HA-PLGA/CTD NPs exhibit promising potential as a therapeutic approach for HCC treatment and lymphatic metastasis inhibition, providing a potential strategy for the application of PTCMs in HCC treatment.
Jinsong Zhang,Jie Cui,Xinying Li,Xiaohui Hao,Lingli Guo,Hongli Wang,Heliang Liu
Silicosis, a type of lung inflammation and fibrosis caused by long-term inhalation of SiO 2 particles, lacks effective treatment currently. Based on the results of our previous animal experiments, in lungs of SiO 2 -induced silicosis rats, a large number of lymphatic vessels are generated in the early stage of inflammation, which is of great significance for the removal of dust and inflammatory mediators. Here, the molecular mechanism of lymphangiogenesis is further studied. Vascular endothelial growth factor (VEGF-C) is a key pro-lymphangiogenic factor, and its elevated expression is closely related to lymphangiogenesis. In this investigation, we demonstrated that the protein level of VEGF-C was differentially expressed in bronchoalveolar lavage fluid (BALF) and alveolar macrophages (AM) in silicosis patients and healthy controls. We further stimulated human monocyte-macrophage line U937 with SiO 2 , collected the culture supernatants as conditioned medium (CM) for culturing lymphatic endothelial cells (LECs) in vitro, and observed the expression of VEGF-C in the supernatant and its effect on LEC tube formation. The results showed that both CM and single VEGF-C recombinant protein stimulation significantly enhanced LEC proliferation [(1.80 ± 0.18), (1.73 ± 0.16)], chemotaxis [chemotactic cell number (101.40 ± 13.83), (93.40 ± 9.61)], and tube formation [tube number (32.20 ± 7.26), (25.00 ± 6.25); branch number (77.20 ± 6.80), (84.60 ± 7.90)], whereas CM treated with VEGF-CmAb inhibited the proliferation (1.37 ± 0.17), chemotaxis [chemotactic cell number (57.40 ± 8.62)], and tube formation [tube number (7.40 ± 1.85); branch number (47.20 ± 13.44)] of LECs. In addition, CM and VEGF-C can promote the expression of vascular endothelial growth factor receptor 3 (VEGFR-3) and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) in LECs, which may further mediate lymphangiogenesis by up-regulating the Src/eNOS downstream signaling molecular pathway. This study is the first to clarify the molecular mechanism of pulmonary lymphangiogenesis in silicosis and may point in the direction of eventual treatments, surveillance, and regulation at a molecular level.
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