2025-08-15 作者：ZJ 来源：文献：Dual-Ligand-Modified Liposomes Co-Loaded with Anti-Angiogenic and Chemotherapeutic Drugs for Inhibiting Tumor Angiogenesis and Metastasis
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作者：Fangqing Wang,Yanying Li,Hong Jiang ,Chenglei Li,Zhaohuan Li,Cuiping Qi,Zhipeng Li, Zhiqin Gao,Bo
Zhang,Jingliang Wu
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原文摘要：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 antihepatoma efficacy.
DSPE-PEG-NHS是一种线性异双功能聚乙二醇化试剂。DSPE部分具有良好的疏水性和类似细胞膜的结构，能嵌入脂质体等纳米颗粒，增强其生物相容性和稳定性；PEG部分亲水性和水溶性良好，可使分子自组装成纳米脂质体，赋予“隐形”性能，延长化合物循环时间；NHS作为活性基团，在特定pH条件下能与含伯胺基团的分子反应，实现靶向分子偶联。该产品用于脂质双分子层的靶向化合物递送，以及对蛋白质类化合物、肽类化合物、脂质体、有机小分子化合物等的修饰。该文献研究制备了含有姜黄素和A-4磷酸盐（CUCA/GA&Gal-Lip）的CA&Gal双配体修饰脂质体。具体过程如下：
图：脂质体制剂
CUCA/GA&Gal-Lip脂质体的制备
用DMTMM（交联剂）激活GA，然后滴入乙二胺得到二胺改性的GA（GA-N）。在EDC存在下，在DSPE-PEG-NHS溶液中，合成了DSPE-PEG-GA。DSPE-PEG -Gal是由DSPE-PEGCOOH和D-GalN在EDC和NHS的存在下反应合成的。采用反相蒸发法制备CUCA/GA&Gal-Lip。首先将EPC和胆固醇与氯仿混合，然后将DSPE-PEG-Gal、DSPE-PEG-GA和Cur（DSPE-PEG-GAL/EPC、DSPE-PEG-GA/EPC和Cur/EPC以一定比例）。其次，CA4P在PBS中溶解，并转移到脂质溶液中。混合体系超声，生成油中水（W/O）均匀乳液。在减压旋转蒸发下去除氯仿形成凝胶。然后，加入PBS，水合1h。最后，将脂质体在冰浴中超声过滤。
图：BEL7402细胞对FITC标记的Lip、FITC标记的Gal-Lip和FITC标记的GA&Gal-Lip的摄取0.5 h。绿色和蓝色荧光分别代表FITC和DAPI，放大后的图像为红色虚线框圆圈区域。
结论：：与其他联合应用相比，DSPE-PEG-NHS参与制备的CUCA/GA&Gal-Lip双配体修饰的脂质体对tumor转移有更大的抑制作用。机制分析显示姜黄素和A-4磷酸盐可以分别通过下调VEGF和VEGFR2的表达来抑制tumor转移，GA和Gal-Lip可以通过GA/Gal介导的活性靶向传递来提高抗tumor作用。CUCA/GA&Gal-Lip可以通过同时阻断VEGF/VEGFR2信号通路来实现作用。
