Hepatocellular carcinoma (HCC) is one of the most common cancers, with high mortality. Chemotherapy is one of the main treatment options for HCC. However, the high toxicity and poor specificity of chemotherapeutic drugs have limited their clinical application. In this study, dual-ligand liposomes modified with glycyrrhetinic acid (GA) and cyclic arginine–glycine–aspartic acid (cRGD) (GA/cRGD-LP) were designed to target the GA receptor and αvβ3 integrin, respectively. The aim was to develop a highly selective targeted drug delivery system and further enhance the antitumor efficiency of drugs by targeting both hepatic tumor cells and vasculature. A novel lipid conjugate (mGA-DOPE) by coupling dioleoylphosphatidyl ethanolamine (DOPE) with methyl glycyrrhetinic acid (mGA) was synthesized, and its structure was confirmed. The targeting efficiency of GA/cRGD-LP by in vitro cellular uptake and ex vivo imaging was assessed. GA- and cRGD-modified doxorubicin-loaded liposomes (GA/cRGD-LP-DOX) were prepared, and their cytotoxicity in HepG2 and antitumor activity were evaluated. The results showed that the average particle size of the GA/cRGD-LP-DOX was 114 ± 4.3 nm, and the zeta potential was −32.9 ± 2.0 mV. The transmission electron microscopy images showed that the shapes of our liposomes were spherical. cGA/cRGD-LP-DOX displayed an excellent cellular uptake in both HepG2 and human umbilical vein endothelial cells. In the in vivo study, pharmacokinetic parameters indicated that cGA/cRGD-LP can prolong the circulation time of DOX in the blood. GA/cRGD-LP-DOX showed greater inhibition of tumor growth for HepG2-bearing mice than either the single-ligand-modified liposomes or nontargeted liposomes. GA/cRGD-LP-DOX displayed higher liver tumor localization than that of single-ligand-modified liposomes or free DOX. GA/cRGD-LP is a promising drug delivery system for liver cancer targeting and therapy and is worthy of further study.

中文翻译：

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基于甘草次酸和 cRGD 的双配体功能化脂质体用于肝细胞癌的靶向治疗

肝细胞癌（HCC）是最常见的癌症之一，死亡率很高。化疗是 HCC 的主要治疗选择之一。然而，化疗药物的高毒性和特异性差限制了其临床应用。在这项研究中，设计了用甘草次酸 (GA) 和环状精氨酸-甘氨酸-天冬氨酸 (cRGD) (GA/cRGD-LP) 修饰的双配体脂质体，分别靶向 GA 受体和 αvβ3 整合素。目的是开发一种高选择性的靶向药物递送系统，并通过靶向肝肿瘤细胞和脉管系统进一步提高药物的抗肿瘤效率。通过偶联二油酰磷脂酰乙醇胺 (DOPE) 与甲基甘草次酸 (mGA) 合成了一种新型脂质偶联物 (mGA-DOPE)，并确定了其结构。通过体外细胞摄取和体外成像评估 GA/cRGD-LP 的靶向效率。制备了 GA 和 cRGD 修饰的阿霉素负载脂质体 (GA/cRGD-LP-DOX)，并评估了它们在 HepG2 中的细胞毒性和抗肿瘤活性。结果表明，GA/cRGD-LP-DOX的平均粒径为114±4.3nm，zeta电位为-32.9±2.0mV。透射电子显微镜图像显示我们的脂质体的形状是球形的。cGA/cRGD-LP-DOX 在 HepG2 和人脐静脉内皮细胞中表现出极好的细胞摄取。在体内研究中，药代动力学参数表明cGA/cRGD-LP可以延长DOX在血液中的循环时间。与单配体修饰的脂质体或非靶向脂质体相比，GA/cRGD-LP-DOX 对携带 HepG2 的小鼠的肿瘤生长有更大的抑制作用。GA/cRGD-LP-DOX 显示出比单配体修饰的脂质体或游离 DOX 更高的肝肿瘤定位。GA/cRGD-LP 是一种很有前途的肝癌靶向和治疗药物递送系统，值得进一步研究。