Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China.
Wuhan Grand Hoyo Pharmaceutical Co., Ltd., Wuhan 430074, China.
Mol Pharm. 2023 Apr 3;20(4):1951-1963. doi: 10.1021/acs.molpharmaceut.2c00842. Epub 2023 Mar 23.
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.
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低特异性限制了它们的临床应用。在这项研究中，设计了同时修饰有甘草次酸 (GA) 和环精氨酸-甘氨酸-天冬氨酸 (cRGD) 的双配体脂质体 (GA/cRGD-LP)，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血管进一步提高药物的抗肿瘤效率。通过将二油酰基磷脂酰乙醇胺 (DOPE) 与甲基甘草次酸 (mGA) 偶联合成了一种新型脂质偶联物 (mGA-DOPE)，并对其结构进行了确认。通过体外细胞摄取和离体成像评估了 GA/cRGD-LP 的靶向效率。制备了 GA 和 cRGD 修饰的载多柔比星脂质体 (GA/cRGD-LP-DOX)，并评估了其在 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，我们的脂质体形状为球形。cGA/cRGD-LP-DOX 在 HepG2 和人脐静脉内皮细胞中均表现出优异的细胞摄取。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。GA/cRGD-LP-DOX 对荷 HepG2 小鼠的肿瘤生长抑制作用强于单配体修饰的脂质体或非靶向脂质体。GA/cRGD-LP-DOX 对肝肿瘤的定位高于单配体修饰的脂质体或游离 DOX。GA/cRGD-LP 是一种有前途的肝癌靶向治疗药物递送系统，值得进一步研究。
