肝癌(Hepatocellular carcinoma, HCC) 細胞大量表現可辨識半乳糖基團的去唾液酸糖蛋白受體(ASGPR)，可藉由半乳糖基團針對肝癌細胞作為有力的標靶物質。然而正常肝細胞亦會大量表現ASGPR，使得半乳糖同時會被兩者辨識，因此在肝癌治療中利用半乳糖基團針對肝癌作為選擇性標靶物質，仍然是需要克服的困境之一。為了藉由半乳糖基團對於肝癌建立更有力和有選擇性標靶的基因或藥物遞送，我們修飾半乳糖的結構並驗證半乳糖衍生物對肝癌細胞能產生較高的親和性。在本研究中，我們在脂質磷酸鈣(Lipid/Calcium/Phosphate, LCP) 奈米載體 (NPs) 上各別結合不同種的半乳糖衍生物，並證實經由β苯基半乳糖苷修飾的奈米粒子對於肝癌細胞和正常肝細胞表現出可區別的結合親合力。我們以L4修飾的LCP NPs (L4-LCP NPs)遞送血管內皮生長因子之小分子干擾核糖核酸 (VEGF siRNA)，能夠在體外實驗及動物實驗中降低血管內皮生長因子的表現量，並在小鼠原位肝癌模型中展現有效力的抗血管生成作用，且導致顯著的腫瘤消退。實驗結果指出苯基半乳糖苷是能有希望成為標靶肝癌的半乳糖衍生物，並作為非常有潛力的基因遞送方式達到治療肝癌的目的。

Successful siRNA therapy requires suitable delivery systems with targeting moieties such as small molecules, peptides, antibodies, or aptamers. Galactose (Gal) residues recognized by the asialoglycoprotein receptor (ASGPR) can serve as potent targeting moieties for hepatocellular carcinoma (HCC) cells. However, efficient targeting to HCC via galactose moieties rather than normal liver tissues in HCC patients remains a challenge. To achieve more efficient siRNA delivery in HCC, we synthesized various galactoside derivatives and investigated the siRNA delivery capability of nanoparticles modified with those galactoside derivatives. In this study, we assembled lipid/calcium/phosphate nanoparticles (LCP NPs) conjugated with eight types of galactoside derivatives and demonstrated that phenyl β-D-galactoside-decorated LCP NPs (L4-LCP NPs) exhibited a superior siRNA delivery into HCC cells compared to normal hepatocytes. VEGF siRNAs delivered by L4-LCP NPs downregulated VEGF expression in HCC in vitro and in vivo, and led to a potent anti-angiogenic effect in the tumor microenvironment of a murine orthotopic HCC model. The efficient delivery of VEGF siRNA by L4-LCP NPs that resulted in significant tumor regression indicates that phenyl galactoside could be a promising HCC-targeting ligand for therapeutic siRNA delivery to treat liver cancer.

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