Cytidinyl/Cationic Lipid Encapsulating Insulin-Like Growth Factor 1 Receptor siRNA for Hepatocellular Carcinoma Therapy

Hepatocellular carcinoma (HCC) is the most prevalent form of invasive liver cancer, representing over 90% of all liver cancer cases. Currently, there is a lack of targeted therapy for HCC. Insulin-like growth factor 1 receptor (IGF1R) is abnormally expressed in HCC, leading to the malignant proliferation and contributing to the antiapoptosis mechanisms in tumor cells. In this study, small interfering RNAs targeting IGF1R mRNA (siIGF1Rs) have been designed. Additionally, a full 2'-F/2'-OMe modification with partial phosphorothioation was applied to improve the biological properties of these siIGF1Rs. Based on previous research, stable lipid complexes with uniform particle sizes were constructed using cytidinyl lipid DNCA/cationic lipid CLD (Mix) supplemented with DSPE-PEG (siIGF1R/Mix/PEG). The complexes were formed through hydrogen-bonding, π-π stacking, and electrostatic interactions. The siIGF1R/Mix/PEG complex entered the cytoplasm and nucleus of HCC cells, reduced IGF1R mRNA and pre-mRNA levels by over 95% and 50% respectively, further arrested the cell cycle in the S phase, and promoted cell apoptosis. Importantly, siIGF1R/Mix/PEG (0.8 mg/kg, i.v.) selectively accumulated in the tumor, significantly inhibiting tumor growth by 91.31% compared to the naked siRNA group, with slower release and a more prolonged effect.