Lu Xing, Cheng Hao, Xu Qiming, Tan Xiangshi
Department of Chemistry, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Cancer Biother Radiopharm. 2023 Oct;38(8):543-557. doi: 10.1089/cbr.2020.4085. Epub 2021 Mar 12.
2',3'-cGAMP (2',3'-cyclic AMP-GMP) has been reported as an agonist of the STING (stimulator of interferon genes) signaling pathway. However, cGAMP has poor membrane permeability and can be hydrolyzed by ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1), limiting its ability to activate the STING-IRF3 pathway. This study aimed to investigate that the folate-targeted liposomal cGAMP could overcome the defects of free cGAMP to enhance the antitumor effect. cGAMP was encapsulated in PEGylated folic acid-targeted liposomes to construct a carrier-delivered formulation. The particle size and morphology were detected by dynamic light scattering and transmission electron microscopy. The sustained-release ability was measured by drug release and pharmacokinetics. Animal models were applied to evaluate the tumor inhibition efficiency . Flow cytometry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction were used to detect the expression of immune cells, secreted cytokines, and target genes. The activation of the STING-IRF3 pathway was evaluated by immunofluorescence. Physical characters of liposomes revealed that the prepared liposomes were stable in neutral humoral environments and released more internal drugs in acidic tumor tissues. Systemic therapy with liposomes on Colorectal 26 tumor-bearing mice effectively inhibited tumor growth via stimulating the expression of CD8 T cells and reversed the immunosuppressed tumor microenvironment (TME). The study suggests that the folic acid-targeted cGAMP-loaded liposomes deliver drugs to the TME to enhance the STING agonist activity, improving the efficiency of tumor therapy via the cGAMP-STING-IRF3 pathway.
2',3'-环磷酸鸟苷-腺苷（2',3'-cGAMP）已被报道为干扰素基因刺激因子（STING）信号通路的激动剂。然而，cGAMP的膜通透性较差，且可被胞外核苷酸焦磷酸酶/磷酸二酯酶（ENPP1）水解，这限制了其激活STING-IRF3通路的能力。本研究旨在探究叶酸靶向脂质体包裹的cGAMP能否克服游离cGAMP的缺陷以增强抗肿瘤效果。将cGAMP包裹于聚乙二醇化叶酸靶向脂质体中，构建载体递送制剂。通过动态光散射和透射电子显微镜检测粒径和形态。通过药物释放和药代动力学测定缓释能力。应用动物模型评估肿瘤抑制效率。采用流式细胞术、酶联免疫吸附测定和实时聚合酶链反应检测免疫细胞表达、细胞因子分泌及靶基因情况。通过免疫荧光评估STING-IRF3通路的激活情况。脂质体的物理特性显示，所制备的脂质体在中性体液环境中稳定，在酸性肿瘤组织中释放更多内部药物。对荷结直肠癌26肿瘤小鼠进行脂质体全身治疗，通过刺激CD8 T细胞表达有效抑制肿瘤生长，并逆转免疫抑制的肿瘤微环境（TME）。该研究表明，叶酸靶向负载cGAMP的脂质体将药物递送至TME以增强STING激动剂活性，通过cGAMP-STING-IRF3通路提高肿瘤治疗效率。
