■胰腺癌的肿瘤微环境(TME)具有高度免疫抑制性,其特征是大量与癌症相关的成纤维细胞,骨髓来源的抑制细胞,和调节性T细胞。干扰素基因刺激因子(STING)是一种内质网受体,在免疫中起着至关重要的作用。STING激动剂已经证明了煽动TME的能力,减轻肿瘤负担,并在小鼠模型中赋予抗肿瘤活性。2'3'环磷酸鸟苷一磷酸腺苷(2'3'-cGAMP)是STING的高亲和力内源性配体。然而,将cGAMP递送至细胞质内的抗原呈递细胞和肿瘤细胞仍然具有挑战性,这归因于膜不渗透性和差的稳定性。
■在这项研究中,我们将2'3'-cGAMP封装在设计用于有效细胞递送的脂质纳米颗粒(cGAMP-LNP)中。我们使用一系列旨在评估其细胞摄取的体外研究来评估纳米颗粒的特性,胞质释放,和最小的细胞毒性。此外,我们研究了纳米颗粒在同系小鼠胰腺癌模型中的抗肿瘤作用。
■脂质平台显着增加了2'3'-cGAMP的细胞摄取。cGAMP-LNP在胰腺癌的同基因小鼠模型中显示出有希望的抗肿瘤活性。
■LNP平台有望在癌症治疗中提供外源性2'3'-cGAMP或其衍生物。
UNASSIGNED: The tumor microenvironment (TME) of pancreatic cancer is highly immunosuppressive and characterized by a large number of cancer-associated fibroblasts, myeloid-derived suppressor cells, and regulatory T cells. Stimulator of interferon genes (STING) is an endoplasmic reticulum receptor that plays a critical role in immunity. STING agonists have demonstrated the ability to inflame the TME, reduce tumor burden, and confer anti-tumor activity in mouse models. 2\'3\' cyclic guanosine monophosphate adenosine monophosphate (2\'3\'-cGAMP) is a high-affinity endogenous ligand of STING. However, delivering cGAMP to antigen-presenting cells and tumor cells within the cytosol remains challenging due to membrane impermeability and poor stability.
UNASSIGNED: In this study, we encapsulated 2\'3\'-cGAMP in a lipid nanoparticle (cGAMP-LNP) designed for efficient cellular delivery. We assessed the properties of the nanoparticles using a series of in-vitro studies designed to evaluate their cellular uptake, cytosolic release, and minimal cytotoxicity. Furthermore, we examined the nanoparticle\'s anti-tumor effect in a syngeneic mouse model of pancreatic cancer.
UNASSIGNED: The lipid platform significantly increased the cellular uptake of 2\'3\'-cGAMP. cGAMP-LNP exhibited promising antitumor activity in the syngeneic mouse model of pancreatic cancer.
UNASSIGNED: The LNP platform shows promise for delivering exogenous 2\'3\'-cGAMP or its derivatives in cancer therapy.