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脂质纳米颗粒递送 STING 激动剂抑制胰腺癌生长。

Delivery of a STING Agonist Using Lipid Nanoparticles Inhibits Pancreatic Cancer Growth.

机构信息

Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA.

Department of Pathology, University Health/Truman Medical Center, School of Medicine, University of Missouri-Kansas City, Kansas, MO, USA.

出版信息

Int J Nanomedicine. 2024 Aug 27;19:8769-8778. doi: 10.2147/IJN.S462213. eCollection 2024.

DOI:10.2147/IJN.S462213
PMID:39220196
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11365503/
Abstract

INTRODUCTION

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.

METHODS

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.

RESULTS

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.

DISCUSSION

The LNP platform shows promise for delivering exogenous 2'3'-cGAMP or its derivatives in cancer therapy.

摘要

简介

胰腺癌的肿瘤微环境（TME）高度免疫抑制，其特征是大量的癌相关成纤维细胞、髓系来源的抑制细胞和调节性 T 细胞。干扰素基因刺激物（STING）是一种内质网受体，在免疫中发挥着关键作用。STING 激动剂已被证明能够使 TME 发炎，减少肿瘤负担，并在小鼠模型中赋予抗肿瘤活性。2'3' 环鸟苷单磷酸腺苷（2'3'-cGAMP）是 STING 的高亲和力内源性配体。然而，由于膜的不可渗透性和较差的稳定性，将 cGAMP 递送到抗原呈递细胞和肿瘤细胞的细胞质内仍然具有挑战性。

方法

在这项研究中，我们将 2'3'-cGAMP 包裹在一种用于高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、细胞质释放和最小细胞毒性的体外研究来评估纳米颗粒的特性。此外，我们还在胰腺癌的同基因小鼠模型中研究了该纳米颗粒的抗肿瘤作用。

结果

脂质平台显著增加了 2'3'-cGAMP 的细胞摄取。cGAMP-LNP 在胰腺癌的同基因小鼠模型中表现出有希望的抗肿瘤活性。

讨论

LNP 平台有望在癌症治疗中递送外源性 2'3'-cGAMP 或其衍生物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a153/11365503/29589b372f4b/IJN-19-8769-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a153/11365503/4226146cbb0f/IJN-19-8769-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a153/11365503/46b9254c4bea/IJN-19-8769-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a153/11365503/587dbc60f2b1/IJN-19-8769-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a153/11365503/d530956ea1a3/IJN-19-8769-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a153/11365503/0a0b3b82d582/IJN-19-8769-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a153/11365503/29589b372f4b/IJN-19-8769-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a153/11365503/4226146cbb0f/IJN-19-8769-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a153/11365503/46b9254c4bea/IJN-19-8769-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a153/11365503/587dbc60f2b1/IJN-19-8769-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a153/11365503/d530956ea1a3/IJN-19-8769-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a153/11365503/0a0b3b82d582/IJN-19-8769-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a153/11365503/29589b372f4b/IJN-19-8769-g0006.jpg

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