适体介导的多柔比星递送降低了 3D 类器官模型中的 HCC 负担。

Aptamer-mediated doxorubicin delivery reduces HCC burden in 3D organoids model.

机构信息

Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW 2145, Australia.

Department of Urology, the Second Affiliated Hospital of Anhui Medical University, 230601, Anhui, China; Renal Inflammation and Immunology Group, Westmead Institute for Medical Research, the University of Sydney, Westmead, NSW 2145, Australia.

出版信息

J Control Release. 2022 Jan;341:341-350. doi: 10.1016/j.jconrel.2021.11.036. Epub 2021 Nov 27.

DOI:10.1016/j.jconrel.2021.11.036

PMID:34848243

Abstract

Epithelial cell adhesion molecule (EpCAM) is a surface marker which is frequently overexpressed in hepatocellular carcinoma (HCC) but minimally expressed on mature hepatocytes. We developed a specific aptamer against EpCAM (EpCAM-apt) and tested its potential as a drug delivery agent for HCC. The targeting ability of EpCAM-apt was confirmed in vitro and in vivo after which the complex was conjugated with doxorubicin (Dox) to form EpCAM-apt-Dox. The targeting efficacy of the drug-loaded complex against liver cancer stem-like cells (LCSCs) and therapeutic effects in HCC were evaluated. EpCAM-expressing (EpCAM) HCC cells showed characteristics of stem like cells including greater proliferative capacity and tumour sphere formation. EpCAM-apt-Dox selectively delivered Dox to EpCAM HCC cells with high drug retention and accumulation versus control. EpCAM-apt-Dox reduced the self-renewal capacity and stem-like cell frequency in vitro. Elimination of cancer stem-like cells (CSCs) with EpCAM-apt-Dox significantly inhibited the growth of HCC cells and patient-derived HCC organoids but exerted minimal cytotoxicity to normal liver organoids. Moreover, EpCAM-apt-Dox suppressed the growth of xenograft tumours derived from HCC organoids in vivo and prolonged mouse survival without inducing adverse effects to major organs. Thus, aptamer-based drug delivery to the stem-like cell population is a promising strategy for HCC treatment.

摘要

上皮细胞黏附分子（EpCAM）是一种表面标志物，在肝细胞癌（HCC）中经常过度表达，但在成熟肝细胞中很少表达。我们开发了一种针对 EpCAM 的特异性适配体（EpCAM-apt），并测试了其作为 HCC 药物递送剂的潜力。在体外和体内证实了 EpCAM-apt 的靶向能力，然后将其与多柔比星（Dox）缀合形成 EpCAM-apt-Dox。评估了载药复合物对肝癌干细胞样细胞（LCSCs）的靶向疗效和在 HCC 中的治疗效果。表达 EpCAM（EpCAM）的 HCC 细胞表现出干细胞样细胞的特征，包括更强的增殖能力和肿瘤球体形成能力。EpCAM-apt-Dox 选择性地将 Dox 递送至 EpCAM HCC 细胞，与对照组相比，药物保留和积累更高。EpCAM-apt-Dox 在体外降低了自我更新能力和干细胞样细胞频率。用 EpCAM-apt-Dox 消除癌症干细胞样细胞（CSCs）显著抑制了 HCC 细胞和源自 HCC 类器官的患者源性 HCC 类器官的生长，但对正常肝类器官的细胞毒性最小。此外，EpCAM-apt-Dox 在体内抑制了源自 HCC 类器官的异种移植瘤的生长，并延长了小鼠的存活时间，而不会对主要器官产生不良反应。因此，基于适配体的药物递送至干细胞样细胞群是 HCC 治疗的一种有前途的策略。