Liu Di, Lu Na, Zang Fengchao, Lu Mingze, Zhang Jingyue, Zhao Ying, Wan Hao, Wang Mengjun, Li Qian-Qian, Wang Fei, Luo Shouhua, Ma Ming, Shi Fangfang, Wu Haoan, Tu Jing, Zhang Yu
State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering & Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, Southeast University, Nanjing 211102, P. R. China.
Jiangsu Key Laboratory of Molecular and Functional Imaging, School of Medicine, Southeast University, Nanjing 210096, P. R. China.
ACS Nano. 2024 Dec 24;18(51):34615-34629. doi: 10.1021/acsnano.4c09387. Epub 2024 Dec 12.
Even though the enhanced permeability and retention (EPR) effect is applicable for the passive targeting of solid tumors, many nanodrugs have failed to achieve meaningful clinical outcomes due to the heterogeneity of EPR effect. Therefore, understanding the mechanism of the EPR effect is crucial to overcome the obstacles nanomedicines face in clinical translation. The aim of this study was to establish a reliable method to increase awareness of the critical influencing factors of nanoparticle (NP) transport into tumors based on the EPR effect using a combined radiogenomics and clinical magnetic resonance imaging (MRI) technique and gene set pathway enrichment analysis. Employing poly(lactic--glycolic acid) (PLGA)-coated FeO NPs as the contrast agent, the monolayer and multilayer distribution of the NPs were observed and quantitatively analyzed by MRI, improving the accuracy of evaluating vascular permeability by MRI. By performing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of genes and pathways, we identified a variety of genes affecting vascular permeability, such as Cldn1, Dlg2, Bves, Prkag3, Cldn10, and Cldn8, which are related to tight junctions and control the permeability of blood vessels in tumors. The method presented here provides an MRI-supported approach to increase the breadth of data collected from genetic screens, reveals genetic evidence of the presence of NPs in tumors and lays a foundation for clinical patient stratification and personalized treatment.
尽管增强渗透与滞留（EPR）效应适用于实体瘤的被动靶向，但由于EPR效应的异质性，许多纳米药物未能取得有意义的临床结果。因此，了解EPR效应的机制对于克服纳米药物在临床转化中面临的障碍至关重要。本研究的目的是建立一种可靠的方法，通过结合放射基因组学和临床磁共振成像（MRI）技术以及基因集通路富集分析，提高对基于EPR效应的纳米颗粒（NP）向肿瘤内转运的关键影响因素的认识。以聚乳酸-乙醇酸共聚物（PLGA）包裹的FeO NPs作为造影剂，通过MRI观察并定量分析了NPs的单层和多层分布，提高了MRI评估血管通透性的准确性。通过对基因和通路进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集分析，我们鉴定了多种影响血管通透性的基因，如Cldn1、Dlg2、Bves、Prkag3、Cldn10和Cldn8，它们与紧密连接相关并控制肿瘤血管的通透性。本文提出的方法提供了一种MRI支持的方法，以增加从基因筛选中收集的数据广度，揭示肿瘤中NP存在的遗传证据，并为临床患者分层和个性化治疗奠定基础。
