Magnetic\nResonance Imaging-Based Radiogenomic Analysis\nReveals Genomic Determinants for Nanoparticle Delivery into Tumors

Even\nthough the enhanced permeability and retention (EPR) effect\nis applicable for the passive targeting of solid tumors, many nanodrugs\nhave failed to achieve meaningful clinical outcomes due to the heterogeneity\nof EPR effect. Therefore, understanding the mechanism of the EPR effect\nis crucial to overcome the obstacles nanomedicines face in clinical\ntranslation. The aim of this study was to establish a reliable method\nto increase awareness of the critical influencing factors of nanoparticle\n(NP) transport into tumors based on the EPR effect using a combined\nradiogenomics and clinical magnetic resonance imaging (MRI) technique\nand gene set pathway enrichment analysis. Employing poly(lactic-<i>co</i>-glycolic acid) (PLGA)-coated Fe<sub>3</sub>O<sub>4</sub> NPs as the contrast agent, the monolayer and multilayer distribution\nof the NPs were observed and quantitatively analyzed by MRI, improving\nthe accuracy of evaluating vascular permeability by MRI. By performing\nGene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG)\nenrichment analyses of genes and pathways, we identified a variety\nof genes affecting vascular permeability, such as Cldn1, Dlg2, Bves,\nPrkag3, Cldn10, and Cldn8, which are related to tight junctions and\ncontrol the permeability of blood vessels in tumors. The method presented\nhere provides an MRI-supported approach to increase the breadth of\ndata collected from genetic screens, reveals genetic evidence of the\npresence of NPs in tumors and lays a foundation for clinical patient\nstratification and personalized treatment.