Nanotension Relief Agent Enhances Tissue Penetration by Reducing Solid Stress in Pancreatic Ductal Adenocarcinoma via Rho/ROCK Pathway Inhibition

Abstract

The formidable contractile tension exerted by cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC) tissue is crucial for maintaining high tissue solid stress (TSS), which impedes the delivery and penetration of chemotherapeutic drugs. To address this obstacle, we constructed a pH-responsive nanotension relief agent (FS@MMS), in which fasudil (FS) was ingeniously conjugated to mesoporous silica encapsulated with magnetic iron oxide (MMS). The nanotension relief agent was demonstrated to inhibit the synthesis of phosphorylated myosin light chain by blocking the Rho/ Rho-associated serine/threonine kinase (ROCK) pathway, triggering the swift transformation of high-tension CAFs into low-tension CAFs in PDAC tissue, which relieves TSS and enhances drug penetration in Panc02/NIH-3T3 multicellular tumor spheroids. When the nanotension relief agent was further loaded with the chemotherapeutic drug gemcitabine (GEM), as FS@MMS-GEM, the enhanced permeation of GEM progressively killed tumor cells and amplified their TSS-relief properties, thereby maximizing the anticancer efficacy of chemotherapeutic agents in Panc02/NIH-3T3 coplanted model mice. The magnetic resonance imaging results revealed that the synergistic effect substantially improved drug delivery and penetration efficiency. The developed approach holds great potential for improving chemotherapy efficacy in PDAC and provides a novel therapeutic approach for the treatment of related stroma-rich tumors.