Dual-stimuli responsive 4-arm PEG-SS-SN38 nanoparticles: ultrasound-controlled size switching and GSH-triggered release for enhanced pancreatic cancer penetration

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy due to late-stage diagnosis and dense fibrotic stroma that impedes the penetration of drugs. In this study, a novel prodrug molecule was developed based on the efficient coupling of SN38 through disulfide (S–S) bonds by four-arm polyethylene glycol (4-arm PEG-SS-SN38), with the aim of enhancing the efficiency and safety of SN38 in the treatment of PDAC. This system can self-assemble into stable nanoparticles (∼118 nm) relying on molecular entanglement, and prolong circulation and tumor accumulation through the EPR effect. Ultrasound stimulation can trigger the disbanding of molecular entanglement, reduce the nanoparticle size to ∼30 nm, and enhance their deep penetration ability into tumor tissue, and the glutathione-sensitive S–S linker enables the prodrug molecule to specifically release free SN38 within tumor cells. In vitro experiments showed that ultrasound activation significantly improved the cytotoxicity of 4-arm PEG-SS-SN38, which is significantly superior to irinotecan. In vivo, the tumor growth inhibition of the prodrug reached 96.92%, which could reach 113.39% after combined ultrasound treatment, with no obvious systemic toxicity. This “target–penetrate–release” cascade synergy resolves the delivery challenges of PDAC and provides a modular clinical translation strategy for ultrasound-responsive nanomedicines.