Sono-promoted drug penetration and extracellular matrix modulation potentiate sonodynamic therapy of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) exhibits difficult penetration of most drugs, leading to a very poor therapeutic outcome with a quite low five-year survival rate. The foremost reason is the highly-dense extracellular matrix (ECM) with abundant collagen and fibronectin secreted by the activated pancreatic stellate cells (PSCs). Here, we constructed a sono-responsive polymeric perfluorohexane (PFH) nanodroplet to elicit a deep drug penetration in PDAC via the combination of exogenous ultrasonic (US) exposure and endogenous ECM modulation for potent sonodynamic therapy (SDT) of PDAC. Under US exposure, the rapid drug release and deep penetration in PDAC tissues were realized. The released and well penetrated all-trans retinoic acid (ATRA) as an inhibitor of activated PSCs successfully reduced the secretion of ECM components to form a non-dense matrix conducive to drug diffusion. Meanwhile, the sonosensitizer, manganese porphyrin (MnPpIX), was triggered to produce robust reactive oxygen species (ROS) to exert the SDT effect under US exposure. Furthermore, oxygen (O2) delivered by PFH nanodroplets alleviated tumor hypoxia and enhanced the eradication of cancer cells. Overall, the sono-responsive polymeric PFH nanodroplets were successfully developed as an efficient strategy for PDAC therapy. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is a representative refractory cancer with a highly dense extracellular matrix (ECM), making it difficult for most drugs to penetrate the nearly impenetrable desmoplastic stroma. Seeking methods for deep drug penetration is an extremely pressing matter for the treatment of PDAC and many other solid tumors. Herein, we designed a fluoroalkane-modified polymer to prepare a sono-responsive polymeric perfluorohexane (PFH) nanodroplet for loading sonosensitizers, and inhibitors of activated PSCs and O2. Under ultrasonic exposure, the nanodroplet elicited deep drug penetration in PDAC via ultrasonic disturbance and stromal remodeling, inducing potent sonodynamic therapy (SDT) of PDAC. By combining exogenous ultrasonic exposure and endogenous ECM modulation, this work successfully alleviated the severe physiological barrier of PDAC and achieved a favourable treatment effect.