Cavitation assisted endoplasmic reticulum targeted sonodynamic droplets to enhanced anti-PD-L1 immunotherapy in pancreatic cancer

Abstract

Background Sonodynamic therapy (SDT) induces immunogenic cell death (ICD) in tumors and promises to play an assistive role in immunotherapy in pancreatic cancer. However, the short half-life and limited diffusion distance of reactive oxygen species (ROS) impair ICD induction, especially in tumors with relatively poor blood perfusion and dense stroma. Results To address this problem, we fabricated cavitation-assisted endoplasmic reticulum (ER) targeted sonodynamic nanodroplets (PMPS NDs, 329 nm). The good sonodynamic effect and precise endoplasmic reticulum target effect was verified. After intravenous injection, the cRGD peptide modified nanodroplets initially aggregated around the tumor vascular endothelial cells. Stimulated by ultrasound, the liquid-to-gas bubbles began to oscillate and cavitate. This acoustic droplet evaporation strategy facilitated transport of the nanoparticle across the vessel, with deep penetration. This loosened the tumor stroma and facilitated accumulation and penetration of loaded sonosensitizer after 6 h. The modified sonosensitizer can selectively accumulate in the ER to generate a large amount of ROS in situ, inducing potent ER stress, amplified ICD and dendritic cell maturation in vitro and in vivo. Furthermore, the elevated antitumor effect of SDT plus anti-PD-L1 immunotherapy was verified using an orthotopic tumor model. Conclusions This study reports a cavitation assisted ER targeted sonodynamic therapy that can enhance the effect of anti-PD-L1 immunotherapy effectively in orthotopic and distant pancreatic cancer. Graphical Abstract

Recent Advances in Well-Designed Therapeutic Nanosystems for the Pancreatic Ductal Adenocarcinoma Treatment Dilemma

“…In addition, the MOF can efficiently produce ROS in hypoxic environments, and thus, has great prospects for the treatment of hypoxic tumors. In another study, Chen et al designed an ER-targeted nanodroplet that selectively accumulated in the ER, generated large amounts of ROS, induced intense ER stress, and finally, triggered strong ICD effects [ 142 ]. In addition to enhancing the ability to produce ROS under hypoxic conditions through type I SDT, another strategy is to enhance the efficacy of type II SDT by providing oxygen.…”

Emerging Sonodynamic Therapy‐Based Nanomedicines for Cancer Immunotherapy

“…[ 18 , 60 ] Specially, sonosensitizers have been developed to enhance the therapeutic effect of SDT‐based immunotherapy with the rapid development of nanotechnology and nanoscience. Well‐designed sonosensitizers greatly improved the SDT‐induced ROS yield by enhancing acoustic cavitation effect [ 61 ] or alleviating tumor hypoxia. [ 62 ] Modifiable nanocarriers also significantly increased the bioavailability and tumor targeting of sonosensitizers by prolonging the blood circulation time and the accumulation in tumor tissues.…”

Activating Nanomedicines with Electromagnetic Energy for Deep‐Tissue Induction of Immunogenic Cell Death in Cancer Immunotherapy

“…[ 36 ] To achieve enhanced ICD effect and combinational immunotherapy, Huang's group reported a cavitation‐assisted ER‐targeted nanodroplet for treatment of orthotopic and distant pancreatic cancer. [ 37 ] PpIX‐modified 4‐methylphenylsulfonylurea (MPSU) was integrated into cRGD‐conjugated liposome with loading of perfluoropentane. The conjugated cRGD increased the aggregation and penetration of nanodroplets in tumors.…”