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
Background Pancreatic cancer remains among the most prevalent and aggressive forms of cancer. While immunotherapeutic treatment strategies have shown some promise in affected patients, the benefits of these interventions have been limited by insufficient tumor infiltration by activated T cells. Results Here, Titanium diselenide (TiSe2) nanosheets were synthesized with good stability. When exposed to ultrasound (US), the TiSe2 nanosheets served as a reliable nano-sensitizer capable of inducing large amounts of reactive oxygen species (ROS) mediating sonodynamic therapy (SDT) under hypoxic and normoxic conditions. The tumor-released TAAs induced by TiSe2 nanosheet-mediated SDT promoted immunogenic cell death (ICD) conducive to the maturation of dendritic cells (DCs), and cytokine secretion and the subsequent activation and infiltration of T cells into the tumor. Combining TiSe2-mediated SDT with anti-PD-1 immune checkpoint blockade treatment led to the efficient suppression of the growth of both primary tumor and distant tumor, while simultaneously preventing lung metastasis. These improved immunotherapeutic and anti-metastatic outcomes were associated with activated systematic antitumor immune responses, including the higher levels of DC maturation and cytokine secretion, the increased levels of CD8+ T cells and the decreased levels of Treg cells infiltrated in tumors. Conclusion TiSe2 can be used as a sonosensitizer with good efficacy and high safety to mediate efficient SDT. The combination treatment strategy comprised of TiSe2-mediated SDT and PD-1 blockade activate anti-tumor immune responses effectively thorough inducing ICD, resulting in the inhibition the growth and metastasis of tumor. The combination therapy holds promise as a novel immunotherapy-based intervention strategy for pancreatic cancer patients.
Background: Sex cord-stromal tumors (SCSTs) are uncommon neoplasms that are typically difficult to diagnose before surgery due to limited experience in their medical imaging. Contrast-enhanced ultrasonography (CEUS) can evaluate the microvessel density of tumors, and the microvessel density of malignant tumors is significantly greater than that of benign tumors, so this provides a method for CEUS to differentiate benign and malignant tumors. Methods:The CEUS diagnoses of 31 patients with pathologically confirmed SCSTs were retrospectively analyzed and compared to conventional ultrasound-based diagnoses. Based on the pathological results, the patients were divided into benign and non-benign groups. Using pathology as the gold standard, four-table data were used to evaluate the authenticity of conventional ultrasonography and CEUS.Results: Among these 31 SCST patients, only the size of the lesion and the stripy hypoenhancement on CEUS differed significantly between the benign group and the non-benign group (P<0.05). In the benign group (n=25), 22 patients showed sparse stripes of hypoenhancement, 1 showed no enhancement, and 2 showed hyperenhancement. In 5 cases of malignant SCSTs, 4 showed hyperenhancement (with nonenhanced areas inside the tumor), and 1 showed sparse strips of hypoenhancement; in 1 case of borderline SCST, the tumor showed uniform hyperenhancement. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate of the conventional ultrasound diagnoses for the 31 SCST patients were 52.0%, 16.7%, 72.2%, 7.7%, and 45.2%, respectively. In relation to CEUS, sparse strips of hypoenhancement or no enhancement were valuable diagnostic criteria for diagnosing benign SCSTs. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate of CEUS were 92.0%, 83.3%, 95.8%, 71.4%, and 90.3%, respectively. The accuracy of CEUS was higher than that of conventional US, and the difference was statistically significant (χ 2 =14.467, P=0.000).Conclusions: Sparse strips of hypoenhancement or no enhancement on CEUS are the characteristic manifestations of benign SCSTs, and hyperenhancement (with a non-enhanced area observable inside the mass) may be suggestive of malignant tumors. CEUS significantly improved the differentiation of benign and malignant SCSTs.
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