Luo Lijia, Wang Xiang, Liao Yu-Pei, Xu Xiao, Chang Chong Hyun, Nel Andre E
Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA 90095, USA.
California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA.
Nano Today. 2024 Feb;54. doi: 10.1016/j.nantod.2023.102058. Epub 2023 Nov 15.
The prevailing desmoplastic stroma and immunosuppressive microenvironment within pancreatic ductal adenocarcinoma (PDAC) pose substantial challenges to therapeutic intervention. Despite the potential of protein tyrosine kinase (PTK) inhibitors in mitigating the desmoplastic stromal response and enhancing the immune milieu, their efficacy is curtailed by suboptimal pharmacokinetics (PK) and insufficient tumor penetration. To surmount these hurdles, we have pioneered a novel strategy, employing lipid bilayer-coated mesoporous silica nanoparticles (termed "silicasomes") as a carrier for the delivery of Nintedanib. Nintedanib, a triple PTK inhibitor that targets vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor receptors, was encapsulated in the pores of silicasomes via a remote loading mechanism for weak bases. This innovative approach not only enhanced pharmacokinetics and intratumor drug concentrations but also orchestrated a transformative shift in the desmoplastic and immune landscape in a robust orthotopic KRAS-mediated pancreatic carcinoma (KPC) model. Our results demonstrate attenuation of vascular density and collagen content through encapsulated Nintedanib treatment, concomitant with significant augmentation of the CD8/FoxP3 T-cell ratio. This remodeling was notably correlated with tumor regression in the KPC model. Strikingly, the synergy between encapsulated Nintedanib and anti-PD-1 immunotherapy further potentiated the antitumor effect. Both free and encapsulated Nintedanib induced a transcriptional upregulation of PD-L1 via the extracellular signal-regulated kinase (ERK) pathway. In summary, our pioneering approach involving the silicasome carrier not only improved antitumor angiogenesis but also profoundly reshaped the desmoplastic stromal and immune landscape within PDAC. These insights hold excellent promise for the development of innovative combinatorial strategies in PDAC therapy.
胰腺导管腺癌（PDAC）中普遍存在的促结缔组织增生性基质和免疫抑制微环境对治疗干预构成了重大挑战。尽管蛋白酪氨酸激酶（PTK）抑制剂有减轻促结缔组织增生性基质反应和改善免疫环境的潜力，但其疗效因药代动力学（PK）不理想和肿瘤穿透不足而受到限制。为了克服这些障碍，我们开创了一种新策略，采用脂质双层包裹的介孔二氧化硅纳米颗粒（称为“硅体”）作为递送尼达尼布的载体。尼达尼布是一种三联PTK抑制剂，靶向血管内皮生长因子、血小板衍生生长因子和成纤维细胞生长因子受体，通过弱碱的远程加载机制封装在硅体的孔中。这种创新方法不仅提高了药代动力学和肿瘤内药物浓度，还在强大的原位KRAS介导的胰腺癌（KPC）模型中使促结缔组织增生和免疫格局发生了变革性转变。我们的结果表明，通过封装尼达尼布治疗可降低血管密度和胶原蛋白含量，同时显著提高CD8/FoxP3 T细胞比率。这种重塑与KPC模型中的肿瘤消退显著相关。引人注目的是，封装的尼达尼布与抗PD-1免疫疗法之间的协同作用进一步增强了抗肿瘤效果。游离和封装的尼达尼布均通过细胞外信号调节激酶（ERK）途径诱导PD-L1的转录上调。总之，我们涉及硅体载体 的开创性方法不仅改善了抗肿瘤血管生成，还深刻重塑了PDAC内的促结缔组织增生性基质和免疫格局。这些见解为PDAC治疗中创新联合策略的开发带来了极好的前景。
