Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, Hubei 430070, China.
Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
J Control Release. 2019 Sep 10;309:173-180. doi: 10.1016/j.jconrel.2019.07.039. Epub 2019 Jul 29.
Phosphoinositide-3-kinases (PI3Ks) are part of signal transducing enzymes that mediate key cellular functions in cancer and immunity. PI3K-γ is crucial for cellular activation and migration in response to certain chemokines. PI3K-γ is highly expressed in myeloid cells and promotes their migration and the production of inflammatory mediators. We found that PI3K-γ was also highly expressed in tumor-associated B cells. IPI-549, the only PI3K-γ inhibitor in clinical development, offers a unique approach to enhance the anti-tumor immune response. We encapsulated IPI-549 in targeted polymeric nanoparticles (NP) and tested its activity in both murine pancreatic cancer and melanoma models. IPI-549 NP significantly decreased tumor growth and prolonged host survival in both models. Importantly, IPI-549 NP treatment reduced the suppressive tumor microenvironment by decreasing both suppressive myeloid and plasma cells in the tumor. We concluded that IPI-549 NP delivery could be a promising method for treating pancreatic cancer and other immune-suppressive tumors.
磷酸肌醇 3-激酶 (PI3Ks) 是信号转导酶的一部分，可介导癌症和免疫中的关键细胞功能。PI3K-γ 对于细胞对某些趋化因子的激活和迁移至关重要。PI3K-γ 在髓样细胞中高度表达，并促进其迁移和炎症介质的产生。我们发现 PI3K-γ 在肿瘤相关 B 细胞中也高度表达。IPI-549 是唯一处于临床开发阶段的 PI3K-γ 抑制剂，为增强抗肿瘤免疫反应提供了一种独特的方法。我们将 IPI-549 包裹在靶向聚合物纳米颗粒 (NP) 中，并在小鼠胰腺癌和黑色素瘤模型中测试了其活性。IPI-549 NP 显著降低了两种模型中的肿瘤生长并延长了宿主的存活时间。重要的是，IPI-549 NP 治疗通过减少肿瘤中的抑制性髓样细胞和浆细胞来降低抑制性肿瘤微环境。我们得出结论，IPI-549 NP 递送可能是治疗胰腺癌和其他免疫抑制性肿瘤的有前途的方法。
