细胞周期的干扰是增加肿瘤细胞放射敏感性最有效的方法之一。然而，存在剂量限制的副作用妨碍了靶向细胞周期的酪氨酸激酶抑制剂的临床应用。为应对这一挑战，我们在高密度脂蛋白纳米颗粒（HDL NPs）中发现了一种有前途的放射增敏剂——博苏替尼纳米制剂。博苏替尼是一种经临床批准用于治疗慢性髓性白血病的激酶抑制剂，通过细胞周期检查点抑制具有放射增敏性质。我们发现，在最佳制备条件下，可可靠地实现博苏替尼-HDL NPs的显著高负荷（＞10%）。博苏替尼-HDL纳米制剂的放射增敏活性首次在头颈部鳞癌（HNSCC）细胞系UM-SCC-1中体外评估，确认了对放射线诱导的G2/M细胞周期阻滞的有效干扰。有趣的是，博苏替尼纳米制剂优于游离博苏替尼，可能是因为HDL NPs与肿瘤细胞的特异亲和力。博苏替尼-HDL NPs与放射治疗的联合能显著控制免疫竞争力的小鼠HNSCC模型中的肿瘤生长。博苏替尼-HDL纳米制剂还通过将肿瘤相关巨噬细胞极化为前炎性表型来增强放射线诱导的免疫反应。©2023. 作者 (们)。

Disruption of the cell cycle is among the most effective approach to increase tumour cells' radio-sensitivity. However, the presence of dose-limiting side effects hampers the clinical use of tyrosine kinase inhibitors targeting the cell cycle. Towards addressing this challenge, we identified a bosutinib nanoformulation within high density lipoprotein nanoparticles (HDL NPs) as a promising radiosensitiser. Bosutinib is a kinase inhibitor clinically approved for the treatment of chronic myeloid leukemia that possesses radiosensitising properties through cell cycle checkpoint inhibition. We found that a remarkably high bosutinib loading (> 10%) within HDL NPs could be reliably achieved under optimal preparation conditions. The radiosensitisation activity of the bosutinib-HDL nanoformulation was first assessed in vitro in UM-SCC-1 head and neck squamous cell carcinoma (HNSCC) cells, which confirmed efficient disruption of the radiation induced G2/M cell cycle arrest. Interestingly, the bosutinib nanoformulation out-performed free bosutinib, likely because of the specific affinity of HDL NPs with tumour cells. The combination of bosutinib-HDL NPs and radiotherapy significantly controlled tumour growth in an immunocompetent murine HNSCC model. The bosutinib-HDL nanoformulation also enhanced the radiation induced immune response through the polarisation of tumour associated macrophages towards proinflammatory phenotypes.© 2023. The Author(s).