Overactivation of the PI3K/mTOR signaling has been identified in non-Hodgkin's lymphoma. BEZ235 is an effective dual PI3K/mTOR inhibitor, but it was withdrawn from early-phase clinical trials owing to poor solubility and on-target/off-tumor toxicity. Here, we developed a nanoparticle (NP)-based pretargeted system for the therapeutic delivery of BEZ235 to CD20- and HLA-DR-expressing lymphoma cells for targeted therapy. The pretargeted system is composed of dibenzocyclooctyne-functionalized anti-CD20 and anti-Lym1 antibodies as the tumor-targeting components and azide-functionalized BEZ235-encapsulated NPs as the effector drug carrier. Using lymphoma cell lines with different CD20 and HLA-DR antigen densities as examples, we demonstrate that the dual antibody pretargeted strategy effectively raises the number of NPs retained on the target tumor cells and improves the in vitro and in vivo antitumor activity of BEZ235 through the inhibition of the PI3K/mTOR pathway. Our data demonstrate that the NP-based pretargeted system improves the therapeutic window of small-molecule kinase inhibitor.

中文翻译：

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预靶向递送 PI3K/mTOR 小分子抑制剂负载纳米粒子用于治疗非霍奇金淋巴瘤。

已在非霍奇金淋巴瘤中发现 PI3K/mTOR 信号传导的过度激活。BEZ235 是一种有效的双重 PI3K/mTOR 抑制剂，但由于溶解度差和靶向/非肿瘤毒性而退出早期临床试验。在这里，我们开发了一种基于纳米颗粒 (NP) 的预靶向系统，用于将 BEZ235 治疗性递送至表达 CD20 和 HLA-DR 的淋巴瘤细胞进行靶向治疗。预靶向系统由二苯并环辛炔功能化的抗 CD20 和抗 Lym1 抗体作为肿瘤靶向成分和叠氮功能化的 BEZ235 封装的 NPs 作为效应药物载体组成。以不同CD20和HLA-DR抗原密度的淋巴瘤细胞系为例，我们证明了双抗体预靶向策略有效地提高了保留在靶肿瘤细胞上的 NP 数量，并通过抑制 PI3K/mTOR 通路提高了 BEZ235 的体外和体内抗肿瘤活性。我们的数据表明，基于 NP 的预靶向系统改善了小分子激酶抑制剂的治疗窗口。