Laboratory of Nano- and Translational Medicine, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Sci Adv. 2020 Apr 1;6(14):eaaz9798. doi: 10.1126/sciadv.aaz9798. eCollection 2020 Apr.
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 BEZ235 is an effective dual PI3K/mTOR inhibitor, but it was withdrawn from early-phase clinical trials owing to poor solubility and on-target/off-tumor toxicity.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.
PI3K/mTOR 信号的过度激活已在非霍奇金淋巴瘤中被发现。BEZ235 是一种有效的双重 PI3K/mTOR 抑制剂，但由于溶解度差和靶内/靶外毒性，它已从早期临床试验中撤出。在这里，我们开发了一种基于纳米颗粒（NP）的 Pretargeted 系统，用于将 BEZ235 递送至表达 CD20 和 HLA-DR 的淋巴瘤细胞，以进行靶向治疗。Pretargeted 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化物功能化的 BEZ235 包封的 NPs 作为效应药物载体组成。使用具有不同 CD20 和 HLA-DR 抗原密度的淋巴瘤细胞系作为示例，我们证明了双重抗体 Pretargeted 策略通过抑制 PI3K/mTOR 通路，有效地增加了保留在靶肿瘤细胞上的 NP 数量，并提高了 BEZ235 的体外和体内抗肿瘤活性。我们的数据表明，基于 NP 的 Pretargeted 系统提高了小分子激酶抑制剂的治疗窗口。
