LBPO.CL03 · 临床研究 · Late-Breaking
利用P-selectin靶向纳米药物突破血脑屏障以增强GD2-CAR-T疗法
Overcoming the blood-brain barrier to potentiate GD2-CAR T therapy using P-selectin-targeted nanomedicine
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
儿科脑肿瘤是儿童癌症相关死亡的首要原因，而弥漫性内生型脑桥胶质瘤（DIPG）和髓母细胞瘤（MB）等高级别恶性肿瘤仍难以治疗。DIPG因其位于脑干且呈弥漫性浸润而无法手术，而MB的治疗（手术、全脑全脊髓放疗、化疗）伴有复发和长期神经毒性。血脑屏障（BBB）进一步限制了治疗进展，它阻止大多数全身性疗法到达肿瘤部位。为克服这些挑战，我们设计了放射引导、P-selectin靶向的PLGA-PEG-(SO₃)₂纳米颗粒（sNPs），包载多激酶抑制剂zotiraciclib（TG02），并探索了使用GD2-CAR-T细胞的联合疗法以进一步增强治疗疗效。sNPs通过微流控混合制备，其表面硫酸化（模拟内源性P-selectin配体）经X射线光电子能谱确认。对其理化性质、稳定性、血液相容性和药物释放动力学进行了表征。使用3D肿瘤芯片模型评估BBB转运，并在由患者来源的儿科脑肿瘤细胞系生成的2D单层和3D肿瘤模型中评估治疗疗效。sNPs表现出良好的胶体性质（流体动力学直径约100 nm，多分散指数约0.1，负ζ电位），实现了高包封效率及约60%的制剂产率，并在生理条件下表现出缓释。放射诱导DIPG和MB肿瘤细胞以及血管生成内皮上的P-selectin上调，显著增强了sNP的肿瘤蓄积。值得注意的是，包载TG02的sNP与GD2-CAR-T细胞联合治疗显著优于任一单药治疗，在3D肿瘤模型中使肿瘤生长减少且免疫逃逸减弱。总体而言，这项工作展示了一种可穿透BBB、肿瘤选择性的纳米药物策略，可增强GD2-CAR-T疗法在儿科脑肿瘤中的疗效。通过整合放射引导、靶向药物递送和细胞免疫疗法，该平台解决了儿科神经肿瘤学中的关键障碍，并支持针对DIPG和MB的进一步开发。
查看英文原文 English abstract
Pediatric brain tumors are the leading cause of cancer‑related death in children, and high‑grade malignancies such as diffuse intrinsic pontine glioma (DIPG) and medulloblastoma (MB) remain intractable. DIPG is inoperable due to its brainstem location and diffuse infiltration, while MB therapy (surgery, craniospinal irradiation, chemotherapy) carries recurrence and long‑term neurotoxicity. Progress is further constrained by the blood-brain barrier (BBB), which prevents most systemic therapies from reaching the tumor site. To overcome these challenges, we engineered radiation-guided, P-selectin-targeted PLGA-PEG-(SO 3 ) 2 nanoparticles (sNPs) encapsulating the multikinase inhibitor zotiraciclib (TG02) and explored a combination therapy using GD2-CAR T cells to further enhance therapeutic efficacy. sNPs were fabricated via microfluidic mixing, and surface sulfation, mimicking endogenous P-selectin ligand, was confirmed by X-ray photoelectron spectroscopy. Physicochemical properties, stability, hemocompatibility, and drug release kinetics were characterized. BBB transport was evaluated using a 3D tumor-on-a-chip model, and therapeutic efficacy was assessed in both 2D monolayers and 3D tumor models generated from patient-derived pediatric brain tumor cell lines. sNPs exhibited favorable colloidal properties (hydrodynamic diameter ~100 nm, polydispersity index ~0.1, negative ζ-potential), achieved high encapsulation efficiency with a ~60% formulation yield, and demonstrated sustained release under physiological conditions. Radiation-induced P-selectin upregulation on DIPG and MB tumor cells, as well as angiogenic endothelium, significantly enhances sNP tumor accumulation. Notably, combination treatment with sNP encapsulating TG02 and GD2-CAR T cells markedly outperformed either monotherapy, resulting in reduced tumor growth and diminished immune evasion in 3D tumor models. Overall, this work demonstrates a BBB-penetrant, tumor-selective nanomedicine strategy that enhances the efficacy of GD2-CAR T therapy in pediatric brain tumors. By integrating radiation guidance, targeted drug delivery, and cellular immunotherapy, this platform addresses key barriers in pediatric neuro-oncology and supports further development for DIPG and MB.
利益披露 Disclosure
G. Longobardi, None..
A. Miari, None..
Y. Liubomirski, None..
E. Buderovsky, None..
A. Globerson Levin, None.
R. Satchi-Fainaro,
Teva Pharmaceutical Industries Ltd. g., Board of Directors, non-salaried role).
Merck KGaA ).
Selectin Therapeutics Inc. Cofounder and officer with an equity interest.