PO.TB02.01 · 肿瘤生物学
放射激活光动力疗法（radioPDT）的生物物理增强及转化性脑肿瘤模型
Biophysical enhancement of radiation-activated photodynamic therapy (radioPDT) and translational brain tumor models
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：放射激活光动力疗法（radioPDT）利用X射线激发的纳米闪烁体在组织深处激活光敏剂，产生细胞毒性活性氧，而无需受体表达。这种生物物理策略非常适合诸如胶质母细胞瘤（GBM）等异质性肿瘤，因为受体靶向方法在这些肿瘤中往往失效。一个主要的转化障碍是血脑屏障（BBB），它限制了纳米颗粒的进入。通过聚焦超声（FUS）和微泡空化进行的物理调控可以增强纳米颗粒递送并可能提高radioPDT的疗效。为评估这种方法，我们建立了一个多模型流程，纳入侧腹异种移植、颅内GBM模型和鸡胚绒毛尿囊膜（CAM）系统，从而能够对纳米颗粒转运、血管效应和治疗反应进行可视化。
方法：荷有PC3侧腹肿瘤的SCID小鼠接受对照、放射、FUS、NP+RAD、NP+FUS+RAD或NP+微泡+FUS+RAD处理。使用多重免疫荧光对肿瘤进行分析，包括增殖/凋亡（Ki67、切割的Caspase-3）、DNA损伤（gamma-H2AX、53BP1）、氧化损伤（4-HNE、TUNEL）、血管结构（CD31、NG2）、缺氧（CA9、HIF-1alpha）和炎症（CD45、Iba1）。对于转化研究，验证了表达LUC-GFP的U87和U251 GBM细胞，并用于生成颅内异种移植以进行生物发光成像，以及CAM模型以快速评估纳米颗粒行为和radioPDT效应。
结果：单独radioPDT破坏了内皮细胞，而radioPDT联合微泡增强的FUS同时产生了内皮细胞和周细胞的破坏，提示其在调控BBB方面的潜力。多重肿瘤分析正在进行中。已建立LUC-GFP GBM模型，颅内和CAM肿瘤提供了互补的系统，用于研究radioPDT期间FUS介导的BBB开放和纳米颗粒递送。
结论：radioPDT可能在无需受体特异性靶向的情况下放大超声介导的血管调控。整合的PC3、颅内GBM和CAM平台建立了一条评估可穿透BBB的、基于物理的radioPDT的转化途径。这些研究旨在明确物理力——而非受体介导的摄取——如何塑造纳米颗粒分布、血管反应、DNA损伤、氧化损伤和整体radioPDT效力。
查看英文原文 English abstract
Background: Radiation-activated photodynamic therapy (radioPDT) uses X-ray-excited nanoscintillators to activate photosensitizers deep within tissues, generating cytotoxic reactive oxygen species without requiring receptor expression. This biophysical strategy is well suited for heterogeneous tumors such as glioblastoma (GBM), where receptor-targeted approaches often fail. A major translational barrier is the blood-brain barrier (BBB), which restricts nanoparticle entry. Physical modulation via focused ultrasound (FUS) and microbubble cavitation can enhance nanoparticle delivery and potentially improve radioPDT efficacy. To evaluate this approach, we established a multi-model pipeline incorporating flank xenografts, intracranial GBM models, and the chick CAM system, allowing visualization of nanoparticle transport, vascular effects, and treatment response.
Methods: SCID mice bearing PC3 flank tumors received control, radiation, FUS, NP+RAD, NP+FUS+RAD, or NP+microbubbles+FUS+RAD. Tumors were analyzed using multiplex immunofluorescence for proliferation/apoptosis (Ki67, cleaved Caspase-3), DNA damage (gamma-H2AX, 53BP1), oxidative injury (4-HNE, TUNEL), vascular structure (CD31, NG2), hypoxia (CA9, HIF-1alpha), and inflammation (CD45, Iba1). For translational studies, U87 and U251 GBM cells expressing LUC-GFP were validated and used to generate intracranial xenografts for bioluminescence imaging and a CAM model enabling rapid assessment of nanoparticle behavior and radioPDT effects.
Results: radioPDT alone disrupted endothelial cells, while radioPDT combined with microbubble-enhanced FUS produced both endothelial and pericyte disruption, suggesting potential for BBB modulation. Multiplex tumor analysis is ongoing. LUC-GFP GBM models have been established, and intracranial and CAM tumors provide complementary systems to study FUS-mediated BBB opening and nanoparticle delivery during radioPDT.
Conclusions: radioPDT may amplify ultrasound-mediated vascular modulation without requiring receptor-specific targeting. The integrated PC3, intracranial GBM, and CAM platforms establish a translational pathway to evaluate BBB-penetrant, physics-based radioPDT. These studies are designed to define how physical forces-rather than receptor-mediated uptake-shape nanoparticle distribution, vascular response, DNA damage, oxidative injury, and overall radioPDT potency.
利益披露 Disclosure
M. Muralidharan, None.