Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
J Control Release. 2023 Apr;356:185-195. doi: 10.1016/j.jconrel.2023.02.037. Epub 2023 Mar 7.
Intracerebral hemorrhage (ICH) is one of the most common causes of fatal stroke, yet has no specific drug therapies. Many attempts at passive intravenous (IV) delivery in ICH have failed to deliver drugs to the salvageable area around the hemorrhage. The passive delivery method assumes vascular leak through the ruptured blood-brain barrier will allow drug accumulation in the brain. Here we tested this assumption using intrastriatal injection of collagenase, a well-established experimental model of ICH. Fitting with hematoma expansion in clinical ICH, we showed that collagenase-induced blood leak drops significantly by 4 h after ICH onset and is gone by 24 h. We observed passive-leak brain accumulation also declines rapidly over ∼4 h for 3 model IV therapeutics (non-targeted IgG; a protein therapeutic; PEGylated nanoparticles). We compared these passive leak results with targeted brain delivery by IV monoclonal antibodies (mAbs) that actively bind vascular endothelium (anti-VCAM, anti-PECAM, anti-ICAM). Even at early time points after ICH induction, where there is high vascular leak, brain accumulation via passive leak is dwarfed by brain accumulation of endothelial-targeted agents: At 4 h after injury, anti-PECAM mAbs accumulate at 8-fold higher levels in the brain vs. non-immune IgG; anti-VCAM nanoparticles (NPs) deliver a protein therapeutic (superoxide dismutase, SOD) at 4.5-fold higher levels than the carrier-free therapeutic at 24 h after injury. These data suggest that relying on passive vascular leak provides inefficient delivery of therapeutics even at early time points after ICH, and that a better strategy might be targeted delivery to the brain endothelium, which serves as the gateway for the immune attack on the peri-hemorrhage inflamed brain region.
脑出血（ICH）是最常见的致命性中风原因之一，但目前尚无特定的药物治疗方法。许多旨在通过被动静脉（IV）给药的ICH 治疗方法都未能将药物递送至出血周围可挽救的区域。被动给药方法假设通过破裂的血脑屏障的血管渗漏将允许药物在大脑中积累。在这里，我们使用胶原酶的纹状体内注射来测试这种假设，胶原酶是一种成熟的 ICH 实验模型。与临床 ICH 中的血肿扩展一致，我们表明，ICH 发作后 4 小时内胶原酶诱导的血液渗漏显著下降，24 小时后消失。我们还观察到，对于 3 种模型 IV 治疗药物（非靶向 IgG；蛋白质治疗药物；PEG 化纳米颗粒），被动渗漏脑内积累也在约 4 小时内迅速下降。我们将这些被动渗漏结果与通过 IV 单克隆抗体（mAb）进行的靶向脑内递送进行了比较，这些 mAb 主动结合血管内皮细胞（抗 VCAM、抗 PECAM、抗 ICAM）。即使在ICH 诱导后早期，即血管渗漏高的时期，通过被动渗漏进行脑内积累也远远低于内皮靶向药物的脑内积累：在损伤后 4 小时，抗 PECAM mAb 在脑内的积累水平比非免疫 IgG 高 8 倍；抗 VCAM 纳米颗粒（NPs）在损伤后 24 小时以比载体游离治疗药物高 4.5 倍的水平递送蛋白质治疗药物（超氧化物歧化酶，SOD）。这些数据表明，即使在 ICH 后早期，依赖于被动血管渗漏的治疗方法提供的药物递送效率也很低，而更好的策略可能是针对大脑内皮细胞的靶向递送，大脑内皮细胞是针对出血后炎症脑区的免疫攻击的门户。
