Bioengineered Boronic Ester Modified Dextran Polymer Nanoparticles as Reactive Oxygen Species Responsive Nanocarrier for Ischemic Stroke Treatment
Bioengineered Boronic Ester Modified Dextran Polymer Nanoparticles as Reactive Oxygen Species Responsive Nanocarrier for Ischemic Stroke Treatment
复制标题
生物工程硼酸酯改性右旋糖酐聚合物纳米颗粒作为活性氧响应纳米载体用于治疗缺血性中风
DOI：
10.1021/acsnano.8b00477
复制
发表时间：
2018-06-01
期刊：
影响因子：
17.1
通讯作者：
Xin, Hongliang
中科院分区：
文献类型：
--
作者：
Lv, Wei;Xu, Jianpei;Xin, Hongliang
缺血性中风是全球范围内长期残疾和死亡的主要原因。目前用于治疗缺血性中风的药物递送载体不太令人满意，这在很大程度上是由于它们的循环寿命短、缺乏对缺血部位的特异性靶向以及药物释放的可控性差。鉴于缺血性神经元中活性氧（ROS）的上调，我们在此开发了一种生物工程ROS响应性纳米载体，用于针对缺血性脑损伤的神经保护剂NR 2B 9 C的中风特异性递送。该纳米载体由经ROS响应性硼酸酯修饰的葡聚糖聚合物核心和插入有卒中归巢肽（SHp）的红细胞（RBC）膜壳组成。因此，这些靶向的“核-壳”纳米颗粒（命名为SHp-RBC-NP）在归巢到缺血性脑组织后可以具有由缺血性神经元中的高细胞内ROS触发的NR 2B 9 C的受控释放。在体外和大鼠大脑中动脉闭塞（MCAO）模型中系统地评估了SHp-RBC-NP用于缺血性中风治疗的潜力。体外实验结果表明，SHp-RBC-NP对谷氨酸诱导的PC-12细胞毒性有明显的保护作用。体内药代动力学（PK）和药效学（PD）测试进一步证明，生物工程纳米粒可以显著延长NR 2B 9 C的体循环，增强MCAO大鼠缺血区域的主动靶向，并减少缺血性脑损伤。
Ischemic stroke is a leading cause of long-term disability and death worldwide. Current drug delivery vehicles for the treatment of ischemic stroke are less than satisfactory, in large part due to their short circulation lives, lack of specific targeting to the ischemic site, and poor controllability of drug release. In light of the upregulation of reactive oxygen species (ROS) in the ischemic neuron, we herein developed a bioengineered ROS-responsive nanocarrier for stroke specific delivery of a neuroprotective agent, NR2B9C, against ischemic brain damage. The nanocarrier is composed of a dextran polymer core modified with ROS-responsive boronic ester and a red blood cell (RBC) membrane shell with stroke homing peptide (SHp) inserted. These targeted "core-shell" nanoparticles (designated as SHp-RBC-NP) could thus have controlled release of NR2B9C triggered by high intracellular ROS in ischemic neurons after homing to ischemic brain tissues. The potential of the SHp-RBC-NP for ischemic stroke therapy was systematically evaluated in vitro and in rat models of middle cerebral artery occlusion (MCAO). In vitro results showed that the SHp-RBC-NP had great protective effects on glutamate-induced cytotoxicity in PC-12 cells. In vivo pharmacokinetic (PK) and pharmacodynamic (PD) testing further demonstrated that the bioengineered nanoparticles can drastically prolong the systemic circulation of NR2B9C, enhance the active targeting of the ischemic area in the MCAO rats, and reduce ischemic brain damage.