Chen Jyh-Ping, Liu Chih-Hsin, Hsu Hao-Lung, Wu Tony, Lu Yu-Jen, Ma Yunn-Hwa
Department of Chemical and Materials Engineering and Biomedical Engineering Research Center, Chang Gung University, Kwei-San, Taoyuan 333, Taiwan, Republic of China.
J Mater Chem B. 2016 Apr 21;4(15):2578-2590. doi: 10.1039/c5tb02579f. Epub 2016 Mar 24.
Ionic cross-linking of water-soluble chitosan with sodium tripolyphosphate in the presence of recombinant tissue plasminogen activator (rtPA) and magnetite (FeO) nanoparticles could produce rtPA-encapsulated magnetic chitosan nanoparticles (MCNPs-rtPA). MCNPs do not elicit cytotoxicity and hemolysis in vitro. MCNPs-rtPA showed a negligible release of the rtPA protein when stored in phosphate buffer for 28 days. In contrast, the burst release of rtPA from MCNPs-rtPA was found in the serum with 60% of the original activity released in 30 min. The drug release into the serum is also magnet-sensitive; the release could be turned down with a magnetic field when MCNPs-rtPA was pelleted and reversibly turned on after removing the magnetic field when MCNPs-rtPA was dispersed. An in vitro thrombolytic study by thromboelastometry indicated a controlled release of rtPA from MCNPs-rtPA. In a rat embolic model where a preformed blood clot lodged in the left iliac artery upstream of the pudic epigastric branch, MCNPs-rtPA (0.2 mg kg rtPA) was administered and guided magnetically to the clot, followed by mobile magnetic guidance for 60 min. Iliac blood flow increased immediately in response to the treatment, and reached a stable level ∼50 min after drug administration and the hind limb perfusion rate was restored from 53% to 75% of the basal level. Effective thrombolysis was therefore successfully demonstrated at an rtPA dose equivalent to 20% of the regular dose when the MCNPs-rtPA pellet was magnet-guided to the blood clot, followed by a triggered release of rtPA when switched to mobile magnetic guidance.
在重组组织型纤溶酶原激活剂（rtPA）和磁铁矿（FeO）纳米颗粒存在的情况下，水溶性壳聚糖与三聚磷酸钠进行离子交联可制备包载rtPA的磁性壳聚糖纳米颗粒（MCNPs-rtPA）。MCNPs在体外不会引起细胞毒性和溶血。MCNPs-rtPA在磷酸盐缓冲液中储存28天时，rtPA蛋白的释放量可忽略不计。相比之下，在血清中发现MCNPs-rtPA会出现rtPA的突释，30分钟内释放出60%的原始活性。药物向血清中的释放也具有磁敏感性；当MCNPs-rtPA形成沉淀时，施加磁场可使释放量降低，而去除磁场使MCNPs-rtPA分散后，释放又会可逆地开启。通过血栓弹力测定法进行的体外溶栓研究表明，rtPA从MCNPs-rtPA中可控释放。在一个大鼠栓塞模型中，预先形成的血凝块位于阴部腹壁分支上游的左髂动脉中，给予MCNPs-rtPA（0.2 mg/kg rtPA）并通过磁力引导至血凝块处，随后进行60分钟的移动磁引导。治疗后髂动脉血流量立即增加，给药后约50分钟达到稳定水平，后肢灌注率从基础水平的53%恢复到75%。因此，当MCNPs-rtPA沉淀被磁引导至血凝块处，随后切换至移动磁引导时触发rtPA释放，成功证明了在rtPA剂量相当于常规剂量20%时的有效溶栓效果。
