Targeted delivery of tissue plasminogen activator by binding to silica-coated magnetic nanoparticle.
Targeted delivery of tissue plasminogen activator by binding to silica-coated magnetic nanoparticle.
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DOI：
10.2147/ijn.s36197
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发表时间：
2012
影响因子：
8
通讯作者：
Lu YJ
中科院分区：
文献类型：
--
作者：
Chen JP;Yang PC;Ma YH;Tu SJ;Lu YJ
采用溶胶-凝胶法制备了二氧化硅包覆的磁性纳米粒子（SiO2-MNP），并将其作为组织型纤溶酶原激活剂（tPA）的纳米靶向载体进行了研究。该纳米载体由超顺磁性氧化铁核和SiO2壳组成，并通过透射电子显微镜、傅里叶变换红外光谱、X射线衍射、超导量子干涉仪和热重分析对其进行表征。胺封端的表面硅烷化剂（3-氨丙基三甲氧基硅烷）被用来官能化的SiO2表面，这提供了丰富的-NH 2官能团与tPA共轭。当0.5 mg/mL tPA与5 mg SiO2-MNP偶联时达到最佳载药量，其中94%的tPA连接到载体上，具有86%的酰胺溶解活性保留和完全保留的纤溶活性。乳酸脱氢酶释放和细胞增殖测定的体外生物相容性表明SiO2-MNP不会引起细胞毒性。静脉给药后从小鼠抽取的血液样品的血液学分析表明，tPA-缀合的SiO2-MNP（SiO2-MNP-tPA）不改变血液组分浓度。与SiO2-MNP缀合后，tPA在缓冲液中的储存稳定性和在全血中的操作稳定性分别增强了9.5倍和2.8倍。在离体血栓溶解模型中证明了在磁性引导下使用SiO2-MNP-tPA的有效血栓溶解，其中与使用相同药物剂量的无磁性靶向和游离tPA的运行相比，分别观察到血凝块溶解时间减少34%和40%。通过显微计算机断层扫描分析证实了SiO2-MNP-tPA在磁引导下进入血凝块的增强渗透。本研究开发的生物相容性SiO2-MNP作为磁靶向药物载体将有助于改善临床溶栓治疗。
Silica-coated magnetic nanoparticle (SiO2-MNP) prepared by the sol-gel method was studied as a nanocarrier for targeted delivery of tissue plasminogen activator (tPA). The nanocarrier consists of a superparamagnetic iron oxide core and an SiO2 shell and is characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, superconducting quantum interference device, and thermogravimetric analysis. An amine-terminated surface silanizing agent (3-aminopropyltrimethoxysilane) was used to functionalize the SiO2 surface, which provides abundant –NH2 functional groups for conjugating with tPA. The optimum drug loading is reached when 0.5 mg/mL tPA is conjugated with 5 mg SiO2-MNP where 94% tPA is attached to the carrier with 86% retention of amidolytic activity and full retention of fibrinolytic activity. In vitro biocompatibility determined by lactate dehydrogenase release and cell proliferation indicated that SiO2-MNP does not elicit cytotoxicity. Hematological analysis of blood samples withdrawn from mice after venous administration indicates that tPA-conjugated SiO2-MNP (SiO2-MNP-tPA) did not alter blood component concentrations. After conjugating to SiO2-MNP, tPA showed enhanced storage stability in buffer and operation stability in whole blood up to 9.5 and 2.8-fold, respectively. Effective thrombolysis with SiO2-MNP-tPA under magnetic guidance is demonstrated in an ex vivo thrombolysis model where 34% and 40% reductions in blood clot lysis time were observed compared with runs without magnetic targeting and with free tPA, respectively, using the same drug dosage. Enhanced penetration of SiO2-MNP-tPA into blood clots under magnetic guidance was confirmed from microcomputed tomography analysis. Biocompatible SiO2-MNP developed in this study will be useful as a magnetic targeting drug carrier to improve clinical thrombolytic therapy.