Nanoparticulate delivery system of a tyrphostin for the treatment of restenosis
Nanoparticulate delivery system of a tyrphostin for the treatment of restenosis
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DOI：
10.1016/s0168-3659(99)00244-8
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发表时间：
2000-03-01
影响因子：
10.8
通讯作者：
Golomb, G
中科院分区：
文献类型：
--
作者：
Fishbein, I;Chorny, M;Golomb, G
再狭窄是经皮冠状动脉腔内成形术的主要并发症，是造成冠状动脉血运重建后 35-40% 长期失败率的原因。新内膜形成是再狭窄的形态学基础，依赖于平滑肌细胞（SMC）的增殖和迁移。通过血小板衍生生长因子 (PDGF)/PDGF 受体系统的信号转导参与血管成形术后再狭窄的过程。通过全身药物干预控制再狭窄的不成功尝试促使许多研究人员寻找更有前景的治疗方法，例如局部给药。酪氨酸磷酸化抑制剂是蛋白酪氨酸激酶的低分子量抑制剂。我们评估了含有 PDGF 受体 β (PDGFR β) 酪氨酸磷酸化抑制剂 AG-1295 的纳米颗粒的释放动力学和体内效应。 AG-1295负载的聚(DL-丙交酯)(PLA)纳米颗粒：通过自发乳化/溶剂置换技术制备。测定了体外释放速率以及药物/聚合物比例对纳米颗粒尺寸的影响。使用大鼠 SMC 提取物中的磷酸酪氨酸特异性抗体通过蛋白质印迹评估酪氨酸磷酸化程度。 PDCF BE刺激的SMC的几个特征带在酪氨酸磷酸酶治疗后消失或减弱。将负载 AG-1295 的 PLA 纳米颗粒局部腔内递送至受伤的大鼠颈动脉，对血管成形动脉的内侧和新内膜室的增殖活性没有影响，表明 AG-1295 对内侧 SMC 具有主要的抗迁移作用。 (C) 2000 Elsevier Science B.V. 保留所有权利。
Restenosis, the principal complication of percutaneous transluminal coronary angioplasty is responsible for the 35-40% long-term failure rate following coronary revascularization. The neointimal formation, a morphological substrate of restenosis, is dependent on smooth muscle cells (SMC) proliferation and migration. Signal transduction through the platelet-derived growth factor (PDGF)/PDGF receptors system is involved in the process of post-angioplasty restenosis. The unsuccessful attempts to control restenosis by systemic pharmacological interventions have prompted many researchers to look for more promising therapeutic approaches such as local drug delivery. Tyrphostins are low molecular weight inhibitors of protein tyrosine kinases. We assessed the release kinetics and in vivo effects of nanoparticles containing PDGF-Receptor beta (PDGFR beta) tyrphostin inhibitor, AG-1295. AG-1295-loaded poly(DL-lactide) (PLA) nanoparticles: were prepared by spontaneous emulsification/solvent displacement technique. In vitro release rate and the impact of drug/polymer ratio on the nanoparticle size were determined. The degree of tyrosine phosphorylation was assessed by Western blot with phosphotyrosine-specific antibody in rat SMC extracts. Several bands characteristic of PDCF BE-stimulated SMC disappeared or weakened following tyrphostin treatment. Local intraluminal delivery of AG-1295-loaded PLA nanoparticles to the injured rat carotid artery had no effect on proliferative activity in medial and neointimal compartments of angioplastisized arteries, indicating a primary antimigration effect of AG-1295 on medial SMC. (C) 2000 Elsevier Science B.V. All rights reserved.