Near-infrared -triggered release of tirofiban from nanocarriers for the inhibition of platelet integrin αIIbβ3 to decrease early-stage neointima formation
Near-infrared -triggered release of tirofiban from nanocarriers for the inhibition of platelet integrin αIIbβ3 to decrease early-stage neointima formation
复制标题
近红外触发纳米载体释放替罗非班，抑制血小板整合素αIIbβ3，减少早期新内膜形成
DOI：
10.1039/d0nr00555j
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发表时间：
2020-02-21
期刊：
影响因子：
6.7
通讯作者：
Li, Bo
中科院分区：
文献类型：
--
作者：
Zhao, Zhen;Qiu, Peng;Li, Bo
血小板在损伤后动脉重塑的早期阶段起重要作用。整合素GPIIb/III α（α IIb β 3）在由内向外和由外向内信号通路中调节血小板活化。替罗非班是一种整合素α IIb β 3抑制剂，其在临床治疗中的应用受到体内循环时间短的限制。本文中，使用CuS@mSiO（2）-PEG核-壳纳米颗粒作为近红外触发的纳米载体配制药物控释系统以按需释放替罗非班。纳米载体具有良好的胶体稳定性和非常高的负载效率的整合素α IIb β 3抑制剂（替罗非班14.5重量%）。局部应用α IIb β 3拮抗剂替罗非班对损伤的动脉壁抑制血小板活化，这是由激光照射加速。体外血小板促进的单核细胞迁移trans-well试验显示血小板活化被替罗非班抑制后单核细胞迁移减少。在导丝诱导损伤后两周，分析内膜面积和细胞含量。CuS@mSiO（2）-PEG/替罗非班和激光照射促进的替罗非班释放可减少ApoE（-/-）小鼠的新生内膜面积，从而限制了新生内膜的形成。与无替罗非班抑制的ApoE（-/-）小鼠相比，病变显示巨噬细胞和平滑肌细胞含量降低。因此，血小板整合素α IIb β 3在血管损伤后新生内膜形成中的作用通过使用近红外触发的纳米载体的替罗非班的受控释放在体内被成功地抑制，导致早期新生内膜形成的减少。这项研究还强调了血小板在血管重塑中的作用，并提供了一个新的靶点，即整合素α IIb β 3，用于抑制血管炎症过程中的新生内膜增生。
Platelets play an important role in the early stage of arterial remodeling after injury. Integrin GPIIb/III alpha (alpha IIb beta 3) regulates platelet activation in the inside-out and outside-in signaling pathways. The use of tirofiban, an integrin alpha IIb beta 3 inhibitor, in clinical therapy is limited by its short in vivo circulation time. Herein, a controlled drug-release system was formulated using CuS@mSiO(2)-PEG core-shell nanoparticles as near-infrared-triggered nanocarriers to release tirofiban on demand. The nanocarriers possessed good colloidal stability and very high loading efficiency for the integrin alpha IIb beta 3 inhibitor (14.5 wt% for tirofiban). Local application of alpha IIb beta 3 antagonist-tirofiban on an injured arterial wall inhibited platelet activation, which was accelerated by laser irradiation. Ex vivo platelet-promoted monocyte transmigration trans-well assays revealed decreased monocyte transmigration after platelet activation was inhibited by tirofiban. Two weeks after the wire-induced injury, the intimal area and cellular content were analyzed. The neointimal area was decreased in ApoE(-/-) mice with CuS@mSiO(2)-PEG/tirofiban and laser irradiation-promoted tirofiban release, which had limited the neointima formation. The lesions showed a decreased content of macrophages and smooth muscle cells compared with ApoE(-/-) mice without tirofiban inhibition. Therefore, the action of platelet-integrin alpha IIb beta 3 in neointima formation after vascular injury was successfully inhibited in vivo through the controlled release of tirofiban using a near-infrared-triggered nanocarrier, leading to the decrease of early-stage neointima formation. This study also emphasizes the role of platelets in vascular remodeling and provides a new target, namely integrin alpha IIb beta 3, for the inhibition of neointimal hyperplasia during vascular inflammation.