Sequential Release Platform of Heparin and Urokinase with Dual Physical (NIR-II and Bubbles) Assistance for Deep Venous Thrombosis
Sequential Release Platform of Heparin and Urokinase with Dual Physical (NIR-II and Bubbles) Assistance for Deep Venous Thrombosis
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具有双重物理（NIR-II 和气泡）辅助的肝素和尿激酶顺序释放平台，用于治疗深静脉血栓
DOI：
10.1021/acsbiomaterials.0c01372
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发表时间：
2020-12-01
影响因子：
5.8
通讯作者：
Wang, Xiaolei
中科院分区：
文献类型：
--
作者：
Zhong, Zhiwei;Fang, Cuifu;Wang, Xiaolei
急性血栓造成的残疾甚至死亡仍然是对公共卫生的严重威胁。目前临床溶栓中以尿激酶（UK）为代表的传统药物，在用量过量时会产生出血的副作用。因此，迫切需要一种更有效、更安全的溶栓方法。本文以聚多巴胺（PDA）修饰的中空介孔硅（HMSNs）为载体，负载UK和未分级肝素（UH），通过双物理辅助（NIR-II和气泡）构建了多功能双药顺序释放溶栓平台（UK-UH@PDA@HMSNs）。在近红外- ii （NIR-II, 1064 nm, 1.0 W cm(-2)）激光的辅助下，PDA的光热效应可以促进UH的释放，从而加速血栓的溶解。随后，局部热疗效应可加速l -薄荷醇在hmsn中的相变，产生气泡促进UK的释放，从而实现两种溶栓药物的顺序释放。重要的是，该方法巧妙地克服了UK和UH不能直接结合的固有障碍。体内和体外实验证明，NIR-II刺激UK-UH@PDA@HMSNs的溶栓效率是单独UK的近3倍。综上所述，在限制药物剂量的前提下，提出的双物理辅助和顺序双药物递送系统显著提高了溶栓效率；因此，颅内出血死亡的风险可以从根本上降低。
Disability and even death from acute thrombosis remain a grave menace to public health. At present, the traditional drugs represented by urokinase (UK) in clinical thrombolysis can cause side effects of bleeding when the dosage is excess. Therefore, a more effective and safer method of thrombolysis is urgently needed. In this paper, a multifunctional dual-drug sequential release thrombolysis platform (UK-UH@PDA@HMSNs) consisting of polydopamine (PDA)-modified hollow mesoporous silicon (HMSNs) loading with UK and unfractionated heparin (UH) was constructed with a double physical assistance (NIR-II and bubbles). With the aid of near infrared-II (NIR-II, 1064 nm, 1.0 W cm(-2)) laser, the photothermal effect of PDA could be motivated to facilitate the UH release, thereby accelerating the dissolution of thrombus. Afterward, the local hyperthermia effect could expedite the phase transition of L-menthol in HMSNs to generate bubbles to promote the release of UK, thereby realizing the sequential release of two thrombolytic drugs. Importantly, this method deftly conquered the inherent obstacle that UK and UH cannot be combined directly. In vivo and in vitro experiments proved that the thrombolytic efficiency of UK-UH@PDA@HMSNs stimulated by NIR-II was nearly 3 times than that of UK alone. Collectively, the proposed dual physical assistance and sequential dual-drug delivery system significantly improved the efficiency of thrombolysis under the premise of limiting drug doses; the risk of death from intracranial hemorrhage thus could be decreased radically.