Zhong Zhiwei, Fang Cuifu, He Shasha, Zhang Teng, Liu Shichen, Zhang Yini, Wang Qingqing, Ding Xingwei, Zhou Weimin, Wang Xiaolei
Department of Vascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.
Department of Endocrinology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
ACS Biomater Sci Eng. 2020 Dec 14;6(12):6790-6799. doi: 10.1021/acsbiomaterials.0c01372. Epub 2020 Nov 17.
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) 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. and 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.
急性血栓形成导致的残疾甚至死亡仍然是对公众健康的严重威胁。目前，临床溶栓中以尿激酶（UK）为代表的传统药物在剂量过大时会引起出血副作用。因此，迫切需要一种更有效、更安全的溶栓方法。本文构建了一种多功能双药序贯释放溶栓平台（UK-UH@PDA@HMSNs），该平台由负载UK和普通肝素（UH）的聚多巴胺（PDA）修饰的中空介孔硅（HMSNs）组成，并具有双重物理辅助（近红外二区光和气泡）。借助近红外二区（NIR-II，1064 nm，1.0 W/cm）激光，可激发PDA的光热效应以促进UH释放，从而加速血栓溶解。随后，局部热疗效应可加速HMSNs中L-薄荷醇的相变以产生气泡，促进UK释放，从而实现两种溶栓药物的序贯释放。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。实验证明，NIR-II刺激的UK-UH@PDA@HMSNs的溶栓效率几乎是单独使用UK的3倍。总的来说，所提出的双重物理辅助和双药序贯递送系统在限制药物剂量的前提下显著提高了溶栓效率；从而可从根本上降低颅内出血导致死亡的风险。
