Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, P. R. China.
Key Laboratory for Meat Processing of Sichuan Province, School of Food and Biological Engineering, Chengdu University, Chengdu 610106, P. R. China.
ACS Appl Mater Interfaces. 2022 Aug 24;14(33):37553-37565. doi: 10.1021/acsami.2c11213. Epub 2022 Aug 10.
Antithrombotic therapy is confronted with short half-lives of thrombolytic agents and high bleeding risks. Challenges remain in the development of drug delivery systems for thorough destruction of thrombi and timely restoration of blood flow while minimizing side effects. Herein, polydopamine capsule-like micromotors with urokinase (uPA) loadings and Arg-Gly-Asp (RGD) grafts (r-u@PCM) were constructed using rod-shaped bacteria as the template, and one single opening was created on each capsule through bacterial ghost (BG) formation. Glucose oxidase and catalase were encapsulated in the large cavity of microcapsules, and their successive oxidation of glucose produced O bubbles, which ejected out through the single opening to propel the motion of r-u@PCM. In vitro targeting testing of r-u@PCM shows significant higher accumulations on the activated platelets than those without RGD grafts (u@PCM, 7 folds) or without enzyme loadings (r-u@PC, 11 folds). Compared with the major distribution of r-u@PC on the clot surface, r-u@PCM efficiently penetrates into clots with dense fibrin networks, and near-infrared (NIR) irradiation (r-u@PCM/NIR) promotes thrombus infiltration through increasing uPA release and thermolysis of the networks. Pharmacokinetic study shows that the loading of uPA in r-u@PCM extends the terminal half-life from 24 min to 5.5 h and the bioavailability increased 13 times. In a hindlimb venous thrombosis model, r-u@PCM/NIR treatment promotes uPA accumulations in thrombi and disrupts all the thrombi after 8 h with a full recovery of blood flows. Effective thrombolysis is also achieved even after reducing the uPA dose 5 times. Thus, this is the first attempt to fabricate rod-shaped microcapsule motors through a biologically derived method, including bacterial templating and BG formation-induced opening generation. r-u@PCM/NIR treatment promotes thrombolysis through the photothermal effect, self-propelled infiltration into thrombi, and accelerated local release of uPA, providing a prerequisite for reducing uPA dose and bleeding side effects.
抗血栓治疗面临溶栓药物半衰期短和出血风险高的挑战。在开发药物输送系统以彻底破坏血栓并及时恢复血流的同时，最大限度地减少副作用，仍然存在挑战。在此，使用棒状细菌作为模板构建了载尿激酶（uPA）和精氨酸-甘氨酸-天冬氨酸（RGD）接枝的聚多巴胺胶囊状微马达（r-u@PCM），并通过细菌幽灵（BG）形成在每个胶囊上创建了一个单一开口。葡萄糖氧化酶和过氧化氢酶被包裹在微胶囊的大腔室中，它们连续氧化葡萄糖产生 O 泡，通过单一开口喷出，推动 r-u@PCM 的运动。r-u@PCM 的体外靶向测试表明，与没有 RGD 接枝（u@PCM，7 倍）或没有酶负载（r-u@PC，11 倍）的微马达相比，r-u@PCM 在激活的血小板上的积累显著更高。与 r-u@PC 主要分布在血栓表面相比，r-u@PCM 能够有效地穿透致密纤维蛋白网络的血栓，近红外（NIR）照射（r-u@PCM/NIR）通过增加 uPA 释放和网络的热解促进血栓渗透。药代动力学研究表明，r-u@PCM 中 uPA 的负载将末端半衰期从 24 分钟延长至 5.5 小时，生物利用度增加了 13 倍。在后肢静脉血栓形成模型中，r-u@PCM/NIR 治疗可促进 uPA 在血栓中的积累，并在 8 小时后破坏所有血栓，血流完全恢复。即使将 uPA 剂量减少 5 倍，也能实现有效的溶栓。因此，这是首次尝试通过生物衍生方法制造棒状微胶囊马达，包括细菌模板和 BG 形成诱导的开口生成。r-u@PCM/NIR 治疗通过光热效应、自身推进渗透到血栓中以及加速局部释放 uPA 来促进溶栓，为减少 uPA 剂量和出血副作用提供了前提。
