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基于金纳米粒-白蛋白融合蛋白递送系统的非药物靶向溶栓策略

Drug-free targeted thrombolytic strategy based on gold nanoparticles-loaded human serum albumin fusion protein delivery system
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摘要 血栓是导致心肌梗塞、脑卒中等心血管疾病的主要因素之一。纤维蛋白溶酶类抗血栓药物虽然已被广泛应用于临床,但依然受到治疗窗口狭窄、半衰期短、易失活和因非靶向性造成的异常出血等不良反应的限制。因此,有效地将溶栓物质靶向输送到血栓部位并将不良反应降至最低至关重要。基于人血清白蛋白(human serum albumin,HSA)在血液中的长循环效果和优异的载药特性,本研究运用基因工程技术在HSA的N末端融合一段能靶向血栓部位的功能肽(P-selectin binding peptide,PBP),经毕赤酵母表达并纯化得到具有血栓靶向功能的白蛋白融合蛋白。该融合蛋白包载金纳米粒子(gold nanoparticles,Au NPs)后能够形成均一稳定的纳米粒(PBP-HSA@Au),粒径为17.7±1.0 nm,zeta电位为-11.3±0.2 mV。细胞毒性和溶血实验证明PBP-HSA@Au生物相容性好,血小板靶向实验表明PBP的引入赋予了PBP-HSA@Au血栓靶向能力,近红外光(near infrared ray,NIR)照射后,PBP-HSA@Au能将光能快速转化为热能进而破坏纤维蛋白,表现出优异的溶栓效果。本研究设计的白蛋白融合蛋白递送系统为血栓治疗提供了一种精准、快速、非药物的治疗策略,该体系设计简单、生物相容性高,具有较强的临床应用性。研究涉及的所有动物实验均按照江南大学动物实验伦理委员会批准的方案执行[JN.No20230915S0301015(423)]。 Thrombus is a major factor leading to cardiovascular diseases such as myocardial infarction and stroke.Although fibrinolytic anti-thrombotic drugs have been widely used in clinical practice,they are still limited by narrow therapeutic windows,short half-lives,susceptibility to inactivation,and abnormal bleeding caused by non-targeting.Therefore,it is crucial to effectively deliver thrombolytic agents to the site of thrombus with minimal adverse effects.Based on the long blood circulation and excellent drug-loading properties of human serum albumin(HSA),we employed genetic engineering techniques to insert a functional peptide(P-selectin binding peptide,PBP)which can target the thrombus site to the N-terminus of HSA.The fusion protein was expressed using Pichia pastoris and purified by Ni-chelating affinity chromatography.After being loaded with gold nanoparticles(Au NPs),the fusion protein formed homogeneous and stable nanoparticles(named as PBP-HSA@Au)with a diameter of 17.7±1.0 nm and a zeta potential of-11.3±0.2 mV.Cytotoxicity and hemolysis tests demonstrated the superb biocompatibility of PBP-HSA@Au.Platelet-targeting experiments confirmed the thrombus-targeting ability conferred by the introduction of PBP into PBP-HSA@Au.Upon near-infrared ray(NIR)irradiation,PBP-HSA@Au rapidly converted light energy into heat,thereby disrupting fibrinogen and exhibiting outstanding thrombolytic efficacy.The designed HSA fusion protein delivery system provides a precise,rapid,and drug-free treatment strategy for thrombus therapy.This system is characterized by its simple design,high biocompatibility,and strong clinical applicability.All animal experiments involved in this study were carried out under the protocols approved by the Animal Experiment Ethics Committee of Jiangnan University[JN.No20230915S0301015(423)].
作者 鲁津津 刘春 孙思荣 陈敬华 高敏 LU Jin-jin;LIU Chun;SUN Si-rong;CHEN Jing-hua;GAO Min(School of Life Sciences and Health Engineering,Jiangnan University,Wuxi 214122,China)
出处 《药学学报》 CAS CSCD 北大核心 2024年第2期455-463,共9页 Acta Pharmaceutica Sinica
基金 国家自然科学基金资助项目(32101072) 江苏省自然科学基金项目(BK20210473)。
关键词 血栓 光热治疗 靶向溶栓 融合蛋白 人血清白蛋白 金纳米粒 thrombus photothermal therapy targeted thrombolysis fusion protein human serum albumin gold nanoparticle
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