ACS AMI:急性肺损伤治疗与药物递送研究取得新进展

2022-09-04 中科院上海药物所 中科院上海药物所

ALI的病因复杂,在全球范围内都有很高的发病率和致死率,造成了严重的社会负担和经济负担。

2022年8月10日,中国科学院上海药物研究所张继稳课题组与安徽中医药大学李泽庚课题组合作,在ACS Applied Materials & Interfaces上发表了题为“Antioxidant Biodegradable Covalent Cyclodextrin Frameworks as Particulate Carriers for Inhalation Therapy against Acute Lung Injury”的内封面研究论文。

该研究报道了一种对活性氧敏感的干粉吸入剂新型载体,与其递送的药物发挥协同作用,在急性肺损伤(ALI)的治疗与药物递送新辅料研究上取得进展。

ALI的病因复杂,在全球范围内都有很高的发病率和致死率,造成了严重的社会负担和经济负担。近年来,新冠肺炎的全球肆虐更引起了人们对肺部疾病的重视。提高ALI早期治疗效果、增加肺部药物递送效率,始终是肺损伤治疗药物递送研究的重点和难点。

由于肺脏独特的生理屏障,口服、注射等方式给药时,药物在肺部的滞留量低,难以达到理想效果。干粉吸入剂能直接将药物递送到病灶部位,提高药物疗效的同时,还能减少给药剂量、降低全身性毒副作用,是ALI治疗中的重要研究方向。对于不稳定、水难溶、难以微粉化的原料药,新型辅料与可吸入载体对这些药物的干粉吸入剂研发尤为重要。

目前常用的干粉吸入载体,如乳糖、甘露醇、聚乳酸-羟基乙酸共聚物等,存在微粒粒径不均一、降解速率慢、肺部递送效率低、无响应性等问题;而通过物理粉碎获得的原料药粉体往往粒径分布不够理想。因此,亟需开发新型辅料,研制粒径可控的干粉吸入载体,将药物装载在可吸入的载体中,以提高肺部递送效率及改善药物治疗效果。

氧化应激在肺部炎症性疾病的发生发展过程中起着非常重要的作用。炎症诱导的活性氧过量产生导致肺内氧化失衡,过量的活性氧则会进一步触发促炎介质的释放,使炎症反应持续并加剧,进而导致组织损伤。研究发现,在炎症性肺病中,呼吸道粘膜细胞的活性氧水平是健康组织的20倍。

基于此,张继稳研究团队设计了一种新型的活性氧敏感性新材料,共价环糊精骨架(OC-COF),作为干粉吸入剂的新型载体。该干粉吸入剂载体以环糊精金属有机骨架(CD-MOF)作为模板,草酰氯为交联剂,合成含有过氧草酸酯键的新载体OC-COF,其孔隙率高、能载药,粒径均一(2~3 μm)、可吸入;具有过氧化氢敏感性和良好的生物相容性、适宜的生物降解性,肺部递送后不会造成蓄积毒性。

新辅料OC-COF的合成和载药微粒LIG@OC-COF的制备及用于急性肺损伤治疗的示意图

将OC-COF负载上天然药物分子川芎嗪(LIG)后,制得LIG@OC-COF干粉吸入剂,其在肺部的沉积率较高。在活性载体材料OC-COF与LIG药物分子协同作用下,LIG@OC-COF在体外细胞水平和体内ALI动物模型上均表现出良好的抗氧化作用和抗炎作用,有效地提升了LIG的治疗效果,将LIG的给药剂量降低了5倍。

该活性氧敏感型干粉吸入剂新载体OC-COF的设计与应用,为ALI等肺部炎症性疾病的治疗提供了一种新的策略。

上海药物所博士生何思钰为本文的第一作者,设计、评价了新载体OC-COF;安徽中医药大学朱洁博士等完成了ALI的动物药效学评价;上海药物所与沈阳药科大学联合培养硕士研究生刘珺为本文封面的主要设计者;上海药物所张继稳研究员、安徽中医药大学李泽庚教授、朱洁博士为本文共同通讯作者。本研究得到了国家重点研发计划、国家自然科学基金区域联合创新发展项目和上海药物所研究基金的支持。

 

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    2022-09-24 ms2000001001023431

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    2022-09-05 yaanren
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    2022-09-05 tastas

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