Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria, 3010, Australia.
NanoBiotechnology Laboratory, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Victoria, 3004, Australia.
Adv Healthc Mater. 2022 Nov;11(21):e2201151. doi: 10.1002/adhm.202201151. Epub 2022 Sep 13.
The safe administration of thrombolytic agents is a challenge for the treatment of acute thrombosis. Lipid-based nanoparticle drug delivery technologies present opportunities to overcome the existing clinical limitations and deliver thrombolytic therapy with enhanced therapeutic outcomes and safety. Herein, lipid cubosomes are examined as nanocarriers for the encapsulation of thrombolytic drugs. The lipid cubosomes are loaded with the thrombolytic drug urokinase-type plasminogen activator (uPA) and coated with a low-fouling peptide that is incorporated within a metal-phenolic network (MPN). The peptide-containing MPN (pep-MPN) coating inhibits the direct contact of uPA with the surrounding environment, as assessed by an in vitro plasminogen activation assay and an ex vivo whole blood clot degradation assay. The pep-MPN-coated cubosomes prepared with 22 wt% peptide demonstrate a cell membrane-dependent thrombolytic activity, which is attributed to their fusogenic lipid behavior. Moreover, compared with the uncoated lipid cubosomes, the uPA-loaded pep-MPN-coated cubosomes demonstrate significantly reduced nonspecific cell association (<10% of the uncoated cubosomes) in the whole blood assay, a prolonged circulating half-life, and reduced splenic uPA accumulation in mice. These studies confirm the preserved bioactivity and cell membrane-dependent release of uPA within pep-MPN-coated lipid cubosomes, highlighting their potential as a delivery vehicle for thrombolytic drugs.
溶栓药物的安全给药是急性血栓治疗的一个挑战。基于脂质的纳米颗粒药物递送技术为克服现有的临床限制提供了机会，可实现溶栓治疗的增强疗效和安全性。本文研究了脂质立方纳米载体作为包裹溶栓药物尿激酶型纤溶酶原激活剂(uPA)的纳米载体。脂质立方纳米载体负载溶栓药物 uPA，并通过低蛋白吸附肽包被，该肽整合在金属-酚醛网络(MPN)中。含肽的 MPN(pep-MPN)涂层通过体外纤溶酶原激活测定和体外全血凝块降解测定来抑制 uPA 与周围环境的直接接触。用 22wt%肽制备的 pep-MPN 包被的立方纳米载体表现出依赖于细胞膜的溶栓活性，这归因于其融合脂质行为。此外，与未包被的脂质立方纳米载体相比，负载 uPA 的 pep-MPN 包被的立方纳米载体在全血测定中表现出明显降低的非特异性细胞结合(低于未包被的立方纳米载体的 10%)、更长的循环半衰期和在小鼠中减少的脾脏 uPA 积累。这些研究证实了 pep-MPN 包被的脂质立方纳米载体中 uPA 的生物活性和细胞膜依赖性释放得到了保留，突出了它们作为溶栓药物递送载体的潜力。
