Drug delivery under cover of erythrocytes extends drug half-life: A thrombolytic targeting therapy utilizing microenvironment-responsive artificial polysaccharide microvesicles. Carbohydrate Polymers 2024, 343, 122505.
Published in Carbohydrate Polymers, 2024
The development of thrombolytic drug carriers capable of thrombus-targeting, prolonged circulation time, intelligent responsive release, and the ability to inhibit thrombotic recurrences remains a promising but significant challenge. To tackle this, an artificial polysaccharide microvesicle drug delivery system (uPA-CS/HS@RGD-ODE) was constructed. It is composed of cationic chitosan and anionic heparin assembled in a layer by layer structure, followed by surface modification using RGD peptide and 2-(N-oxide-N,N-diethylamino) ethylmethacrylate (ODE) before encapsulation of urokinase-type plasminogen activator (uPA). The effect of chitosan on the basic performances of uPA-CS/HS@RGD-ODE was estimated. The in vitro results suggest the uPA carrier, CS/HS@RGD-ODE, displayed outstanding targeting specific to activated platelets (61 %) and microenvironment-responsiveness at pH 6.5, facilitating thrombus-targeting and a controlled drug release, respectively. Most importantly, in vivo experiment suggests ODE from uPA-CS/HS@RGD-ODE substantially extends the half-life of uPA (120 min), as uPA-CS/HS@RGD-ODE can adhere onto erythrocytes and deliver uPA under cover of erythrocytes enabling a prolonged circulation time in the bloodstream. Further tail vein and abdominal aorta thrombosis models confirmed uPA-CS/HS@RGD-ODE exhibited superior targeting and thrombolysis capabilities compared to systemic administration of free uPA. To the knowledge of authors, this may be the first study to develop new drug carriers for delivery of thrombolytic drugs under the cover of erythrocytes for extended drug half-lives.