An activated-platelet-sensitive nanocarrier enables targeted delivery of tissue plasminogen activator for effective thrombolytic therapy

• Published in: Journal of controlled release Vol. 300; pp. 1 - 12
• Main Authors: Huang, Yu, Yu, Li, Ren, Jie, Gu, Boram, Longstaff, Colin, Hughes, Alun D., Thom, Simon A., Xu, Xiao Yun, Chen, Rongjun
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 28.04.2019
• Subjects: Activated platelet; adverse effects; Animals; blood coagulation; Blood Platelets; Controlled release mechanism; drugs; encapsulation; fibrin; Fibrinolytic Agents - administration & dosage; GPIIb-IIIa integrin; Liposome; Liposomes; membrane fusion; nanocarriers; Nanoparticles - administration & dosage; Sheep; t-plasminogen activator; Targeted delivery; Thrombolysis; Thrombolytic Therapy - methods; thrombosis; Thrombosis - metabolism; Tissue plasminogen activator; Tissue Plasminogen Activator - administration & dosage; Controlled release mechanism; Activated platelet; Tissue plasminogen activator; Targeted delivery; Liposome; Thrombolysis; GPIIb-IIIa integrin
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2019.02.033

It remains a major challenge to develop a selective and effective fibrinolytic system for thrombolysis with minimal undesirable side effects. Herein, we report a multifunctional liposomal system (164.6 ± 5.3 nm in diameter) which can address this challenge through targeted delivery and controlled release of tissue plasminogen activator (tPA) at the thrombus site. The tPA-loaded liposomes were PEGylated to improve their stability, and surface coated with a conformationally-constrained, cyclic arginine–glycine–aspartic acid (cRGD) to enable highly selective binding to activated platelets. The in vitro drug release profiles at 37 °C showed that over 90% of tPA was released through liposomal membrane destabilization involving membrane fusion upon incubation with activated platelets within 1 h, whereas passive release of the encapsulated tPA in pH 7.4 PBS buffer was 10% after 6 h. The release of tPA could be readily manipulated by changing the concentration of activated platelets. The presence of activated platelets enabled the tPA-loaded, cRGD-coated, PEGylated liposomes to induce efficient fibrin clot lysis in a fibrin-agar plate model and the encapsulated tPA retained 97.4 ± 1.7% of fibrinolytic activity as compared with that of native tPA. Furthermore, almost complete blood clot lysis was achieved in 75 min, showing considerably higher and quicker thrombolytic activity compared to the tPA-loaded liposomes without cRGD labelling. These results suggest that the nano-sized, activated-platelet-sensitive, multifunctional liposomes could facilitate selective delivery and effective release of tPA at the site of thrombus, thus achieving efficient clot dissolution whilst minimising undesirable side effects. [Display omitted] •Activated-platelet-sensitive nanoliposomes with encapsulation of tPA was developed.•The nanoliposomes had a highly specific binding to activated platelets.•Efficient tPA release was induced by activated platelets through membrane fusion.•The nanoliposomes enabled a selective and efficient lysis of fibrin and blood clots.