Reprogramming the rapid clearance of thrombolytics by nanoparticle encapsulation and anchoring to circulating red blood cells

• Published in: Journal of controlled release Vol. 329; pp. 148 - 161
• Main Authors: Singh, Mohit Pratap, Flynn, Nicholas H., Sethuraman, Sri Nandhini, Manouchehri, Saeed, Ritchey, Jerry, Liu, Jing, Ramsey, Joshua D., Pope, Carey, Ranjan, Ashish
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.01.2021
• Subjects: Erythrocyte; Glycophorin A; Nanoparticle; Polymer; Red blood cell; Ter119; Erythrocyte; Glycophorin A; Red blood cell; Polymer; Ter119; Nanoparticle
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2020.11.034

Rapid clearance of thrombolytics from blood following intravenous injection is a major clinical challenge in cardiovascular medicine. To overcome this barrier, nanoparticle (NP) based drug delivery systems have been reported. Although superior than conventional therapy, a large proportion of the injected NP is still cleared by the reticuloendothelial system. Previously, we and others showed that ex vivo attachment of bioscavengers, thrombolytics, and nanoparticles (NPs) to glycophorin A receptors on red blood cells (RBCs) improved the blood half-life. This is promising, but ex-vivo approaches are cumbersome and challenging to translate clinically. Here, we developed a novel Ter119-polymeric NP containing tissue plasminogen activator for on-demand targeting of GPA receptors in vivo. Upon intravenous injection, the Ter119-NPs achieved remarkable RBC labeling efficiencies (>95%), resulting in marked enhancement of blood residence time of tPA from minutes to several days without any morphological, hematological, and histological complications. Our approach of RBC labeling with the NPs also prevented reticuloendothelial detections and the activations of innate and adaptive immune system. Data suggest that real-time targeting of therapeutics to RBC with NPs can potentially improve outcomes and reduce complications against a variety chronic disease. [Display omitted] •Real-time targeting of circulatory erythrocytes with nanoparticles can be attained using the Ter119 antibody.•Ter119 nanoparticles prolong circulation half-life of thrombolytics from min to days.•Ter119 nanoparticles do not influence hematological parameters and are safe to use in murine models.