Delivery of thrombolytic therapy using rod-shaped plant viral nanoparticles decreases the risk of hemorrhage

Abstract

Cardiovascular thrombotic disease is an underlying cause of stroke, myocardial infarction and pulmonary embolism - some of the leading causes of death worldwide. Reperfusion therapy with anticoagulant, antiplatelet, and fibrinolytic agents has significantly reduced early mortality and morbidity from acute myocardial infarction and stroke. Nevertheless, bleeding side effects (e.g., intracranial hemorrhage) associated with the anti-thrombotic therapy can offset its benefits and limit its applicability to strictly defined short therapeutic windows. We have previously shown that elongated plant virus based nanoparticles can target cardiovascular thrombi and exhibited their utility for the delivery of streptokinase in an ex vivo model of thrombosis. Herein, we build upon our previous findings and demonstrate plant viral delivery of the current standard-of-care tissue plasminogen activator (tPA). Studies on a pre-clinical mouse model of arterial thrombosis indicate that while the therapeutic efficacy of free tPA and tPA-conjugated TMV are similar, the safety profile of the tPA-TMV formulation is improved, i.e. administration of the latter has less impact on hemostasis as demonstrated by decreased bleeding time. Thus, our data suggest that TMV-based delivery of thrombolytic therapies could be a promising and safer alternative to reperfusion therapy with the tPA.

Viral nanoparticles for drug delivery, imaging, immunotherapy, and theranostic applications

“…Illumination of the right carotid artery of C57BL/6 mice with a 540 nm green laser produced thrombi. TMV-tPA was delivered via tail vein injection and maintained its efficacy and performed similarly to free tPA; more importantly, the TMV-tPA formulations displayed an improved safety profile indicated by a decreased average bleeding time of 429 s to 858 by the free tPA [94]. The decreased bleeding time is of noteworthy importance as tPA does not specifically congregate at the diseased area, and systemic administration can lead to life-threatening systemic hemorrhaging and/or angioedema [95].…”

Application of Plant Viruses in Biotechnology, Medicine, and Human Health

“…Functioned efficiently equivalent to free tPA and enhanced safety profile as shown by diminished average bleeding times and therefore applicable for cardiovascular therapy [81] (b) Applications of TMV in cancer treatment…”

Advances in Nanomaterials for Injured Heart Repair

“…Subsequently, through intramyocardial injection and magnetic guidance, the nanovesicles successfully promote early transfer from the inflammation promotion phase to the reparative phase, significantly alleviate apoptosis and fibrosis, and enhance the healing of cardiac function. In addition, Pitek et al indicated that one plant viral NPs can also target thrombi and exhibited their capability for streptokinase delivery in thrombosis model animals ( Pitek et al, 2018 ).…”