(556e) Cell Membrane-Derived Nanoscale Systems for Delivery of Thrombolytic Therapeutics

Designing drug delivery systems that evade an individual’s immune system and reach their target is crucial for its success. By utilizing naturally derived materials instead of synthetic, there is a higher probability that the particles will be able to reach their target. The nanoparticles can reach a higher level of complexity using a top-down approach, unattainable using a bottom up approach. Therefore, making a drug delivery platform using isolated red blood cell membranes as a starting material increases the likelihood it will inherit properties of the original source, such as long circulation time, biocompatibility and biodegradability.

Cardiovascular diseases are the leading cause of death worldwide [1]. Stroke, myocardial ischemia and venous thromboembolism, the main cardiovascular disorders, are all initiated by the formation of a thrombus in a blood vessel [2]. Currently, there is only one Food and Drug Administration (FDA) approved treatment for acute ischemic stroke; tissue plasminogen activator (tPA) [3]. Unfortunately, tPA has several limitations that reduce the potential of this therapeutic: a short half-life of 4 to 8 minutes and potential bleeding complications due to a lack of specificity to the target blood clot [3].

One step to increase the therapeutic index of tPA is to specifically target clots through activated platelets. During activation, platelets change their confirmation and several integrins are activated. The most abundant upregulated integrin is αIIbβ3 [4]. Studies have shown that the peptide cyclic arginine glycine aspartic acid (cRGD) can bind to αIIbβ3, on the surface of activated platelets [5]. Liposomes [6,7] and a chitosan based nanocoacervate system [8] both decorated with cRGD have proven to enhance thrombolysis. Therefore, when designing a thrombolytic system, incorporating cRGD can produce a clot targeting system.

By loading tPA into red blood cell derived vesicles (RBCVs) and functionalizing cRGD on the surface, a more complex clot specific thrombolytic nanoparticle can be produced. Specific binding to activated platelets was observed using confocal microscopy and flow cytometry for cRGD-RBCVs. tPA loaded RBCVs with and without cRGD present showed fibrinolysis and thrombolysis in static models. Preliminary results also showed comparable thrombolysis for free tPA and RBCVs with and without cRGD under physiological flow conditions. The presence of cRGD showed an enhanced targeting of thrombi. These results suggest that a clot specific naturally derived nanoparticle could be produced and selectively delivery tPA to blood clots.

References:

1. Ritchie, H., Spooner, F. & Roser, M. 2018. Causes of death. OurWorldInData.org.
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3. Marshall, R. S. 2015. Progress in Intravenous Thrombolytic Therapy for Acute Stroke. JAMA Neurology, 72, 928-934.
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5. Srinivasan, R., Marchant, R. E. & Gupta, A. S. 2010. In vitro and in vivo platelet targeting by cyclic RGD-modified liposomes. J Biomed Mater Res A, 93, 1004-15.
6. Huang, Y., Yu, L., Ren, J., Gu, B., Longstaff, C., Hughes, A. D., Thom, S. A., Xu, X. Y. & Chen, R. 2019. An activated-platelet-sensitive nanocarrier enables targeted delivery of tissue plasminogen activator for effective thrombolytic therapy. J Control Release, 300, 1-12.
7. Huang, Y., Gu, B., Salles-Crawley, I., Taylor, K. A., Yu, L., Ren, J., Liu, X., Emerson, M., Longstaff, C., Hughes, A. D., Thom, S. A., Xu, X. Y. & Chen, R. 2021. Fibrinogen-mimicking, multiarm nanovesicles for human thrombus-specific delivery of tissue plasminogen activator and targeted thrombolytic therapy. Sci Adv, 7.
8. Huang, Y., Jiang, J., Ren, J., Guo, Y., Zhao, Q., Zhou, J., Li, Y. & Chen, R. 2022. A Fibrinogen-Mimicking, Activated-Platelet-Sensitive Nanocoacervate Enhances Thrombus Targeting and Penetration of Tissue Plasminogen Activator for Effective Thrombolytic Therapy. Adv Healthc Mater, 11, e2201265.