Abstract Number: PB0426
Meeting: ISTH 2021 Congress
Background: We reported that tissue plasminogen activator (tPA) immobilized on magnetically powered microwheels can increase the rate of fibrinolysis by five-fold compared to therapeutic concentrations of tPA (Tasci et al., Small, 2017). This rate increase is due to the accumulation and penetration of microwheels into a thrombus. However, at these high tPA concentrations, the availability of plasminogen becomes the rate-limiting step in fibrinolysis.
Aims: To co-deliver tPA and plasminogen on microwheels to overcome plasminogen depletion and hasten fibrinolysis.
Methods: Mesoporous silica nanoparticles (MSN) and tPA were coupled to 1 µm superparamagnetic beads (DynabeadsTM) via biotin-streptavidin binding (Fig. 1). The MSN were loaded with plasminogen and their release kinetics were measured by spectroscopy. The MSN decorated beads were subject to a rotating magnetic field (8 mT, 10 Hz) to induce the self-assembly of wheel-like disks that rolling. Fibrinolysis of a plasma clot (4.5 nM thrombin, 20 mM CaCl2) was measured by optical microscopy.
Results: Plasminogen-tPA-beads accumulated at the clot and were estimated to achieve a local tPA and plasminogen concentrations of 40 nM and 2.5 µM, respectively. Pgn-tPA-microwheels driven in a direct line motion into the plasma clot, lyse fibrin at a rate of 13.6 ± 1.8 µm/min compared to 2.5 ± 0.7 µm/min for tPA-microwheels, and 0.4 ± 0.1 µm/min for 40 nM tPA (Fig. 2). Pgn-tPA-microwheels driven in corkscrew motion penetrate into clot, further accelerating lysis to 21.0 ± 2.9 µm/min (Fig. 2).
Conclusions: The co-delivery of plasminogen and tPA on microwheels overcomes substrate limited fibrinolysis, resulting in over a five-fold increase in lysis rate compared to tPA alone. When combined with a corkscrew motion, wherein microwheels can bore their way into a clot, the lysis rate is further enhanced. These data establish the utility of combining enzyme and substrate delivery as a thrombolysis strategy.
To cite this abstract in AMA style:Disharoon D, Marr D, Neeves K. Co-delivery of Tissue Plasminogen Activator and Plasminogen Using Magnetically Powered Microwheels [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/co-delivery-of-tissue-plasminogen-activator-and-plasminogen-using-magnetically-powered-microwheels/. Accessed May 16, 2022.
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