Abstract
Thrombolytic therapy by infusion of analogs of tissue plasminogen activator (tPA),
other recombinant-based plasminogen activators (e.g., alteplase, reteplase, and tenecteplase),
streptokinase, and urokinase (uPA) aims to clear blood clots and restore blood flow
in occluded blood vessels. Thrombolytic therapy is thereby frequently used in patients
with myocardial infarction, stroke, peripheral arterial disease, and massive pulmonary
embolism. The leading drawbacks of thrombolysis and associated therapy are represented
by a significant burden of inefficacy combined with a high risk of bleeding complications.
Recent advances in understanding the complex pathophysiology of vascular occlusions,
combined with important technological innovations, are notably improving the therapeutic
armamentarium against thrombotic and occlusive disorders. Most of the past and ongoing
research in this area have entailed thrombus-targeted fibrinolytic therapy with either
tissue- and fibrin-specific immunoconjugates, fibrinolytic-bearing erythrocytes, or
fibrinolytic-bearing nanoparticles. The greatest advantages of thrombus-targeted fibrinolysis,
especially with biocompatible nanoparticles, are represented by their preferential
localization within developing clots, effectual thrombolysis and enhanced safety due
to substantial reduction of the dosage of fibrinolytic agents, and reduced onstream
adverse effects. These positive biological features, coupled with minimal extravasation
and favorable clearance from the circulation, appear advantageous for obtaining more
efficacious and durable thrombolytic effects while concomitantly lowering or even
eliminating the risk of systemic bleeding complications that typically accompany the
injection of free or soluble plasminogen activators. Although an ideal technique has
not been definitely established so far, tPA-bearing nanoparticles exhibiting affinity
for clot-specific cells and biomolecules coupled with low-frequency ultrasound seem
to bear the greatest advantages for prevention and therapy of acute thrombosis, with
the possibility to specifically guide and concentrate the thrombolytic agent at the
site of pathologic thrombi and clear preexisting clots by a series of mechanisms combining
mechanical stress and increased penetration and effectiveness of the drugs employed.
Keywords
thrombosis - fibrinolysis - nanosphere - thrombolysis - biotechnology
