Editors' ChoiceNanomedicine

Who You Gonna Call? Clot-Busters!

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Science Translational Medicine  18 Jul 2012:
Vol. 4, Issue 143, pp. 143ec128
DOI: 10.1126/scitranslmed.3004592

Thrombolytic drugs are a lifeline for many patients with acute myocardial infarction and stroke; however, these drugs come with a risk of unwanted bleeding because they distribute throughout the entire body and inhibit clotting systemwide. A new drug-delivery strategy that relies on shear stress may mitigate clotting risks by activating the clot-busters only when needed.

Korin et al. created 180-nm-large nanoparticles from poly(lactic-co-glycolic acid) and attached the U.S. Food and Drug Administration–approved fibrinolytic agent tPA to the particles’ surfaces. The drug-loaded nanoparticles were then clumped together to form 4-µm-large aggregates, about the size of red blood cells. These larger units were stable in circulation in mice with either arterial thrombosis or pulmonary embolism, until they encountered increased shear stress—for example, in arteries with clots blocking blood flow. The authors observed that if the shear stress reached a certain threshold, the larger microparticles disassembled, setting free numerous nanoparticles carrying the clot-busting drug. When dispersed, the thrombolytic activity of tPA increased nearly 100-fold as compared with free tPA.

This approach by Korin and colleagues limits the drug’s action to the site where it is needed and also increases its efficiency. Clinically, reducing the tPA dose by two orders of magnitude likely reduces the risk of excessive bleeding. The reduced bleeding risk may even expand the patient population and time window deemed safe to receive thrombolytic treatment after stroke. Despite promising preclinical results, large-animal and toxicity studies will be needed to make these clot-buster microparticles on-call in the clinic.

N. Korin et al., Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels. Science, 5 July 2012 (10.1126/science.1217815). [Abstract]

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