PT  - JOURNAL ARTICLE
AU  - Korin, Netanel
AU  - Kanapathipillai, Mathumai
AU  - Matthews, Benjamin D.
AU  - Crescente, Marilena
AU  - Brill, Alexander
AU  - Mammoto, Tadanori
AU  - Ghosh, Kaustabh
AU  - Jurek, Samuel
AU  - Bencherif, Sidi A.
AU  - Bhatta, Deen
AU  - Coskun, Ahmet U.
AU  - Feldman, Charles L.
AU  - Wagner, Denisa D.
AU  - Ingber, Donald E.
TI  - Shear-Activated Nanotherapeutics for Drug Targeting to Obstructed Blood Vessels
AID  - 10.1126/science.1217815
DP  - 2012 Aug 10
TA  - Science
PG  - 738--742
VI  - 337
IP  - 6095
4099  - http://science.sciencemag.org/content/337/6095/738.short
4100  - http://science.sciencemag.org/content/337/6095/738.full
SO  - Science2012 Aug 10; 337
AB  - Noting that platelets naturally migrate to narrowed blood vessels characterized by high fluid shear stress, Korin et al. (p. 738, published online 5 July; see the Perspective by Lavik and Ustin) developed a nanoparticle-based therapeutic that uses a similar targeting mechanism to deliver a drug to vessels obstructed by blood clots. Aggregates of nanoparticles coated with the clot-dissolving drug tPA (tissue plasminogen activator) were designed to fall apart and release the drug only when encountering high fluid shear stress. In preclinical models, the bio-inspired therapeutic dissolved clots and restored normal blood flow at lower doses than free tPA, suggesting that this localized delivery system may help reduce the risk of side effects such as excessive bleeding.Obstruction of critical blood vessels due to thrombosis or embolism is a leading cause of death worldwide. Here, we describe a biomimetic strategy that uses high shear stress caused by vascular narrowing as a targeting mechanism—in the same way platelets do—to deliver drugs to obstructed blood vessels. Microscale aggregates of nanoparticles were fabricated to break up into nanoscale components when exposed to abnormally high fluid shear stress. When coated with tissue plasminogen activator and administered intravenously in mice, these shear-activated nanotherapeutics induce rapid clot dissolution in a mesenteric injury model, restore normal flow dynamics, and increase survival in an otherwise fatal mouse pulmonary embolism model. This biophysical strategy for drug targeting, which lowers required doses and minimizes side effects while maximizing drug efficacy, offers a potential new approach for treatment of life-threatening diseases that result from acute vascular occlusion.