title: Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels.
abstract: 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.
authors: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
authors: Netanel
authors: N
authors: Korin
authors: Mathumai
authors: M
authors: Kanapathipillai
authors: Benjamin D
authors: BD
authors: Matthews
authors: Marilena
authors: M
authors: Crescente
authors: Alexander
authors: A
authors: Brill
authors: Tadanori
authors: T
authors: Mammoto
authors: Kaustabh
authors: K
authors: Ghosh
authors: Samuel
authors: S
authors: Jurek
authors: Sidi A
authors: SA
authors: Bencherif
authors: Deen
authors: D
authors: Bhatta
authors: Ahmet U
authors: AU
authors: Coskun
authors: Charles L
authors: CL
authors: Feldman
authors: Denisa D
authors: DD
authors: Wagner
authors: Donald E
authors: DE
authors: Ingber
mesh_terms: D000818:Animals; D040761:Biomimetic Materials; D001775:Blood Circulation; D016503:Drug Delivery Systems / Q000379:methods*; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D006439:Hemodynamics; D018056:Hemorheology; D019344:Lactic Acid; D008297:Male; D008638:Mesenteric Arteries; D008641:Mesenteric Vascular Occlusion / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D046210:Microfluidic Analytical Techniques; D008953:Models, Anatomic; D053758:Nanoparticles; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011655:Pulmonary Embolism / Q000188:drug therapy*; D013314:Stress, Mechanical; D013927:Thrombosis / Q000188:drug therapy* / Q000517:prevention & control; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*
chemical_list: D005343:Fibrinolytic Agents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D010959:Tissue Plasminogen Activator