title: Celecoxib Nanoparticles for Therapeutic Angiogenesis.
abstract: Controllable induction of blood vessel formation (angiogenesis) presents an important therapeutic goal in ischemic diseases and is also beneficial in various normal physiological processes. In this study, we have shown that nanoparticles of celecoxib, a lipophilic nonsteroidal anti-inflammatory drug, effectively evoke therapeutic angiogenesis in animal models, in both normal and ischemic organs. Celecoxib is widely considered to inhibit angiogenesis, although a recent study suggests that it can instead promote blood vessel growth in cancer cell lines. The hydrophobic nature of this drug necessitates its administration in nanoparticulate form in order to elicit a perceivable pharmacological response. We developed a facile method for nanoparticle formation by solvent extraction from microemulsions in supercritical carbon dioxide. This method exploits a spontaneous formation of nanometric domains within the microemulsion system and their rapid conversion to nanoparticles by supercritical fluid. The resultant nanoparticles were administered subcutaneously to mice in a biocompatible hydrogel, and caused a 4-fold increase in blood vessel count in normally perfused skin compared with drug-free particles. They were at least as effective in inducing angiogenesis as nanoparticles of deferoxamine, a well-established neovascularization promoter. Next, we evaluated their effect on ischemic tissues in murine model of myocardial infarction. We found that celecoxib nanoparticles were able to induce a significant vascularization of ischemic myocardium and hamper the progression of heart failure, which points toward a new approach for treating ischemia.
authors.affiliation: Department of Chemistry, Stanford University , Stanford, California 94305-5080, United States.
authors.forename: Katherine
authors.initials: K
authors.lastname: Margulis
authors.affiliation: Department of Cardiothoracic Surgery, Falk Cardiovascular Research Center, Stanford University School of Medicine , Stanford, California 94305-5407, United States.
authors.forename: Evgenios A
authors.initials: EA
authors.lastname: Neofytou
authors.affiliation: Department of Cardiothoracic Surgery, Falk Cardiovascular Research Center, Stanford University School of Medicine , Stanford, California 94305-5407, United States.|Heart and Vascular Center, NorthBay Medical Center ,1200 B. Gale Wilson Boulevard, Fairfield, California 94533, United States.
authors.forename: Ramin E
authors.initials: RE
authors.lastname: Beygui
authors.affiliation: Department of Chemistry, Stanford University , Stanford, California 94305-5080, United States.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Zare
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage / Q000737:chemistry; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects; D000068579:Celecoxib / Q000008:administration & dosage* / Q000737:chemistry; D004195:Disease Models, Animal; D006801:Humans; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D018919:Neovascularization, Physiologic / Q000187:drug effects*
chemical_list: D043925:Angiogenesis Inducing Agents; D000068579:Celecoxib
keywords: COX-2 inhibitors; angiogenesis; celecoxib; deferoxamine; ischemia; mass spectrometry imaging; nanoparticles