title: Development and in vivo efficacy of targeted polymeric inflammation-resolving nanoparticles.
abstract: Excessive inflammation and failed resolution of the inflammatory response are underlying components of numerous conditions such as arthritis, cardiovascular disease, and cancer. Hence, therapeutics that dampen inflammation and enhance resolution are of considerable interest. In this study, we demonstrate the proresolving activity of sub-100-nm nanoparticles (NPs) containing the anti-inflammatory peptide Ac2-26, an annexin A1/lipocortin 1-mimetic peptide. These NPs were engineered using biodegradable diblock poly(lactic-co-glycolic acid)-b-polyethyleneglycol and poly(lactic-co-glycolic acid)-b-polyethyleneglycol collagen IV-targeted polymers. Using a self-limited zymosan-induced peritonitis model, we show that the Ac2-26 NPs (100 ng per mouse) were significantly more potent than Ac2-26 native peptide at limiting recruitment of polymononuclear neutrophils (56% vs. 30%) and at decreasing the resolution interval up to 4 h. Moreover, systemic administration of collagen IV targeted Ac2-26 NPs (in as low as 1 µg peptide per mouse) was shown to significantly block tissue damage in hind-limb ischemia-reperfusion injury by up to 30% in comparison with controls. Together, these findings demonstrate that Ac2-26 NPs are proresolving in vivo and raise the prospect of their use in chronic inflammatory diseases such as atherosclerosis.
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nazila
authors.initials: N
authors.lastname: Kamaly
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Fredman
authors.forename: Manikandan
authors.initials: M
authors.lastname: Subramanian
authors.forename: Suresh
authors.initials: S
authors.lastname: Gadde
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Pesic
authors.forename: Louis
authors.initials: L
authors.lastname: Cheung
authors.forename: Zahi Adel
authors.initials: ZA
authors.lastname: Fayad
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
authors.forename: Omid Cameron
authors.initials: OC
authors.lastname: Farokhzad
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017305:Annexin A1 / Q000494:pharmacology* / Q000627:therapeutic use*; D024141:Collagen Type IV / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000627:therapeutic use*; D036103:Nanotechnology / Q000379:methods*; D009504:Neutrophils / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use*; D010538:Peritonitis / Q000188:drug therapy*; D015427:Reperfusion Injury / Q000188:drug therapy*
chemical_list: D017305:Annexin A1; D024141:Collagen Type IV; D010455:Peptides; C096153:annexin A1 peptide (2-26)