title: CXCL1 microspheres: a novel tool to stimulate arteriogenesis.
abstract: BACKGROUND
  After arterial occlusion, diametrical growth of pre-existing natural bypasses around the obstruction, i.e. arteriogenesis, is the body's main coping mechanism. We have shown before that continuous infusion of chemokine (C-X-C motif) ligand 1 (CXCL1) promotes arteriogenesis in a rodent hind limb ischemia model.
  
  
  OBJECTIVE
  For clinical translation of these positive results, we developed a new administration strategy of local and sustained delivery. Here, we investigate the therapeutic potential of CXCL1 in a drug delivery system based on microspheres.
  
  
  METHODS
  We generated poly(ester amide) (PEA) microspheres loaded with CXCL1 and evaluated them in vitro for cellular toxicity and chemokine release characteristics. In vivo, murine femoral arteries were ligated and CXCL1 was administered either intra-arterially via osmopump or intramuscularly encapsulated in biodegradable microspheres. Perfusion recovery was measured with Laser-Doppler.
  
  
  RESULTS
  The developed microspheres were not cytotoxic and displayed a sustained chemokine release up to 28 d in vitro. The amount of released CXCL1 was 100-fold higher than levels in native ligated hind limb. Also, the CXCL1-loaded microspheres significantly enhanced perfusion recovery at day 7 after ligation compared with both saline and non-loaded conditions (55.4 ± 5.0% CXCL1-loaded microspheres versus 43.1 ± 4.5% non-loaded microspheres; n = 8-9; p < 0.05). On day 21 after ligation, the CXCL1-loaded microspheres performed even better than continuous CXCL1 administration (102.1 ± 4.4% CXCL1-loaded microspheres versus 85.7 ± 4.8% CXCL1 osmopump; n = 9; p < 0.05).
  
  
  CONCLUSIONS
  Our results demonstrate a proof of concept that sustained, local delivery of CXCL1 encapsulated in PEA microspheres provides a new tool to stimulate arteriogenesis in vivo.
authors.affiliation: a Department of Physiology , CARIM, Maastricht University , The Netherlands.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Caolo
authors.affiliation: a Department of Physiology , CARIM, Maastricht University , The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Vries
authors.affiliation: b DSM , Berkeley , CA , USA.
authors.forename: John
authors.initials: J
authors.lastname: Zupancich
authors.affiliation: c DSM , Heerlen , The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Houben
authors.affiliation: c DSM , Heerlen , The Netherlands.
authors.forename: George
authors.initials: G
authors.lastname: Mihov
authors.affiliation: a Department of Physiology , CARIM, Maastricht University , The Netherlands.
authors.forename: Allard
authors.initials: A
authors.lastname: Wagenaar
authors.affiliation: a Department of Physiology , CARIM, Maastricht University , The Netherlands.
authors.forename: Geertje
authors.initials: G
authors.lastname: Swennen
authors.affiliation: d Department of Surgery , Leiden University Medical Center , The Netherlands , and.
authors.forename: Yaël
authors.initials: Y
authors.lastname: Nossent
authors.affiliation: d Department of Surgery , Leiden University Medical Center , The Netherlands , and.
authors.forename: Paul
authors.initials: P
authors.lastname: Quax
authors.affiliation: e Department of Biochemistry , CARIM, Maastricht University , The Netherlands.
authors.forename: Dennis
authors.initials: D
authors.lastname: Suylen
authors.affiliation: e Department of Biochemistry , CARIM, Maastricht University , The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dijkgraaf
authors.affiliation: a Department of Physiology , CARIM, Maastricht University , The Netherlands.
authors.forename: Daniel
authors.initials: D
authors.lastname: Molin
authors.affiliation: e Department of Biochemistry , CARIM, Maastricht University , The Netherlands.
authors.forename: Tilman
authors.initials: T
authors.lastname: Hackeng
authors.affiliation: a Department of Physiology , CARIM, Maastricht University , The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Post
mesh_terms: D000818:Animals; D054360:Chemokine CXCL1 / Q000008:administration & dosage*; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D005263:Femoral Artery / Q000187:drug effects*; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D011073:Polyamines / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry
chemical_list: D054360:Chemokine CXCL1; D003692:Delayed-Action Preparations; D011073:Polyamines; D011091:Polyesters; C516446:poly(caprolactone-block-ethyleneimine)
keywords: Chemokines; drug delivery systems; peripheral artery disease; sustained release; vascular biology