title: Local delivery of biodegradable microparticles containing colchicine or a colchicine analogue: effects on restenosis and implications for catheter-based drug delivery.
abstract: OBJECTIVE
  This study sought to evaluate the delivery efficiency, intramural retention and antirestenotic efficacy of soluble colchicine or colchicine analogue delivered into the arterial wall after angioplasty as well as the efficacy of these medications after prolonged local release from biodegradable microparticles.
  
  
  BACKGROUND
  Local delivery of pharmacologic agents is a potential treatment for restenosis. However, the delivery efficiency of the technique and the choice of agent to modulate cellular proliferation are unknown. It was hypothesized that restenosis would be unaffected by colchicine or a hydrophobic colchicine analogue with short intramural retention, whereas it would be reduced after prolonged local release.
  
  
  METHODS
  Rabbit atherosclerotic femoral arteries underwent angioplasty followed by local delivery. Delivery efficiency and intramural retention of 3H-colchicine were evaluated. The effect of agents in soluble formulation or released from microparticles on angiographic and morphometric restenosis was evaluated at 2 weeks and compared with that in the control groups (angioplasty only and local infusion of carrier solution).
  
  
  RESULTS
  Delivery of efficiency was 0.01% and intramural retention < 24 h. Neither soluble colchicine formulation reduced restenosis. Microparticles releasing the colchicine analogue reduced restenosis compared with control and colchicine microparticles but not angioplasty alone (p = 0.002). Delivery outside the artery was observed, and the long-term release of both colchicine resulted in toxicity to the adjacent musculature.
  
  
  CONCLUSIONS
  Colchicine or the colchicine analogue did not reduce restenosis, although the long-term local release of the colchicine analogue reduced neointimal proliferation resulting from local delivery. Local delivery of cytotoxic agents with insufficient vascular specificity may be limited by toxicity to adjacent tissues resulting from a larger than expected delivery area and prolonged agent retention.
authors.affiliation: Krannert Institute of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis 46202-4800, USA.
authors.forename: I
authors.initials: I
authors.lastname: Gradus-Pizlo
authors.forename: R L
authors.initials: RL
authors.lastname: Wilensky
authors.forename: K L
authors.initials: KL
authors.lastname: March
authors.forename: N
authors.initials: N
authors.lastname: Fineberg
authors.forename: M
authors.initials: M
authors.lastname: Michaels
authors.forename: G E
authors.initials: GE
authors.lastname: Sandusky
authors.forename: D R
authors.initials: DR
authors.lastname: Hathaway
mesh_terms: D000818:Animals; D001673:Biodegradation, Environmental; D003078:Colchicine / Q000008:administration & dosage* / Q000031:analogs & derivatives; D003327:Coronary Disease / Q000517:prevention & control*; D016503:Drug Delivery Systems / Q000379:methods; D008863:Microspheres; D011817:Rabbits; D012008:Recurrence
chemical_list: D003078:Colchicine