Perivascular sustained release of atorvastatin from a hydrogel-microparticle delivery system decreases intimal hyperplasia.
Intimal hyperplasia (IH) is the major cause of grafted vessel occlusion and occurs frequently after bypass intervention. No pharmaceutical formulation is currently available to prevent this pathology. Local perivascular delivery of an appropriate active compound released in a time-dependent manner (from day one up to 4weeks) is necessary for an efficient single-administration preventive therapy. To this aim, we propose the combination of gel and microparticles delivery system containing atorvastatin (ATV). The incorporation of ATV in a cross-linked hyaluronic acid gel, provided in vitro a fast release over 3days, while ATV-loaded poly-lactic-co-glycolic acid (PLGA) microparticles dispersed in the gel gave a sustained release over 4weeks. In vivo, ATV formulations were applied perivascularly in mice undergoing carotid artery ligation. IH was significantly reduced (-68%) in presence of ATV incorporated in hyaluronic acid gel and encapsulated in microparticles compared to control. No significant IH alteration was observed when ATV was incorporated only in the gel (fast release) or only in the microparticles (slow release) demonstrating that a biphasic release of ATV is essential to interfere with the development of IH. ATV was detected in adjacent tissues 28days after the intervention, showing the sustained presence of the drug in vivo. After four weeks ATV was not detected in remote tissues, except at a very low concentration (0.044ng/mg) in the liver, suggesting a very low risk of systemic toxicity of locally delivered ATV. Additionally, the ex vivo data showed that ATV in solution permeates through isolated human saphenous veins and thus is a good candidate for perivascular delivery. Our data demonstrate that a local biphasic ATV release on the mice ligated carotid efficiently prevents the development of IH without apparent toxicity.
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ansermet, 30, 1205 Geneva, Switzerland.
Ioanna
I
Mylonaki
Department of Vascular Surgery, Lausanne University Hospital, Laboratory of Experimental Medicine, Rue du Bugnon 46, CH 1011, Lausanne, Switzerland.
Francesco
F
Strano
Department of Vascular Surgery, Lausanne University Hospital, Laboratory of Experimental Medicine, Rue du Bugnon 46, CH 1011, Lausanne, Switzerland.
Sebastien
S
Deglise
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ansermet, 30, 1205 Geneva, Switzerland.
Eric
E
Allémann
Department of Vascular Surgery, Lausanne University Hospital, Laboratory of Experimental Medicine, Rue du Bugnon 46, CH 1011, Lausanne, Switzerland.
Florian
F
Alonso
Department of Vascular Surgery, Lausanne University Hospital, Laboratory of Experimental Medicine, Rue du Bugnon 46, CH 1011, Lausanne, Switzerland.
Jean-Marc
JM
Corpataux
Department of Vascular Surgery, Lausanne University Hospital, Laboratory of Experimental Medicine, Rue du Bugnon 46, CH 1011, Lausanne, Switzerland.
Céline
C
Dubuis
Department of Vascular Surgery, Lausanne University Hospital, Laboratory of Experimental Medicine, Rue du Bugnon 46, CH 1011, Lausanne, Switzerland.
Jacques-Antoine
JA
Haefliger
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ansermet, 30, 1205 Geneva, Switzerland.
Olivier
O
Jordan
Department of Vascular Surgery, Lausanne University Hospital, Laboratory of Experimental Medicine, Rue du Bugnon 46, CH 1011, Lausanne, Switzerland.
François
F
Saucy
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ansermet, 30, 1205 Geneva, Switzerland. Electronic address: Florence.Delie@unige.ch.
Florence
F
Delie
D000818:Animals; D000069059:Atorvastatin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002339:Carotid Arteries / Q000473:pathology / Q000601:surgery; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D016503:Drug Delivery Systems; D065546:Drug Liberation; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D020100:Hydrogels / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006965:Hyperplasia / Q000188:drug therapy*; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008026:Ligation; D008297:Male; D008810:Mice, Inbred C57BL; D011100:Polyglycolic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012501:Saphenous Vein / Q000378:metabolism; D014018:Tissue Distribution; D017539:Tunica Intima / Q000473:pathology*
D003692:Delayed-Action Preparations; D020100:Hydrogels; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D006820:Hyaluronic Acid; D000069059:Atorvastatin
Atorvastatin; Hyaluronic acid hydrogel; Intimal hyperplasia; Microparticle; Perivascular administration