Perivascular sustained release of atorvastatin from a hydrogel-microparticle delivery system decreases intimal hyperplasia

Autor: Eric Allémann, Florence Delie, Ioanna Mylonaki, Sébastien Déglise, Jean-Marc Corpataux, Francesco Strano, Florian Alonso, Céline Dubuis, François Saucy, Jacques-Antoine Haefliger, Olivier Jordan
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Male
Intimal hyperplasia
Atorvastatin
Pharmaceutical Science
02 engineering and technology
030204 cardiovascular system & hematology
Pharmacology
chemistry.chemical_compound
Drug Delivery Systems
0302 clinical medicine
Polylactic Acid-Polyglycolic Acid Copolymer
Hyaluronic acid
Medicine
Hyaluronic acid hydrogel
Tissue Distribution
Hyaluronic Acid
ddc:615
Hydrogels
021001 nanoscience & nanotechnology
3. Good health
PLGA
Carotid Arteries
Microparticle
Toxicity
0210 nano-technology
medicine.drug
medicine.medical_specialty
Perivascular administration
In Vitro Techniques
03 medical and health sciences
In vivo
Animals
Humans
Saphenous Vein
Lactic Acid
Ligation
Hyperplasia
business.industry
medicine.disease
Surgery
Mice
Inbred C57BL
Drug Liberation
chemistry
Delayed-Action Preparations
Tunica Intima
business
human activities
Polyglycolic Acid
Ex vivo
Zdroj: Journal of Controlled Release, Vol. 232 (2016) pp. 93-102
Journal of controlled release : official journal of the Controlled Release Society
ISSN: 0168-3659
Popis: 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 4 weeks) 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 3 days, while ATV-loaded poly-lactic-co-glycolic acid (PLGA) microparticles dispersed in the gel gave a sustained release over 4 weeks. 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 in IH 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 28 days 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 (0.044 ng/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.
Databáze: OpenAIRE
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