A doxycycline loaded, controlled-release, biodegradable fiber for the treatment of aortic aneurysms.
The pathogenesis of aortic aneurysm (AA) is characterized by degradation of extracellular matrix with increased matrix metalloproteinases (MMPs) and inflammatory reaction. Doxycycline (DOXY) has been reported to control the extension of AA by regulation of MMP. However, systemic administration may cause adverse side effects. In this study, we demonstrated the possibility of local administration of DOXY controlled-release biodegradable fiber (DCRBF) for AA in mice. DCRBF was fabricated by biodegradable polymer (polylactic acid; PLA) mixed with DOXY using an electrospinning technique. DCRBF was cocultured with SMCs, macrophages and aortic tissue, and placed on an abdominal aortic aneurysm which induced apolipoprotein E-deficient mice. We evaluated gene and protein expression of proteases, elastin and inflammatory markers. In the presence of DCRBF, MMP-12 was significantly decreased, TGF-β1 and Lox were significantly increased in SMC gene expression, MMP-9 and -12 significantly decreased gene expression of macrophages. The DCRBF preserved elastin content and decreased MMP-2 and -9 in aortic tissue. In addition, IGF-1 and TIMP-1 were significantly increased and IL-6 and TNF-α were significantly decreased with DCRBF in vivo. In conclusion, our results suggested that local administration of DCRBF may become a promising alternative therapeutic strategy for AA.
Yamawaki-Ogata
A
A
Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Hashizume
R
R
Satake
M
M
Kaneko
H
H
Mizutani
S
S
Moritan
T
T
Ueda
Y
Y
Narita
Y
Y
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001014:Aortic Aneurysm / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D001672:Biocompatible Materials / Q000494:pharmacology / Q000627:therapeutic use*; D018925:Chemokines / Q000378:metabolism; D018920:Coculture Techniques; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology / Q000627:therapeutic use*; D004548:Elasticity / Q000187:drug effects; D004549:Elastin / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D019344:Lactic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011091:Polyesters; D011108:Polymers / Q000494:pharmacology / Q000627:therapeutic use*; D046509:Tissue Culture Techniques; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
D001672:Biocompatible Materials; D018925:Chemokines; D003692:Delayed-Action Preparations; D036341:Intercellular Signaling Peptides and Proteins; D011091:Polyesters; D011108:Polymers; D019714:Tissue Inhibitor of Metalloproteinases; D019344:Lactic Acid; C033616:poly(lactide); D004549:Elastin; D020782:Matrix Metalloproteinases; D004318:Doxycycline