Gj. Poiani et al., POLYMERIC CARRIER OF PROLINE ANALOG WITH ANTIFIBROTIC EFFECT IN PULMONARY VASCULAR REMODELING, American journal of respiratory and critical care medicine, 155(4), 1997, pp. 1384-1390
Citations number
29
Categorie Soggetti
Emergency Medicine & Critical Care","Respiratory System
The proline analogue cis-4-hydroxy-L-proline (cHyp) inhibits collagen
accumulation but diffuses out of tissues. To prolong the antifibrotic
effect, we used a copolymer of cHyp attached to a backbone of poly(eth
ylene glycol) (PEG) and lysine. The copolymer was encapsulated in lipo
somes conjugated with PEG or in liposomes coated with the polysacchari
de amylopectin to improve uptake by lungs after intravenous infusion.
Amylopectin-liposomes had similar to 3-fold greater uptake in cultured
endothelial cells compared with PEG-liposomes and greater lung retent
ion 1 wk after infusion (5.2 +/- 0.8% versus 2.7 +/- 0.2%, p < 0.05).
Sustained antifibrotic activity, assayed by growth inhibition of smoot
h muscle cells and fibroblasts over 4 d, was greater for amylopectin-l
iposomes/copolymer than PEG-liposomes/copolymer. Inhibition of collage
n accumulation in pulmonary arteries of hypoxic (10% O-2) rats was use
d to assess antifibrotic activity. Amylopectin-liposomes/copolymer att
enuated Increased right ventricular pressure by similar to 50% and com
pletely prevented excess vascular collagen 1 wk after a single intrave
nous injection, The copolymer in liposomes was > 1,000-fold more effec
tive by weight than unencapsulated monomeric cHyp. Thus, the copolymer
, a potent, long-acting antifibrotic agent totally prevented collagen
accumulation for 1 wk in pulmonary arteries undergoing vascular remode
ling when delivered in amylopectin-liposomes.