POLYMERIC CARRIER OF PROLINE ANALOG WITH ANTIFIBROTIC EFFECT IN PULMONARY VASCULAR REMODELING

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.