Albumin microspheres as carrier of an inhibitor of leukocyte elastase: potential therapeutic agent for emphysema.

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Abstract
Methods are described for the covalent attachment of succinoyl-Ala-Ala-Pro-ValCH2Cl, an active site-directed inhibitor of human leukocyte elastase (EC 3.4.21.11) to microspheres of human albumin. The insertion of side arms of various lengths showed that maximum inhibition of the enzyme was obtained when the spacer arm was at least 24.3 .ANG. in length. Approximately 30 molecules of the inhibitor could be attached to each molecule of albumin. Such derivatized microspheres were capable of inhibiting approximately 1 mol of elastase per mole of albumin, comparable to the inhibitory activity of .alpha.1-antitrypsin. Experiments in vivo in which rats were injected i.v. with radiolabeled microspheres to which the inhibitor was attached showed a rapid and exclusive uptake by the lungs. About 40-50% of the injected microspheres subsequently remained in the lungs with a half-life of approximately 17 days. These derivatized microspheres may be a therapeutic agent for emphysema.