| abstract |
In order to meet these needs, the present invention is directed to therapeutic and diagnostic agents capable of forming covalent bonds to blood and pulmonary fluid proteins or other components ex vivo or in vivo. The therapeutic agents of this invention have a long duration of action for the management of disease. The invention relates to ex vivo and in vivo bioconjugation of therapeutic agents to protein (e.g. albumin), as well as an intrapulmonary in vivo bioconjugation of therapeutic agents to endogenous pulmonary fluid proteins or other components to dramatically increase the half life of the therapeutic agents and avoid the need for parenteral administration. This invention is further directed to the use of reactive chemistries including: N-hydroxy sulfosuccinimide, maleimide-benzoyl-succinimide, gamma-maleimido-butyryloxy succinimide ester, maleimidopropionic acid, isocyanate, thiolester, thionocarboxylic acid ester, imino ester, and carbodiimide anhydride. Maleimidopropionic acid is the preferred reactive chemistry, but the invention also contemplates the selection of the above and like reactive chemistries as an electrophilic moeity for bioconjugations with albumin or other proteins. Modified therapeutic agents mentioned are the anti-histamine drug loratidine or cetirizine, a hypothyroid drug, the anti-angina drug tirofiban, the anti-hypertensive drug enalapril, the anti-arrhytmic drug capobenic acid, the antidepressant drug fluoxetine, the bronchodilation drug the obromineacetamine, the antiinflammatory drug loxoprofen, the anti-thyroid deficiency drug thyroxin, and 4-anilino-1-(2-phenethyl)piperidine. |