The development of liposomes targeted to angiogenic endothelial cells offers exciting prospects for intervention in cancer and inflammation. Several proteins are (strongly) over-expressed on angiogenic endothelial cells as compared to the quiescent endothelium, and could potentially serve as targets for site-specific drug delivery. In this contribution particular attention is given to the design of targeted long-circulating liposomes directed against the alpha v beta 3-integrin protein.
We have synthesized a prodrug of the angiotensin-converting enzyme (ACE) inhibitor captopril by coupling this drug covalently to the low molecular weight protein (LMWP) lysozyme. Such drug-LMWP conjugates can be used for renal drug delivery, since LMWPs accumulate specifically in the proximal tubular cells of the kidney. In the present study, we compared the effects of captopril-lysozyme and free captopril in male Wistar rats. ACE activity in plasma and the kidney was measured after intravenous bolus injection of either the captoprillysozyme conjugate (33 mg ⅐ kg Ϫ1 , corresponding to 0.2 mg ⅐ kg Ϫ1 captopril) or equivalent dosages of free captopril and lysozyme. The administration of the captopril-lysozyme conjugate resulted in less plasma ACE inhibition and a longer-lasting renal ACE inhibition compared with the free drug. Effects on blood pressure and natriuresis were studied during intravenous infusion of captopril-lysozyme (275 mg ⅐ kg Ϫ1
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