Rational Design of a Liposomal Drug Delivery System Based on Biophysical Studies of Phospholipase A ₂ Activity on Model Lipid Membranes

Abstract

Secretory phospholipase A 2 (sPLA 2 ) belongs to a family of small interfacially active enzymes that catalyze the hydrolysis of phospholipids, yielding lysolipids and fatty acids. sPLA 2 is found in snake and bee venom and also in inflammatory and cancerous tissue. It is mainly active on organized lipid substrates such as micelles and lipid membranes, and its hydrolytic activity is moreover strongly influenced by the physical properties of the supramolecular lipid substrate. Systematic model studies of the activity of sPLA 2 on lipid-membrane substrates of different compositions have provided insight into the biophysical mechanisms of sPLA 2 activation. In particular, combined theoretical and experimental model studies have revealed an intimate relationship between the activity of sPLA 2 and the formation of small-scale lipid domains in the lipid membrane substrate. This has been used to design and develop a principle for liposomal drug targeting, release, and absorption that is based on the presence of high levels of sPLA 2 activity in certain diseased target tissue.