Random peptide libraries for target definition

Several reports have shown that panning a random peptide library on a purif ied cellular receptor identified novel ligands for the target molecule. Man y novel ligands for integrins, a class of trans-membrane glycoproteins invo lved in cell migration and tumor invasion, have been identified in this way . Peptides binding to integrins contained the RGD recognition motif flanked by residues which determine their specificity for differing integrins. Suc h peptides have been successfully used for targeting various gene and drug delivery vehicles to cell expressing the target integrin. When the target receptor needed to be expressed on the cell surface to reta in its native conformation, peptide libraries have been panned on whole cel ls and different positive selection protocols have been adopted to identify ligands for the receptor of interest. More recently, selections using whol e cells have been directed at identifying ligands for unknown receptors wit h a particular property, for example tissue specificity or internalization. Protocols have been reported that improve the selection efficiency of spec ific ligands. An innovative approach to selecting ligands for receptors selectively expre ssed in the organ vasculature has been to inject a library into the circula tion in mice. Harvesting peptides that distributed to different organs has identified ligands selectively homing to mouse brain or kidney blood vessel s with no previous knowledge of the target receptor. Using the same in vivo panning approach, a library has been injected into the circulation of nude mice bearing human breast carcinoma xenograft, resulting in the identifica tion of ligands for tumor-specific vascular markers. These peptides, previo usly shown to have high affinity for alpha(v) integrins, have been combined with a chemotherapeutic drug and shown to act more effectively than the dr ug alone in tumor-bearing mice.