Targeted drug delivery based on adhesion domains of immunoglobulin superfamily : P0 protein as a model

Abstract

The objectives of this study were (i) to investigate the feasibility of targeting liposomes reconstituted with P0 protein (an immunoglobulin [Ig] superfamily cell adhesion molecule from peripheral nerve myelin) to melanoma cells with high level of intercellular adhesion molecule-1 (ICAM-1) expression, (ii) to analyze selected sequences of P0 protein or leukocyte function associated antigen-1 (LFA-1, the counter receptor of ICAM-1) to find peptides with adhesive activity for ICAM-1 and (iii) to investigate whether these peptides could be used as ligands for targeting liposomes toward ICAM-1 expressing cells. To identify peptides with adhesive activity for ICAM-1 three synthetic P0 peptides (P0-peptide-1, YTDNGTF, extracellular Ig-like domain; P0-peptide-2, VALLVAV, transmembrane region; P0-peptide-3, KAAAEKK, basic intracellular domain) and one peptide from LFA-1 (a 12 amino acids long from 'I' domain) were selected. The effect of these peptides in the inhibition of LFA-1/ICAM-1 interaction might be through adhesion to ICAM-1. Peptides were covalently linked to the liposomes containing N-glutaryl-phosphatidylethanolamine in the presence of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide and N-hydroxysulfosuccinimide. P0-peptide-1, when linked to the liposome surface, increased the extent of binding of liposomes to M21 and A-375 compared to control liposomes of the same lipid composition but without peptide, whereas with MeM 50-10 (1.02 fold) cells no increase was found. Due to the high content of positively charged amino acids, P0-peptide-3 nonspecifically increased binding of liposomes to all the three melanoma cell lines. LFA-1- and RGD-peptides had no effect in the binding of liposomes to M21 cells. The extent of binding of P0-peptide-1-liposomes to human melanoma cell lines correlated with the level of ICAM-1 expression. P0 protein and P0-peptide-1 that mediate specific targeting of liposomes to ICAM-1 expressing cells may be useful for the development of drug delivery systems for the treatment of malignant melanomas and inflammatory skin disorders which have high level of ICAM-1 expression. (Abstract shortened by UMI.)