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PEDS Advance Access published online on July 2, 2004
Protein Engineering Design and Selection, doi:10.1093/protein/gzh055
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Received February 25, 2004
Revised May 12, 2004
Accepted June 21, 2004

Article

Novel RGD lipopeptides for the targeting of liposomes to integrin-expressing endothelial and melanoma cells

Peter Hölig 1, Miriam Bach 1, Tina Völkel 1, Thomas Nahde 1, Sven Hoffmann 1, Rolf Müller 2, Roland E. Kontermann 1*

1 Vectron Therapeutics AG, Rudolf-Breitscheid-Str. 24, 35037 Marburg, Germany
2 Institut für Molekularbiologie und Tumorforschung, Philipps-Universität, Emil-Mannkopff-Str. 2, 35033 Marburg, Germany

* To whom correspondence should be addressed. E-mail: kontermann{at}vectron-ag.com.


  Abstract

RGD peptides targeting {alpha}v-integrins are promising ligands for the generation of vascular targeting agents. We isolated from phage display RGD motif libraries novel high affinity cyclic RGD peptides by selection on either endothelial or melanoma cells. Although the starting sequences contained only 2 cysteine residues flanking the RGD motif, several of the isolated peptides possessed 4 cysteine residues. A high affinity peptide (RGD-10) constrained by only one disulfide bond was used to generate novel lipopeptides composed of a lipid anchor, a short flexible spacer, and the peptide ligand conjugated to the spacer end. Incorporation of RGD-10 lipopeptides into liposomes resulted in specific and efficient binding of the liposomes to integrin-expressing cells. In vivo experiments applying doxorubicin-loaded RGD-10 liposomes in a C26 colon carcinoma mouse model demonstrated improved efficacy compared to free doxorubicin and untargeted liposomes.

Keywords: Integrins; RGD peptides; phage display; vascular targeting; drug delivery.
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