Targeting the Urokinase Plasminogen Activator Receptor with Synthetic Self-Assembly Nanoparticles

Targeting specific receptors is attracting growing interest in the fields of drug delivery and gene therapy for cancer treatment. The urokinase plasminogen activator receptor (uPAR) is overexpressed on many tumors,particularly that of prostate and breast cancers. The aim of this study is to design, prepare, and characterize a synthetic self-assembled nanoparticle that presents targeting ligands at a certain conformation and molar ratio onthe surface of the particles. Here, we describe the synthesis of a novel uPAR targeting ligand consisting of an 11-amino-acid sequence named U11 peptide modified with an alkyl chain to form an U11 peptide-lipid amphiphile.This peptide-lipid is inserted into the outer layer of a parent stealth liposome by post-modification to derive a U11 peptide-targeted nanoparticle. We demonstrate that the peptide moieties become separated into more singular conformations as they are inserted into a liposome membrane, rendering them to be sufficiently biologically active to observe specific receptor-mediated endocytosis (RME) and delivery of plasmid DNA to uPAR positive cells (DU145 cells). The U11 peptide targeted nanoparticle transfection of DU145 cells is essentially 10-fold higher compared to transfection achieved by nanoparticles having a scrambled peptide sequence on their surface.U11 peptide targeted nanoparticles also proved to be uPAR-specific, as they did not improve transfection levels on the uPAR-negative cell line, HEK293.