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Targeting the urokinase plasminogen activator receptor with synthetic self-assembly nanoparticles
Ming Wang1, Dennis W P M Löwik, Andrew D Miller
1Imperial College Genetic Therapies Centre, Department of Chemistry, Flowers Building, Armstrong Road, Imperial College London, London SW72AZ, United Kingdom.
Abstract:
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.
Insights
Researchers developed novel nanoparticles targeting the urokinase plasminogen activator receptor (uPAR) for cancer therapy. These U11 peptide-targeted nanoparticles significantly enhance gene delivery to uPAR-positive cancer cells.
Area of Science:
- Biotechnology
- Nanomedicine
- Cancer Therapy
Background:
- The urokinase plasminogen activator receptor (uPAR) is a key target in cancer, particularly for prostate and breast cancers.
- Targeted drug delivery and gene therapy require precise nanoparticle design for effective cancer treatment.
Purpose of the Study:
- To design, synthesize, and characterize a novel self-assembled nanoparticle for targeted cancer therapy.
- To create a nanoparticle that presents uPAR-targeting ligands in a specific conformation and ratio on its surface.
Main Methods:
- Synthesized an 11-amino-acid U11 peptide-lipid amphiphile for nanoparticle surface modification.
- Post-modified stealth liposomes with the U11 peptide-lipid to create targeted nanoparticles.
- Evaluated nanoparticle efficacy using uPAR-positive (DU145) and uPAR-negative (HEK293) cell lines.
Main Results:
- U11 peptide insertion into liposomes resulted in biologically active, singular conformations.
- Demonstrated specific receptor-mediated endocytosis (RME) and plasmid DNA delivery to uPAR-positive cells.
- Achieved a 10-fold increase in transfection efficiency in DU145 cells compared to scrambled peptide nanoparticles, with no significant effect on HEK293 cells.
Conclusions:
- The developed U11 peptide-targeted nanoparticles are effective for specific gene delivery to uPAR-expressing cancer cells.
- This targeted nanoparticle system shows high specificity and enhanced transfection efficiency, offering a promising approach for cancer gene therapy.
