title: Enhanced cellular uptake of peptide-targeted nanoparticles through increased peptide hydrophilicity and optimized ethylene glycol peptide-linker length.
abstract: Ligand-targeted nanoparticles are emerging drug delivery vehicles for cancer therapy. Here, we demonstrate that the cellular uptake of peptide-targeted liposomes and micelles can be significantly enhanced by increasing the hydrophilicity of the targeting peptide sequence while simultaneously optimizing the EG peptide-linker length. Two distinct disease models were analyzed, as the nanoparticles were functionalized with either VLA-4 or HER2 antagonistic peptides to target multiple myeloma or breast cancer cells, respectively. Our results demonstrated that including a short oligolysine chain adjacent to the targeting peptide sequence effectively increased cellular uptake of targeted nanoparticles up to ∼80-fold using an EG6 peptide-linker in liposomes and ∼27-fold using an EG18 peptide-linker in micelles for the VLA-4/multiple myeloma system. Similar trends were also observed in the HER2/breast cancer system with the EG18 peptide-linker resulting in optimal uptake for both types of nanoparticles. Cellular uptake efficiency of these formulations was also confirmed under fluidic conditions mimicking physiological systems. Taken together, these results demonstrated the significance of using the right design elements to improve the cellular uptake of nanoparticles.
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Jared F
authors.initials: JF
authors.lastname: Stefanick
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ashley
authors.forename: Basar
authors.initials: B
authors.lastname: Bilgicer
mesh_terms: D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000378:metabolism*; D010316:Particle Size; D010455:Peptides / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
chemical_list: D003432:Cross-Linking Reagents; D039041:Integrin alpha4beta1; D053769:Nanocapsules; D010455:Peptides; D011092:Polyethylene Glycols; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human