title: RGD-Targeted Liposome Binding and Uptake on Breast Cancer Cells Is Dependent on Elastin Linker Secondary Structure.
abstract: The linker between the targeting moiety and the nanoparticle is often overlooked when engineering targeted drug delivery vehicles. We hypothesized that pH-triggered conformational changes of an elastin-like peptide (ELP) linker, with repeating VPGVG sequences, could alter the binding affinity of the well-established targeting moiety arginine-glycine-aspartic acid (RGD), which is known to enhance the delivery of nanoparticles to tumor cells via integrin overexpression. The pH change from blood (pH 7.4) to the tumor environment (pH 6) was used to elicit a conformational change in the ELP linker, as described by circular dichroism. Atomic force microscopy confirmed that RGD-ELP resulted in stronger adhesion to both MDA-MB-231 and HCC1806 breast cancer cells at pH 6 relative to pH 7.4. No change in adhesion force was measured as a function of pH for the non-neoplastic MCF-10A cell line and the nontargeting GDR-ELP peptide. This translated to significant binding and uptake of RGD-ELP modified liposomes at pH 6.0 relative to pH 7.4. These results indicate that the pH-triggered conformational structure of the ELP linker shifts RGD-mediated cancer cell targeting from non-active (pH 7.4) to active (pH 6). The reversible shift in ELP secondary structure may be used to engineer targeted drug delivery vehicles with tunable uptake.
authors.affiliation: Department of Biomedical Engineering and ‡Department of Chemical Engineering The City College of New York , New York, New York 10031, United States.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Veneti
authors.affiliation: Department of Biomedical Engineering and ‡Department of Chemical Engineering The City College of New York , New York, New York 10031, United States.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Tu
authors.affiliation: Department of Biomedical Engineering and ‡Department of Chemical Engineering The City College of New York , New York, New York 10031, United States.
authors.forename: Debra T
authors.initials: DT
authors.lastname: Auguste
mesh_terms: D000595:Amino Acid Sequence; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004549:Elastin / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D039081:Integrin alpha5beta1 / Q000737:chemistry / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000737:chemistry / Q000378:metabolism; D008081:Liposomes; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry; D009842:Oligopeptides / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D017433:Protein Structure, Secondary; D021381:Protein Transport
chemical_list: D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D008081:Liposomes; D009842:Oligopeptides; D010446:Peptide Fragments; C047981:arginyl-glycyl-aspartic acid; D004549:Elastin