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Clustered vs. uniform display of GALA-peptides on carrier nanoparticles
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Locke, Trevan. Clustered vs. uniform display of GALA-peptides on carrier nanoparticles. Retrieved from https://doi.org/doi:10.7282/T3736V1C

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TitleClustered vs. uniform display of GALA-peptides on carrier nanoparticles
NameLocke, Trevan (author); Sofou, Stavroula (chair); Yarmush, Martin (internal member); Roth, Charlie (internal member); Nanda, Vikas (outside member); Rutgers University; School of Graduate Studies
Date Created2017
Other Date2017-10 (degree)
SubjectChemical and Biochemical Engineering, Drug delivery systems, Nanoparticles
Extent1 online resource (viii, 59 p. : ill.)
DescriptionGALA-peptide is a random coil in neutral pH; in acidic pH it becomes an amphipathic alpha helix that aggregates in solution, possibly via its hydrophobic facet, that runs along the helix's long axis. In the presence of fluid lipid membranes, the GALA-helix exhibits membrane-active properties that originate from the same hydrophobic facet; these properties make GALA a candidate for inclusion in drug delivery systems requiring permeation of the endosomal membrane to enable drug escape into the cytoplasm. Previous work has shown that uniform functionalization of carrier nanoparticles with GALA-peptides improved their membrane activity and enhanced the endosomal escape of delivered therapeutics. The present study aims to evaluate the potential role of altering membrane activity via cluster-displayed GALA-peptides (for higher local valency) on the surface of carrier nanoparticles. The presentation of GALA-peptides on carrier nanoparticles was designed to also be pH-dependent. The peptide display on the surface of the carrier nanoparticles was uniform in neutral pH; in the acidic endosomal pH, the surface of nanocarriers formed domains (patches) with high local densities of GALA-peptides. The interactions between GALA-functionalized carrier nanoparticles and target lipid vesicles, utilized as endosome membrane surrogates, were studied as a function of pH. At endosomal pH values, ranging from 5.5 to 5.0, greatest permeability of target membranes was induced by nanocarriers with clustered and not with uniformly displayed GALA. This enhancing effect had an optimum; at even more acidic pH values, too close approximation of GALA peptides residing within the same patches resulted in preferential intrapatch peptide interactions rather than interactions with the apposing target lipid membranes. This behavior could have the same physicochemical origin as the aforementioned GALA-peptide aggregation, observed in solution with lowering pH at increasing peptide concentrations. On the translational front, GALA functionalized liposomes were loaded with doxorubicin and were functionalized with folate in order to specifically target folate-receptor expressing cancer cells. The findings suggest advantages in drug delivery in the presence of GALA that potentially mediates fast transmembrane delivery of therapeutics. The findings of this study support the potential of utilizing the clustered display of GALA-peptides on carrier nanoparticles to increase the permeation of endosomal membranes, and to, therefore, improve the endosomal escape of delivered therapeutics, enhancing therapeutic efficacy.
NotePh.D.
NoteIncludes bibliographical references
Noteby Trevan Locke
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3736V1C
Languageeng
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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