title: Characterization and solubilization of pyrrole-imidazole polyamide aggregates.
abstract: To optimize the biological activity of pyrrole-imidazole polyamide DNA-binding molecules, we characterized the aggregation propensity of these compounds through dynamic light scattering and fractional solubility analysis. Nearly all studied polyamides were found to form measurable particles 50-500 nm in size under biologically relevant conditions, while HPLC-based analyses revealed solubility trends in both core sequences and peripheral substituents that did not correlate with overall ionic charge. The solubility of both hairpin and cyclic polyamides was increased upon addition of carbohydrate solubilizing agents, in particular, 2-hydroxypropyl-β-cyclodextrin (HpβCD). In mice, the use of HpβCD allowed for improved injection conditions and subsequent investigations of the availability of polyamides in mouse plasma to human cells. The results of these studies will influence the further design of Py-Im polyamides and facilitate their study in animal models.
authors.affiliation: California Institute of Technology, Division of Chemistry and Chemical Engineering, 1200 East California Boulevard, Pasadena, California 91125, United States.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Hargrove
authors.forename: Jevgenij A
authors.initials: JA
authors.lastname: Raskatov
authors.forename: Jordan L
authors.initials: JL
authors.lastname: Meier
authors.forename: David C
authors.initials: DC
authors.lastname: Montgomery
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dervan
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000737:chemistry*; D007274:Injections, Intraperitoneal; D008027:Light; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D009757:Nylons / Q000737:chemistry* / Q000493:pharmacokinetics; D011758:Pyrroles / Q000097:blood / Q000737:chemistry*; D012542:Scattering, Radiation; D012995:Solubility; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin