title: Specific and cooperative interactions between oximes and PAMAM dendrimers as demonstrated by (1)H NMR study.
abstract: Oximes are important in the treatment of organophosphate (OP) poisoning, but have limited biological half-lives. Complexing these drugs with a macromolecule, such as a dendrimer, could improve their pharmacokinetics. The present study investigates the intermolecular interactions that drive the complexation of oxime-based drug molecules with fifth generation poly(amidoamine) (PAMAM) dendrimers. We performed steady-state binding studies of two molecules, pralidoxime and obidoxime, employing multiple NMR methods, including 1D titration, (1)H-(1)H 2D spectroscopy (COSY, NOESY), and (1)H diffusion-ordered spectroscopy (DOSY). Several important insights were gained in understanding the host-guest interactions occurring between the drug molecules and the polymer. First, the guest molecules bind to the dendrimer macromolecule through a specific interaction rather than through random, hydrophobic encapsulation. Second, this specificity is driven primarily by the electrostatic or H-bond interaction of the oxime at a dendrimer amine site. Also, the average strength for each drug and dendrimer interaction is affected by the surface modification of the polymer. Third, individual binding events between oximes and a dendrimer have a negative cooperative effect on subsequent oxime binding. In summary, this report provides a novel perspective important for designing host systems for drug delivery.
authors.affiliation: Department of Internal Medicine, Michigan Nanotechnology Institute for Medicine and Biological Sciences , ‡Department of Biomedical Engineering, and §Department of Anesthesiology, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Seok Ki
authors.initials: SK
authors.lastname: Choi
authors.forename: Thommey P
authors.initials: TP
authors.lastname: Thomas
authors.forename: Pascale
authors.initials: P
authors.lastname: Leroueil
authors.forename: Alina
authors.initials: A
authors.lastname: Kotlyar
authors.forename: Abraham F L
authors.initials: AF
authors.lastname: Van Der Spek
authors.forename: James R
authors.initials: JR
authors.lastname: Baker
mesh_terms: D050091:Dendrimers / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D010091:Oximes / Q000737:chemistry*; D011522:Protons
chemical_list: D050091:Dendrimers; D010091:Oximes; C104700:PAMAM Starburst; D011522:Protons