title: Solid-state NMR reveals the hydrophobic-core location of poly(amidoamine) dendrimers in biomembranes.
abstract: Poly(amidoamine) (PAMAM) dendrimer nanobiotechnology shows great promise in targeted drug delivery and gene therapy. Because of the involvement of cell membrane lipids with the pharmacological activity of dendrimer nanomedicines, the interactions between dendrimers and lipids are of particular relevance to the pharmaceutical applications of dendrimers. In this study, solid-state NMR was used to obtain a molecular image of the complex of generation-5 (G5) PAMAM dendrimer with the lipid bilayer. Using (1)H radio frequency driven dipolar recoupling (RFDR) and (1)H magic angle spinning (MAS) nuclear Overhauser effect spectroscopy (NOESY) techniques, we show that dendrimers are thermodynamically stable when inserted into zwitterionic lipid bilayers. (14)N and (31)P NMR experiments on static samples and measurements of the mobility of C-H bonds using a 2D proton detected local field protocol under MAS corroborate these results. The localization of dendrimers in the hydrophobic core of lipid bilayers restricts the motion of bilayer lipid tails, with the smaller G5 dendrimer having more of an effect than the larger G7 dendrimer. Fragmentation of the membrane does not occur at low dendrimer concentrations in zwitterionic membranes. Because these results show that the amphipathic dendrimer molecule can be stably incorporated in the interior of the bilayer (as opposed to electrostatic binding at the surface), they are expected to be useful in the design of dendrimer-based nanobiotechnologies.
authors.affiliation: Biophysics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Pieter E S
authors.initials: PE
authors.lastname: Smith
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Brender
authors.forename: Ulrich H N
authors.initials: UH
authors.lastname: Dürr
authors.forename: Jiadi
authors.initials: J
authors.lastname: Xu
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Mullen
authors.forename: Mark M
authors.initials: MM
authors.lastname: Banaszak Holl
authors.forename: Ayyalusamy
authors.initials: A
authors.lastname: Ramamoorthy
mesh_terms: D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D050091:Dendrimers / Q000737:chemistry / Q000378:metabolism*; D004134:Dimyristoylphosphatidylcholine / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008567:Membranes, Artificial
chemical_list: D050091:Dendrimers; D004337:Drug Carriers; D008051:Lipid Bilayers; D008567:Membranes, Artificial; C104700:PAMAM Starburst; D004134:Dimyristoylphosphatidylcholine