A Needle-and-Thread Approach to Bilayer Transport: Permeation of a Molecular Umbrella−Oligonucleotide Conjugate across a Phospholipid Membrane

A di-walled molecular umbrella, composed of two choloyl groups, one spermidine moiety, and a 5-thiol(2-nitrobenzoyl) “handle”, was covalently attached to a 16-mer oligonucleotide (S-dT16) through a disulfide bond. Incubation of this conjugate (1) with vesicles made from 1-palmitoyl-2-oleyol-sn-glycero-3-phosphocholine and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylglycerol (95/5, mol/mol) (200 nm diameter, extrusion) that contained entrapped glutathione (GSH) at 37 °C resulted in the liberation of the oligonucleotide and the umbrella-bound 5-mercapto(2-nitrobenzoyl) moiety (USH) via thiolate−disulfide interchange. The appearance of USH, together with the absence of leakage of entrapped GSH and a vesicular capture of the oligonucleotide that matches the extent of USH formation, provides compelling evidence for delivery of S-dT16 into the aqueous compartment of these vesicles. In a sense, the molecular umbrella functions like a “needle” in providing a pathway for the oligonucleotide (the “thread”) to cross the membrane

Design and Synthesis of Molecular Umbrellas

This paper describes the design and synthesis of a series of conjugates derived from cholic acid, spermidine, and 5-(dimethylamino)-1-naphthalenesulfonyl (dansyl), which effectively shield the dansyl moiety from water. Direct coupling of cholic acid to both terminal amino groups of spermidine, and attachment of the environmentally-sensitive dansyl moiety to the remaining secondary amine, yields a “molecular umbrella” (Ia) whose fluorescent properties (λmax and emission intensity) reflect a nonpolar microenvironment in water and one that is relatively polar in intermediate dimethoxyethane/water mixtures. Comparison of Ia with analogous “single-walled” (II) and “no-walled” (III) umbrellas further indicates that a minimum of two walls is necessary in order to have “umbrella-like” properties. Examination of the fluorescent properties of a related double-walled umbrella, bearing a flexible (2-hydroxyethyl)carbamate moiety at the C-3 position of the sterol (Ib), reveals that “umbrella-like” properties are present even when facial amphiphilicity is not rigorously maintained; however, the molecule's ability to shield the fluorophore, as judged by its relative emission intensity, is diminished. “Methyl-capping” of the (2-hydroxyethyl)carbamate (i.e., Ic) enhances the umbrella's ability to provide a hydrophobic shelter in water. A tetra-walled analogue of Ia, bearing four cholic acid units (i.e., IV), has been synthesized and its dansyl group found to have reduced exposure toward water. The potential utility of molecular umbrellas in the area of drug delivery is briefly discussed

Covalent Gluing and Postgluing of Langmuir−Blodgett Monolayers at Hydrocarbon Surfaces

Langmuir−Blodgett (LB) monolayers of 5,11,17,23,29,35-hexaformyl-37,38,39,40,41,42-hexakis(1-n-octyloxy)calix[6]arene (2), deposited onto silylated silicon wafers, were cross-linked (i.e., “covalently glued”) via Schiff base formation with poly(allylamine). Direct evidence for imine formation was obtained from X-ray photoelectron spectroscopy and from attenuated total reflection IR spectroscopy. These modified surfaces could be removed from the aqueous subphase into air with retention of the assembly and its orientation relative to the surface, as evidenced by atomic force microscopy, water contact angle measurements, and film thickness determinations by ellipsometry. Similar assemblies were also synthesized via a postgluing procedure, in which the substrate containing the LB monolayer was removed from the subphase and rapidly immersed into an aqueous solution containing poly(allylamine). The potential of combining postgluing methods with continuous LB film deposition as a surface modification technique is briefly discussed

Glued Langmuir−Blodgett Bilayers from Calix[<i>n</i>]arenes: Influence of Calix[<i>n</i>]arene Size on Ionic Cross-Linking, Film Thickness, and Permeation Selectivity

A homologous series of calix[4]arene-, calix[5]arene-, and calix[6]arene-based surfactants, containing pendant trimethylammonium and n-hexadecyl groups, have been compared with respect to their ability (i) to undergo ionic cross-linking at the air/water interface, (ii) to incorporate poly(4-styrenesulfonate) (PSS) in Langmuir−Blodgett (LB) bilayers, and (iii) to act as barriers toward He, N2, and CO2 when assembled into cross-linked LB bilayers. As these calix[n]arenes increase in size, their ability to undergo ionic cross-linking has been found to increase, the thickness of corresponding glued LB bilayers has been found to decrease, and their barrier properties and permeation selectivities have been found to increase. The likely origin for these effects and the probable mechanism by which He, N2, and CO2 cross these ultrathin films are discussed

Molecular Umbrellas

Molecular Umbrella

Molecular Umbrellas

Molecular Umbrella

Creating Poly(ethylene oxide)-Based Polyelectrolytes for Thin Film Construction Using an Ionic Linker Strategy

Creating Poly(ethylene oxide)-Based Polyelectrolytes for Thin Film Construction Using an Ionic Linker Strateg

Fully Detachable Molecular Umbrellas as Peptide Delivery Agents

A persulfated molecular umbrella, derived from cholic acid and spermidine, has been covalently attached to H-Tyr-d-Ala-Gly-Phe-d-Leu-OH (DADLE) by use of an o-dithiobenzyl carbamate linkage. Treatment of the resulting conjugate (1) with glutathione in solution resulted in the liberation of the free form of the peptide. Addition of 1 to glutathione-entrapped liposomes, prepared from 1-palmitoyl-2-oleyol-sn-glycero-3-phosphocholine (POPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylglycerol (POPG), and cholesterol [POPC/POPG/cholesterol, 72/4/24 (mol/mol/mol)], resulted in the delivery of DADLE into their aqueous interior

Minimizing Defects in Polymer-Based Langmuir–Blodgett Monolayers and Bilayers via Gluing

Polymeric surfactants were prepared by quaternization of poly­(4-chloromethylstyrene) with <i>N</i>,<i>N</i>-dimethyl-<i>N</i>-<i>n</i>-dodecylamine and <i>N</i>,<i>N</i>-dimethyl-<i>N</i>-<i>n</i>-octylamine to give <b>1</b> and <b>2</b>, respectively. Each of these polymers formed stable monolayers at the air/water interface. Injection of poly­(acrylic acid) (PAA) beneath the surface of these films led to a substantial increase in their cohesiveness (i.e., “gluing”), as evidenced by a dramatic increase in their surface viscosity. Examination of monolayers of <b>1</b> by atomic force microscopy, after being transferred to silicon wafers that were surface-modified with <i>n</i>-octadecyltrichlorosilane, showed that the presence of PAA leads to intact film. In contrast, transfer of unglued monolayers resulted in poor coverage. Comparison of the barrier properties of single glued and unglued LB bilayers formed in the presence and in the absence of PAA have shown that PAA minimizes defect formation within these ultrathin assemblies

Glued Langmuir−Blodgett Bilayers Having Unusually High He/CO₂ Permeation Selectivities

Single Langmuir−Blodgett bilayers derived from 5,11,17,23,29,35-hexakis[(N,N,N-trimethylammonium)-N-methyl-37,38,39,40,41,42-hexakis-n-hexamedecyloxy-calix[6]arene hexachloride (1), which have been ionically cross-linked (i.e., “glued together”) with poly(acrylic acid), have been found to exhibit He/CO2 permeation selectivities as high as 150. This degree of selectivity, for a membrane that is less than 6 nm in thickness, is without precedent. In principle, materials of this type could lead the way to improved membranes for hydrogen purification