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

Exchangeable Mimics of DPPC and DPPG Exhibiting Similar Nearest-Neighbor Interactions in Fluid Bilayers

The interactions between an exchangeable mimic of 1,2-dipalmitoyl-<i>sn</i>-glycero-3-phosphocholine (DPPC), Phos(±), with an exchangeable mimic of cholesterol, Chol, have been analyzed in fluid bilayers by means of nearest-neighbor recognition measurements. These interactions have been found to be very similar to those of an exchangeable mimic of 1,2-dipalmitoyl-<i>sn</i>-glycerol-3-phospho-(1′rac-glycerol) (DPPG), Phos(−), interacting with Chol. Thus, both phospholipids have a similar preference for becoming nearest-neighbors of Chol in the liquid-ordered (<i>l</i>₀) phase, and both mix, ideally, with Chol in the liquid-disordered (<i>l</i>_d) phase. These findings, together with the almost negligible screening effects found for the latter, provide strong evidence that electrostatic forces play a minor role in the preference that both phospholipids have in becoming a favored nearest-neighbor of Chol. They also imply that the main driving force for forming the liquid-ordered phase, and for defining the lateral organization of this phase, is an intrinsic affinity that high-melting lipids and cholesterol have for each other

Clicking the Surface of Poly[1-(trimethylsilyl)propyne] (PTMSP) via a Thiol–Ene Reaction: Unexpected CO₂/N₂ Permeability

The surface modification of poly­[1-(trimethylsilyl)­propyne] (PTMSP) film via a thiol–ene click reaction with sodium 3-mercapto-1-propanesulfonate has yielded membranes having a CO2 permeance as high as 530 GPU with a CO2/N2 selectivity of 21. This level of performance, together with the simplicity of this surface modification, suggests that such materials could become viable alternatives to some of the most promising membrane materials that are currently being explored for the practical capture of CO2 from flue gas

Thermally Gated Liposomes

The combined use of a pore-forming amphiphile, 1 (derived from lysine, cholic acid, and spermine), and thermally sensitive liposomes (made from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPC) to create “thermally gated liposomes” (TGLs) has been demonstrated. Thus, at temperatures that lie above the gel to liquid−crystalline phase transition temperature of DPPC (i.e., 41 °C), 1 creates pores within DPPC membranes through which entrapped aqueous solutes, such as carboxyfluorescein, can readily pass. Below this temperature, efflux rates are greatly reduced. The potential of TGLs as devices for the targeted delivery of therapeutic agents is briefly discussed

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

Kinetic Evidence for the Existence and Mechanism of Formation of a Barrel Stave Structure from Pore-Forming Dendrimers

A dendritic approach to the construction of a homologous series of pore-forming amphiphiles has been developed, based on the use of spermidine, spermine, lysine, and cholic acid. A kinetic analysis of Na+ transport across bilayers of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine by three dendritic amphiphiles has provided the strongest evidence to date for a barrel stave structure

A Synthetic Ionophore That Recognizes Negatively Charged Phospholipid Membranes

A Synthetic Ionophore That Recognizes Negatively Charged Phospholipid Membrane

Molecular Umbrellas

Molecular Umbrella

An Ion Conductor That Recognizes Osmotically-Stressed Phospholipid Bilayers

A synthetic ion conductor (1), derived from cholic acid and spermine, has been found capable of recognizing osmotic stress in liposomes made from 1,2-dipalmitoleoyl-sn-glycero-3-phosphocholine [(C16:1)PC]. Thus, when large unilamellar vesicles of (C16:1)PC are placed under hypotonic conditions, the Na+/Li+ transport activity of 1 increases by as much as 1 order of magnitude, relative to isotonic condition

Influence of the Linkage Region of Sphingolipids on Sphingolipid−Phospholipid Mixing in Cholesterol-Rich Bilayers^†

The influence of the linkage region of a sphingolipid on its mixing with a phospholipid in cholesterol-rich bilayers has been examined by use of the nearest-neighbor recognition method (Davidson, S. K. M.; Regen, S. L. Chem. Rev. 1997, 97, 1269). Thus, an analysis of equilibrium dimer distributions derived from an exchangeable sphingolipid monomer (SL, made from N-stearoyl-d-erythro-sphinganine) or a phospholipid analogue (PL, made from 1-myristoyl-2-stearoyl-sn-glycero-3-phosphoethanolamine) plus a shorter phospholipid (14, made from 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine) has revealed a preference for homolipid association in SL/14-based bilayers; that is, the linkage region of the sphingolipid promotes its segregation from the phospholipid. Inclusion of 20−40 mol % cholesterol increases this preference for homolipid association. The magnitude of this effect is similar to that found in cholesterol-rich bilayers containing two exchangeable phospholipids, which differ in length by four methylene units, that is, 18 (made from 1,2-distearoyl-sn-glycero-3-phosphoethanolamine) and 14. The relevance of these findings to the concept of lipid rafts is briefly discussed