Materials chemistry

Liposomes derived from molecular vases

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Liposomes are ubiquitous components of skin moisturizers and other personal-care products. Modified liposomes prepared from receptor-like molecules open up fresh opportunities for therapeutic and industrial applications.

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The imaginations of diverse groups of scientists, from physicists to pharmacologists, have been captured by liposomes — simple mimics of highly complex cell membranes. Typical liposomes are spheres with walls consisting of bilayers of amphiphilic lipids (molecules that have hydrophilic, polar head groups and hydrophobic, non-polar tails). Their unique structure enables them to trap hydrophobic molecules within their bilayer and hydrophilic molecules within their interior (Fig. 1a). Writing in Chemical Communications, Kubitschke et al.1 add another dimension to this cargo-carrying ability with their report of liposomes derived from vase-shaped cavitands2, which are receptor-like molecules that wrap around 'guest' compounds. The cavitands can encapsulate these guest molecules and present them at high densities at the liposome surface, a capability that might be useful for drug delivery.

Figure 1: The evolution of liposomes.
figure1

a, Simple liposomes are vesicles that have a shell consisting of a lipid bilayer. A liposome can trap hydrophobic guest molecules a few nanometres in diameter (red spheres) within the hydrophobic bilayer, and hydrophilic guests up to several hundred nanometres (green star) in its larger interior. b, In 'stealth' liposomes developed for drug-delivery applications, the lipid bilayer contains a small percentage of polymer lipids. Peptides (blue rectangle) that target specific biological targets may also be attached to the polymers. c, Most cationic liposome–DNA complexes have an onion-like structure, with DNA (purple rods) sandwiched between cationic membranes. d, Kubitschke et al.1 report liposomes in which the bilayer assembles from cavitands — vase-shaped molecules — to which the authors attached hydrophobic and hydrophilic chains. The cavitands can trap ångström-sized guest compounds (yellow diamonds) in their hydrophobic cavities. These vesicles can therefore encapsulate guest molecules of different sizes in the cavitands, the bilayer and the liposome's interior.

Liposomes — also known as vesicles — were serendipitously discovered in 1964 during investigations of phospholipids3. The demonstration of their encapsulation properties, and the remarkable structural resemblance between liposomes and cell membranes in electron micrographs, led to the realization that lipids form the main permeability barriers of biological membranes. Today, by far the largest use of liposomes and their encapsulating properties is in the multibillion-dollar personal-care industry4, as moisturizers and carriers of nutrients in gels and cream formulations. But they have also emerged as a research tool, within which biologists can isolate and study individual proteins (or a few selected proteins), rather than taking on the far more onerous task of working out the functions of the many associated proteins found in biological membranes.

Researchers quickly recognized the promise of liposomes as carriers of drugs and genes for therapeutic applications4. A major early set-back, however, was the realization that, in vivo, drug-carrying liposomes are quickly removed from the bloodstream by immune cells. A clever solution to this problem is to coat liposomes with water-soluble polymers, by chemically attaching polymer molecules to the lipids' polar heads5 (Fig. 1b). This generates 'stealth' liposomes — the polymers prevent the attachment of plasma proteins that label foreign matter for removal by immune cells.

The development of techniques for attaching polymers to liposomes set the stage for further tailoring of vesicles through chemical modification of their lipids' head groups. The protruding polymer chains of stealth liposomes also provide a convenient handle that allows these vesicles to be targeted to specific biological sites: peptides that bind to receptors on specific cells and tissues can be attached at the distal ends5 of the polymers (Fig. 1b).

The generation of cationic liposomes — rather than the neutral or anionic stealth liposomes — greatly expanded the size of the cargo that could be carried by vesicles, and their range of applications. The discovery that cationic liposomes can form electrostatic complexes with DNA and so deliver it to cells6,7 re-energized the field of gene therapy. Liposome–DNA complexes were first tested8 as therapeutic agents in humans in 1993, and are currently being investigated in more than 110 clinical trials worldwide9. These trials address a wide range of disorders9,10, including some associated with a single gene (such as cystic fibrosis) and others that involve multiple genes (such as cancers). Liposome–DNA complexes exhibit a variety of liquid-crystalline phases11, including a multilamellar (onion-like) structure in which single layers of DNA molecules are inserted between lipid bilayers12 (Fig. 1c).

Kubitschke and colleagues' work adds a new dimension to the search for the optimal drug carrier by covalently incorporating cavitands into amphiphiles (Fig. 1d). Cavitands2 contain distinctly shaped 'holes' within a rigid molecular framework, and so can selectively accommodate guest molecules. Previous work had achieved the insertion of only low concentrations of cavitands from solution into phospholipid membranes on solid supports13 and into vesicles14. The selective binding of guests derived from biotin — a molecule that binds to the protein avidin — within a cavitand's hydrophobic pocket has also been described13, together with the ability of these guests to bind avidin-derived proteins at the interface of the liposome with water.

By synthesizing amphiphilic cavitands that themselves form liposomes, Kubitschke et al. have overcome the limitation of low cavitand concentration. The synthesis required some special measures, probably because of the size and hydrophobicity of the cavitand framework — for example, the authors attached four lipid tails to the cavitand, instead of the more commonly used two. The lipid tails contained thioether linkages (a sulphur atom between two carbons), which could be used to anchor the cavitands to gold surfaces. This could enable monolayers of cavitands to be prepared on gold surfaces, which might be useful for applications such as molecular sensors.

When self-assembled into liposomes, the amphiphilic cavitands can encapsulate guests on three distinct length scales: ångström-sized molecules can be trapped in the vase-like hydrophobic cavity of each cavitand; molecules a few nanometres across can be caught in the hydrophobic bilayer of the liposome; and molecules up to 100 nanometres in size, perhaps even up to several hundred nanometres, can be encapsulated in the liposome's interior. Intriguingly, this means that the different-sized guests are entrapped in locations that have distinct dimensionalities — point-like within the cavitand, two-dimensional in the bilayer and three-dimensional in the liposome's centre.

Future work should characterize cavitand liposomes and their cargo in more depth. For example, cryogenic transmission electron microscopy could be used to directly observe the structures of the liposomes without needing to dry the samples. And a technique known as high-resolution X-ray reflectivity could be used to study amphiphilic cavitand bilayers on solid supports — to determine the location of guests in the direction perpendicular to the bilayer with ångström resolution. Such analyses could determine how accessible the guest molecules inside the cavitand are from outside the liposome.

Further development of cavitand liposomes as drug-delivery vehicles will undoubtedly see the addition of stealth and cell-targeting properties. In fact, Kubitschke et al. have already used eight short chains of poly(ethylene glycol) — the water-soluble polymer that forms the repulsive shell of most stealth liposomes — to line the rim of their cavitands so that the molecules retain their binding properties in water (Fig. 1d).

A class of vesicle related to liposomes is the polymersome15 — vesicles that are made from amphiphilic polymers, rather than lipids. Another possible extension of the authors' work would therefore be the development of polymersomes formed from cavitands that have hydrophilic and hydrophobic polymers attached at opposite ends. Polymersomes are tougher than liposomes, and can sustain greater deformation before rupture. Aside from chemical delivery, cavitand polymersomes would therefore be suitable for applications in which assemblies of judiciously chosen guest molecules undergo large rates of deformation, such as molecular coatings that have controlled friction properties.

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Correspondence to Cyrus R. Safinya or Kai K. Ewert.

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