Lipid nanotechnology

Abstract

Nanotechnology is a multidisciplinary field that covers a vast and diverse array of devices and machines derived from engineering, physics, materials science, chemistry and biology. These devices have found applications in biomedical sciences, such as targeted drug delivery, bio-imaging, sensing and diagnosis of pathologies at early stages. In these applications, nano-devices typically interface with the plasma membrane of cells. On the other hand, naturally occurring nanostructures in biology have been a source of inspiration for new nanotechnological designs and hybrid nanostructures made of biological and non-biological, organic and inorganic building blocks. Lipids, with their amphiphilicity, diversity of head and tail chemistry, and antifouling properties that block nonspecific binding to lipid-coated surfaces, provide a powerful toolbox for nanotechnology. This review discusses the progress in the emerging field of lipid nanotechnology.

Figure 1

(a) Physico-chemical properties of phospholipids. Phospholipids are composed of a hydrophilic head group and hydrophobic tails (N = 1–6). PC: phosphatidylcholine, LPC: LysoPC, CL: cardiolipin, LPS: lipopolysaccharide. The head group may carry a positive or negative charge. It may also be neutral but possess a significant electric dipole which enforces particular arrangements in the monolayer and bilayer assemblies. Self assembly of phospholipids results in bilayers or monolayers. Bilayers are birefringent [28], thermally conductive (energy transfer on sub-picosecond time scales; κ~several Watt/mK [20]), behave as insulators perpendicular to the membrane and in the core part whereas they are electrically conductive within the plane of the membrane due to proton hopping in the interfacial water [29]. Assembled bilayers display different phases depending on the temperature (T) and pressure (P) of the environment. The fluid bilayer is also deformable and introducing curvature may lead to spatial redistribution of lipids, some preferring certain curved regions. Lipid bilayer can form topologically rich structures: a spherical bilayer (genus 0) vesicle, a genus 1 and a genus 2 vesicle [17,19] are shown. In addition to phospholipids, also other lipids such as sterols have been used in nanotechnological applications; (b) Lipid based nano-devices. Two examples of hybrid lipid particles are presented: in one case the particles are enclosed by the vesicle and in the other case the particles are embedded in between the leaflets. Nano-containers can be formed when a hard nano well is sealed by a lipid bilayer. Membrane pores can be generated within a bilayer by applying voltages or with the help of carbon nanotubes functionalized with hydrophilic groups at their ends. A composite structure made of silicon nano-wire and enzyme functionalized lipid bilayer is shown. Another example of lipid based nanostructures with applications in electronics is lipid bilayer-graphene hybrid where graphene is embedded in between the leaflets of a bilayer and thereby the graphene’s physical properties are modulated; (c) Liposomes functionalized with nanoparticles allowing for radiation/magnetic field triggered cargo release [–36]. The ticks on the box sides indicate the size or the size range of the synthesized particles.

Figure 1

(a) Physico-chemical properties of phospholipids. Phospholipids are composed of a hydrophilic head group and hydrophobic tails (N = 1–6). PC: phosphatidylcholine, LPC: LysoPC, CL: cardiolipin, LPS: lipopolysaccharide. The head group may carry a positive or negative charge. It may also be neutral but possess a significant electric dipole which enforces particular arrangements in the monolayer and bilayer assemblies. Self assembly of phospholipids results in bilayers or monolayers. Bilayers are birefringent [28], thermally conductive (energy transfer on sub-picosecond time scales; κ~several Watt/mK [20]), behave as insulators perpendicular to the membrane and in the core part whereas they are electrically conductive within the plane of the membrane due to proton hopping in the interfacial water [29]. Assembled bilayers display different phases depending on the temperature (T) and pressure (P) of the environment. The fluid bilayer is also deformable and introducing curvature may lead to spatial redistribution of lipids, some preferring certain curved regions. Lipid bilayer can form topologically rich structures: a spherical bilayer (genus 0) vesicle, a genus 1 and a genus 2 vesicle [17,19] are shown. In addition to phospholipids, also other lipids such as sterols have been used in nanotechnological applications; (b) Lipid based nano-devices. Two examples of hybrid lipid particles are presented: in one case the particles are enclosed by the vesicle and in the other case the particles are embedded in between the leaflets. Nano-containers can be formed when a hard nano well is sealed by a lipid bilayer. Membrane pores can be generated within a bilayer by applying voltages or with the help of carbon nanotubes functionalized with hydrophilic groups at their ends. A composite structure made of silicon nano-wire and enzyme functionalized lipid bilayer is shown. Another example of lipid based nanostructures with applications in electronics is lipid bilayer-graphene hybrid where graphene is embedded in between the leaflets of a bilayer and thereby the graphene’s physical properties are modulated; (c) Liposomes functionalized with nanoparticles allowing for radiation/magnetic field triggered cargo release [–36]. The ticks on the box sides indicate the size or the size range of the synthesized particles.

Figure 2

Shear-stress sensitive nano-sized lipid vesicles for targeted drug delivery. (a) Schematic of the design, in which changes in endogenous shear stress trigger drug release from the vesicles. (b) Experimental set-up. An extracorporeal heart pump is connected to a plastic mimic of normal or constricted arteries and the loaded vesicles are allowed to circulate in the artificial cardio-vascular system for 20 min. (c,d) Fluorescence release patterns of PC vesicles with 0–1 mol% Brij S10 at 37 8 °C. Release in the normal arterial model (c) and in the constricted artery model (d). Brij S10 concentration is plotted versus number of passes through the vascular system, with fluorescence release along the z-axis. After subtraction of background fluorescence release, the fluorescence signal represents the fractional additional release as result of circulation in the arterial model. Figure is adapted from [46] with permission.

Figure 2

Shear-stress sensitive nano-sized lipid vesicles for targeted drug delivery. (a) Schematic of the design, in which changes in endogenous shear stress trigger drug release from the vesicles. (b) Experimental set-up. An extracorporeal heart pump is connected to a plastic mimic of normal or constricted arteries and the loaded vesicles are allowed to circulate in the artificial cardio-vascular system for 20 min. (c,d) Fluorescence release patterns of PC vesicles with 0–1 mol% Brij S10 at 37 8 °C. Release in the normal arterial model (c) and in the constricted artery model (d). Brij S10 concentration is plotted versus number of passes through the vascular system, with fluorescence release along the z-axis. After subtraction of background fluorescence release, the fluorescence signal represents the fractional additional release as result of circulation in the arterial model. Figure is adapted from [46] with permission.

Figure 3

Network of lipid-encapsulated droplets. (a) Schematic illustration of a multisome. An oil drop encapsulates aqueous droplets that are connected by lipid bilayers. The bilayer incorporated protein pores allow the droplets in the network to communicate by exchanging molecules and ions. Similarly, pores in bilayers in contact with bulk solution provide routes for exchange between the droplet network and the bulk. Droplet content release can be triggered by pH- or temperature-induced rupture of the bilayers; (b) Schematic of an encapsulated two-droplet network, showing the lipid monolayers and bilayers. (c–e) Images of the multisomes containing one (c), two (d) and three (e) inner droplets. Oil drops were suspended on wire loops to allow extended analysis. Aqueous droplets were dyed with 25 μM sulphorhodamine 101 (red) or fluorescein (green). Scale bars, 400 μm. Figure is adapted from [112] with permission.

Figure 3

Network of lipid-encapsulated droplets. (a) Schematic illustration of a multisome. An oil drop encapsulates aqueous droplets that are connected by lipid bilayers. The bilayer incorporated protein pores allow the droplets in the network to communicate by exchanging molecules and ions. Similarly, pores in bilayers in contact with bulk solution provide routes for exchange between the droplet network and the bulk. Droplet content release can be triggered by pH- or temperature-induced rupture of the bilayers; (b) Schematic of an encapsulated two-droplet network, showing the lipid monolayers and bilayers. (c–e) Images of the multisomes containing one (c), two (d) and three (e) inner droplets. Oil drops were suspended on wire loops to allow extended analysis. Aqueous droplets were dyed with 25 μM sulphorhodamine 101 (red) or fluorescein (green). Scale bars, 400 μm. Figure is adapted from [112] with permission.

Figure 4

Lipid multilayer optical diffraction grating. (a) Schematic of the functional waveguide grating couplers. Light of a supercontinuum laser source is coupled into a single-mode strip waveguide through an optical fiber and decoupled under different angles by the grating coupler; (b,c) Photographs of the coupler at 308 and 458, where the red and green portions of the guided laser are coupled to radiation modes, respectively; (d,e) Fluorescence overlay of red and green fluorescence from rhodamine and fluorescein labelled lipids, respectively, integrated with a pitch (=2d) of 2 μm by dip-pen nanolithography (DPN) patterning on a waveguide (horizontal green line is due to autofluorescence). Figure is adapted from [157] with permission.

Figure 5

Computer simulation of the translocation of nanoparticles with different shapes across a lipid bilayer (a), an ellipsoid particle is schematically illustrated. (b) The minimum driving forces needed to pass the ellipsoid particles of different volumes through the lipid bilayer. The shape anisotropy of the nanoparticles is adjusted by changing the aspect ratio (L_a/L_c) at fixed L_b and volume. r_c is the force range. (c,d) Snapshots of computer-simulation of the translocation of the particle with vertical (c) and horizontal (d) initial orientations. L_a = 1.6 nm, L_b = 3.2 nm and L_c = 6.4 nm (c); L_a = 6.4 nm, L_b = 3.2 nm and L_c = 1.6 nm (d). Blue, ellipsoid; red, lipid heads; yellow, lipid tails. Figure is adapted from [214] with permission.