Recent advances in lipid molecular design

Recent advances in lipid molecular designSantanu Bhattacharya and Avinash Bajaj

The area of lipid molecular design is attracting widespread

interest among numerous research groups worldwide. Diverse

lipid assemblies in aqueous media, such as vesicles, bilayers

and nanorods, offer new applications in chemical biology.

Lipids with specifically tailored molecular architecture have

been successfully employed as gene delivery vehicles, for

controlled drug release and the preparation of supramolecular

gels. Such molecular design of lipids, as well as their

characterization upon membrane formation, offers an insight

into the possible molecular basis of their properties. This in turn

helps in the design of further generations of lipid systems with

more predictable characteristics. Here, we present an overview

of the current trends in lipid design and their utilization in

various biochemical, physical and chemical applications.

Addresses

Department of Organic Chemistry, Indian Institute of Science,

Bangalore - 560012, India

Corresponding author: Bhattacharya, Santanu

([email protected])

Current Opinion in Chemical Biology 2005, 9:647–655

This review comes from a themed issue on

Model systems

Edited by Paolo Scrimin and Lars Baltzer

Available online 28th October 2005

1367-5931/$ – see front matter

# 2005 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.cbpa.2005.10.016

IntroductionLipids are amphiphilic organic molecules that contain a

hydrophobic part and a hydrophilic head group. Mole-

cules of this nature form aggregates in water, where the

oil-soluble hydrophobic parts of the molecules are direc-

ted into the core of the aggregates, and the water-soluble

hydrophilic parts remain in contact with water. The

various types of aggregates that are formed in water have

found numerous applications. These include gene deliv-

ery, drug encapsulation and release, metal ion sensing,

developing supramolecular assemblies and gels. Thus,

molecular design of lipids is currently an active area of

research in chemical biology. Depending upon the charge

on the head group, lipids can be cationic, anionic or

neutral; but cationic lipids are currently receiving intense

attention among researchers, because of their promise in

gene delivery. In this article, we present the membrane-

forming properties and appropriate applications of differ-

www.sciencedirect.com

ent lipids and their analogues that have been developed

in the past couple of years or so.

Metal-ion sensorsVesicles (liposomes), a type of lipid aggregate possessing

inner aqueous compartments, have been widely used as

models for biological membranes, drug carriers, nanor-

eactors and scaffolds for supramolecular devices. But

most of these applications include liposomes in a ‘uni-

vesicular’ state. Higher levels of self-assembly can be

achieved through specific and reversible associations of

vesicles into stable ‘multi-vesicular’ aggregates. Kikuchi

and co-workers [1] reported a new strategy to create a

reversible assembly system of liposomal membranes by

using an ion-recognizable gemini peptide as an inducer.

These gemini-peptide lipids (Figure 1a) are derived from

lipid units based on an amino acid backbone. Two such

units are then connected via polymethylene or oxyethy-

lene spacers. It has been shown that the transformation

between assembled and disassembled liposomes can be

reversibly controlled through heteroditopic ion recogni-

tion by gemini peptide lipids embedded in the vesicles.

By using a synthetic lipid (Figure 1b) in 1,2-dimyristoyl-

sn-glycero-3-phosphatidylcholine (DMPC) vesicles,

reversible transition between aggregates of lipid vesicles

and stacked vesicle strips was demonstrated by Wang and

co-workers [2]. This transition between two higher-level

self-assembled structures depends on the presence of

Cu2+ concentration, and the observed phenomenon is

metal ion specific.

Sensitization of lanthanide ions is important for specific

ion-based assays and sensing. Various saturated and poly-

merizable lipids (Figure 1c) with different metal-chelat-

ing ligands were developed [3�] to sensitize Eu3+

effectively, which may also be used for protein detection.

Detection of peptides and proteins plays a major role for

the diagnosis of diseases and sensing of toxins, bacteria

and viruses. Lanthanide-ion complexes have been used

during many fluorescence-based protein assays. In design

of such luminescent lanthanide complexes, metal ions

should coordinate to an organic ligand that, upon absorp-

tion of UV light, would efficiently convert the resulting

energy to the system. This combination of absorption and

energy transfer from the ligand is called an ‘antenna

effect’. The emission from the lanthanides is useful as

a sensitive detection method in biological systems. The

changes in the intensity of luminescence of lanthanides

upon binding to proteins and enzymes have been utilized

to examine the ligation sphere within the active site.

These lanthanide-ion complexes are advantageous


648 Model systems

Figure 1

Different metal ion-sensing amphiphilic molecules. (a) Gemini peptide lipids for creating reversible assemblies of liposomal membranes.

(b) Amphiphile shows reversible transition between aggregates of lipid vesicles and stacked vesicle strip. (c) Saturated and polymerizable La3+

sensing lipid moieties. (d) Eu3+ and Tb3+ metal-chelating lipids with EDTA (ethylene diamine tetraacetate) as a head group. (e) Pyrene containing

metal chelating lipids specific to Cu2+ ions. R groups are shown in the grey box.

because of their narrow emission bands, large Stoke’s

shift and long excitation state lifetimes, which are well

suited for protein detection. There was no observation of

metal-induced inter-vesicular aggregation of vesicles in

the case of the lipid shown in Figure 1c.

Malik and co-workers [4] reported the solid-phase synth-

esis of polymerizable Eu3+ and Tb3+ metal chelating

lipids (Figure 1d), bearing different hydrophobic tails

and spacers with the EDTA (ethylenediamine tetraacetic

acid) unit as a head group. These polymerizable lipo-

somes are more stable and less permeable as compared


with liposomes from saturated lipids. These authors also

reported [5�] the synthesis of pyrene-containing metal-

chelating lipids (Figure 1e), which showed selective

sensing of Cu2+ as compared with other transition metal

ions. They used the pyrene excimer/monomer emission

ratio as criteria for Cu2+ detection and showed that the

pyrene monomer emission is selectively quenched in

response to Cu2+.

Gene deliveryBecause of their high affinity with nucleic acids, cationic

lipids significantly neutralize the negative charge of plas-


Recent advances in lipid molecular design Bhattacharya and Bajaj 649

mid nucleic acids and enable them to transfer across the

negatively charged plasma membrane of eukaryotic cells.

Chaudhuri et al. [6] reported the synthesis and transfec-

tion properties of mono-, di-, and tri-lysinated cationic

lipids with various alkyl chains. A monolysinated lipid

(Figure 2a) bearing myrsitoyl chains, when used in com-

bination with helper lipid dioleoyl-L-a-phosphatidy-

lethanolamine (DOPE), shows higher DNA delivery as

compared with other analogues as well as commercially

available Lipofectamine1. Thus, the attachment of

multiple positive charge functionalities at the head

group level does not always increase the transfection

efficiencies.

Figure 2

Different amphiphilic molecules developed for gene transfection and DNA re

lipid with diamino head group. (c) Oxyethylene linkage-based cationic lipid.

with different counter ions. (e) Galactitolbased cationic lipids. (f) Cyclic-hea

(h) Gadolinium-complexed lipid. (i) T-shaped cholesterol-based derivatives.

as a nucleobase. (k) Amphiphiles recognise thymidine bases of polythymidi


A series of diamino cationic lipids [7] possessing hydro-

carbon chains of different lengths (Figure 2b) have been

designed and synthesized. These were tested for their

ability to induce plasmid delivery. The cationic lipid

having myristoyl chains showed DNA binding at low

N/P (1:1) ratio and show better transfection efficiency

as compared with other homologues having longer or

shorter alkyl chains.

Vierling and co-workers [8] have utilized the enhanced

lipophobic and hydrophobic character of fluorinated

hydrocarbon chains in the design of cationic and helper

lipids. It has been shown that lipids bearing fluorocarbon

chains prevent the lipoplexes from disintegration by

cognition studies. (a) Monolysinated cationic lipids. (b) Cationic

(d) Cationic lipid with 2,4,6-trimethyl pyridine head group,

ded cationic lipid. (g) Galactose-based double chain amphiphile.

(j) Nucleoside phosphocholine-based amphiphiles having uridine

ne oligonucleotide.


650 Model systems

detergent micelles; this, in turn, prevents degradation of

DNA from its lipoplexes with these lipids. These lipo-

plexes are also shielded from their interactions with

lipophilic and hydrophilic compounds. Thus the F-

DOSPA/F-PE lipoplexes were shown to be considerably

more stable to lytic activity of sodium taurocholate (STC)

micelles than F-DOSPA/DOPE, whose lipoplexes are

more stable than Lipofectamine1. The higher the degree

of fluorination, the higher is the stability of lipoplexes.

The transfection efficiency of F-DOSPA/F-PE lipo-

plexes was 50-fold better than that of F-DOSPA/DOPE

lipoplexes, and 30-fold better than that of Lipofecta-

mine1 in the presence of 7.5 mM STC micelles. But

the efficiencies of F-DOSPA/F-PE and F-DOSPA/

DOPE lipoplexes for gene delivery were less compared

with F-DOGS lipoplexes, because of the poor miscibility

between STC micelles and F-DOGS, a lipid bearing two

fluorinated alkyl chains. Therefore, lipoplexes from F-

DOGS are more stable than F-DOSPA/F-PE (or DOPE)

lipoplexes.

Bhattacharya and co-workers have shown [9,10] that the

linkage functionality between the hydrocarbon chains and

polar head group has an important impact on the transfec-

tion efficiencies of cationic lipids. Four cationic lipids with

short oxyethylene segments were synthesized. Of these,

the unsymmetrical lipid shown in Figure 2c exhibited

better plasmid delivery compared with its counterparts.

The mismatch in the linkage region induces disorder in

lipid packing of such aggregates [11], making such lipid

assemblies more susceptible to DNA complexation.

Balaban and co-workers [12�] have reported a compre-

hensive structure–activity correlation study of an inter-

esting series of pyridinium cationic lipids with various

structural variations at the hydrophobic anchor, linker and

counterion. Three different series of cationic lipids bear-

ing different linkers and hydrophobic anchors with a

2,4,6-trimethyl pyridinium as a head group were synthe-

sized. The authors demonstrated the better transfecting

properties of lipids bearing aliphatic linkers and myristoyl

fatty acid-based chains (Figure 2d) compared with other

analogues.

Cationic glycolipid analogues possessing various hydro-

carbon chains with different spacers were synthesized and

tested for their gene delivering capabilities by Chaudhuri

and co-workers [13]. The cationic lipids with longer

spacers between the galactosyl moiety and cationic long

alkyl chains were found to be less potent gene delivery

vehicles compared with the galactitol lipid of Figure 2e

devoid of any spacer.

Chaudhuri and co-workers [14] reported the synthesis of

cationic lipids bearing a conformationally strained cyclic

head group (Figure 2f), analogous to cationic lipids pos-

sessing an ‘open’ head group. These lipids show signifi-


cant enhancement in gene transfection across mouse

lungs compared with their open head analogues

Novel galactose-based double-chain bolaamphiphiles

(Figure 2g) [15] have been developed. These are more

efficient as non-specific gene transfer agents than their

counterparts bearing a single long chain. They are pro-

mising vectors for specific in vivo gene delivery to hepa-

tocytes, which have galactose-specific asailoglycoprotein

(ASGP) receptor moieties on their cell surfaces.

Byk et al. [16] reported a new strategy based on magnetic

resonance imaging (MRI) to follow the distribution of

lipoplexes in vivo. They have synthesized a gadolinium-

chelating cationic lipid (Figure 2h) and correlated its invivo distribution with the transfection efficiency of catio-

nic lipid RPR-120535. MRI is advantageous because it

allows non-invasive visualization of gene-delivery com-

plexes. The transfection efficiency of the gadolinium-

chelating cationic lipid–DNA complex itself is lower

because of its reduced binding affinity for DNA, but

addition of 1% and 5% of gadolinium-complex to the

cationic lipid RPR-120535 did not affect the transfection

efficiency of the cationic lipid.

T-shaped polyamines are thought to resemble the cog-

nate ligand for a cell-surface receptor to facilitate the

attachment and entry to cells. On the basis of this ratio-

nale, Park and co-workers [17] have developed new

cholesterol-based cationic lipids (Figure 2i) with T-

shaped configuration for inducing efficient and non-toxic

gene transfer to cells.

Nucleoside phosphocholine amphiphiles are another new

class of lipid design. They possess both the information

required for molecular recognition of specific nucleic acids,

and compartmentalization characteristics of liposomes,

which give rise to novel supramolecular assemblies.

Barthelemy and co-workers [18�] reported the transition

between liposome-like bilayer structures for the fluid

phase above Tm and DNA-like helical fibers in crystalline

solid-state below Tm, for nucleoside phosphocholine-

based amphiphiles (Figure 2j) with uridine as a nucleo-

base. Out of these amphiphiles, three (R = n-C16H33, n-

C18H37, n-C20H41; Figure 2j) form hydrogels, which can

also entrap DNA efficiently, whereas two (R = n-C14H29,

n-C16H33) form organogels in cyclohexane. Different

types of aggregates were also observed from adenosine-

based amphiphiles depending upon the method of the

preparation of supramolecular assembly [19].

Different kinds of amphiphiles [20�] were synthesized

using three monosaccharides (a-D-glucose, a-D-galactose,

a-D-mannose), three C-18 fatty acids (stearic, oleic and

linoleic), and six diamino-aromatic linkers (2,3-, 2,5- and

2,6-diaminopyridine and 1,2-, 1,3- and 1,4-diaminoben-

zene). Out of these derivatives, two (Figure 2k) were



shown to form fibrous assemblies upon dispersion in

water. Combination of hydrophobic interactions and

hydrogen bonding presumably favor the formation of

nanotubular structures. Nanotubes from the amphiphile

with R = 9(z)-C16H31 are shown to bind with thymidine

bases of polythymidine via three-point hydrogen bonded

networks.

A major problem with the use of cationic lipids as gene

carriers is their inadequate compatibility with serum and

other biological fluids, which often renders them unsui-

table for in vivo use. To address this problem, PEG

(polyethylene glycol) has been attached [21] to cationic

lipids to provide stealth character, and thus avoid inter-

actions with plasma proteins, destabilization, and clear-

ance of lipoplexes by macrophages before they reach the

diseased tissue. But PEG also provides a stable barrier,

which strongly inhibits nucleic acid release from endo-

somes. Toward this end, exchangeable PEG derivatives

(Figure 3a) with different alkyl chain lengths were

synthesized to examine the possibility for transient sta-

bilization of lipoplexes [22].

Oligosaccharides are an alternative to PEG as a stealth

polymer; they are able to stabilize non-viral vector sys-

tems in body fluids without affecting transfection effi-

ciencies. Although Miller and co-workers [23] could not

Figure 3

Different PEG-based, carbohydrate based and pH-sensitive based lipids. (a

the carbohydrate part of which can be derived from mannose, glucose, gala

maltoheptose. (c) Cationic lipid based on an acid sensitive acylhydrazone li

pH-sensitive cationic lipid. (f) Lipids bearing a photocleavable moiety.


achieve a substantial stealth activity toward serum with

their neoglycolipids (Figure 3b), their findings do provide

a new pathway for the use of carbohydrate-bearing lipids

toward gene or drug delivery.

Triggerable lipidsIn a recent review, Guo and Szoka [24��] presented

various chemical and physico-chemical approaches to

prepare liposomes that can be triggered to induce the

release of drugs in a controlled fashion. Different triggers

can be used; for example, redox potential, temperature or

the level of a specific enzyme.

Among four cationic lipids, designed on the basis of acid-

sensitive acylhydrazone function [25], that shown in

Figure 3c is the most effective, because of its greater

stability and better DNA-binding capability.

Bessodes and co-workers [26] have shown that lowering

pH results in the precipitation and then degradation of

pH-sensitive PEG lipids (Figure 3d). The non-pH-sen-

sitive PEG lipids maintain the complex colloidal stability.

Therefore, pH-sensitive PEG lipids make better gene

delivery vehicles.

Chaudhuri and co-workers [27�] investigated the issue of

relative transfection efficiencies of pH-sensitive cationic

) Exchangeable PEG-based cationic lipids. (b) Neoglycolipids,

ctose, glucouronic acid, maltose, maltotriose, maltotetrose and

nkage. (d) pH-sensitive PEG orthoester lipid. (e) Histidine-based


652 Model systems

liposomes. They have shown that transfection efficiencies

of lipids cannot be explained only on the basis of pH

sensitivity of lipoplexes. It was shown that the cytosolic

Figure 4

Amphiphilic molecules with different properties and applications. (a) Therma

lipid analogues. (c) Unsymmetrical bolaamphiphiles, which form microtubes

nanotubes in water and, on mixing with tetraethoxysilane, forms a gel. (e) C

that can undergo interleaflet cross-linking.


delivery of DNA with pH-sensitive histidinylated lipid

(Figure 3e) was higher than that of lipids having a less pH-

sensitive histidine head group. With a nuclear gene

lly gated liposomes for drug delivery. (b) Zwitterionic gemini

and nanotubes in water. (d) Proline-based lipid, which forms

hromophoric amphiphiles based on ortho-nitrophenol. (f) Lipids



expression system, transfection efficiency of less pH-

sensitive lipid is more or slightly less than other lipid

analogues.

Cationic lipids (Figure 3f) having photo-cleavable o-nitro-

benzyl moieties as a spacer were tested for gene transfec-

tion [28]. Photo-cleavage of lipids facilitates the escape of

DNA from endosomes to increase their gene transfection

efficiency.

Drug deliveryChen and Regen [29��] described a new approach for

controlled drug delivery using thermally gated liposomes.

These are a combination of pore-forming amphiphile

derived from cholic acid (Figure 4a) and the thermally

sensitive lipid 1,2-dipalmitoyl-sn-glycero-3-phosphati-

dylcholine (DPPC). They clearly showed the thermal

dependence of the release of carboxyfluorescein from

these thermally gated liposomes, which was also linearly

proportional to the mole percentage of these amphiphiles

(Figure 4a) in DPPC co-vesicles.

Applications of other recently developedlipid analoguesMenger and Peresypkin [30�] demonstrated the forma-

tion of strings of vesicles using 10 unsymmetrical zwitter-

ionic gemini lipids (Figure 4b). Nine out of these

unsymmetrical zwitterionic gemini amphiphiles led to

aqueous gel formation. The authors attributed the vesicle

cohesion to the gelation behavior. Rheological experi-

ments confirmed the reversibility of gelation with this

system.

Masuda and Shimizu [31] reported the formation of nano-

and micro-tubes from unsymmetrical bolaamphiphiles,

based on v-[N-b-glucopyranosylcarbamoyl] alkanoic

acids (Figure 4c) with even oligomethylene chains. Nano-

tubes possess both an outer surface covered with sugar

hydroxyl groups and an inner surface covered with car-

boxylic acid groups. The ratio of molecular length (L) to

the thickness (d) of monolayer lipid membrane (MLM)

indicates the unsymmetrical MLM composition of the

nanotubes and polymorphic nature of the microtubes.

Shimizu and co-workers [32] reported the self-assembly

of a proline-based lipid (Figure 4d) in water to form

nanotube structures. These nanotube structures consist

of a single bilayer wall. Aqueous dispersion containing

lipid nanotubes, when mixed with tetraethoxysilane,

leads to slow gelation. Distribution of positive charge

all over the surface of nanotubes and their catalytic

activity in weakly acidic pH helps in the formation of

silica nanotubes of 8 nm wall thickness without the need

of any catalyst.

The 2-nitrophenol group as a pH trigger [33] has been

used to study the pH dependent liposome fusion of egg


phosphatidylcholine (egg PC) liposomes containing chro-

mophoric lipids (Figure: 4e). From absorption spectra, it

has been observed that protonated 2-nitrophenol groups

of the three nitrophenol compounds in Figure 4e are

embedded in bilayer membranes, whereas deprotonated

2-nitrophenol groups of the second and third compounds

are located in less hydrophobic part as compared with the

first, because of greater hydrophobicity of the latter.

‘Face-to-face’ associations in bilayer membranes have

been suggested for protonated 2-nitrophenol groups of

the first and third nitrophenol compounds on the basis of1H-NMR and absorption spectra.

Lipid bilayer systems with increased stability are neces-

sary for their wide applications as molecular sensors,

diagnostic devices and medical implants, where chemical

and physical conditions are more rigorous. Keeping these

applications in mind, different kinds (Figure 4f) of lipids

[34] have been synthesized that can undergo inter-leaflet

cross-linking upon formation of their lipid bilayers. This

inter-leaflet cross-linking is a consequence of simple

bimolecular nucleophilic substitution, Michael addition

and Diels–Alder reactions, and results in an increase in

lipid bilayer stability, while maintaining the membrane

fluidity.

A mechanosensitive channel of large conductance pro-

tects bacteria against severe osmotic downshifts. Poolman

et al. [35] have shown the reversible activation of this

channel with the help of a light-sensitive lipid mimic.

The increase in channel activity is the result of light-

dependent switching of lipid from the trans to cis con-

formation. This cis–trans isomerization causes subtle

changes in overall lateral pressure in the lipid bilayer,

which helps in the activation of the channel.

Conclusions and future directionsNature remains an ultimate source of inspiration and

information for chemical biologists. Many of the newly

designed lipids are distant replicates of natural lipids or

closer analogues. Nevertheless, their functions and utility

may be successfully extended beyond the roles known for

molecules derived from nature. Research into lipid design

in the past couple of years has given additional insights that

justify continuing use of such materials. Their applications

in chemical biology and related areas have opened new

toolboxes for research groups for the utilization of various

types of design. Although diverse kinds of cationic lipids

have been designed and tested as gene delivery vehicles,

there remains a need for further improvement in the

design of lipids for efficient gene transfer to different

kinds of cells in vivo and their ultimate use in gene therapy

AcknowledgementsSB is a recipient of the Bioscience Career Development Award,Department of Biotechnology, India. AB thanks the Council ofScientific and Industrial Research, New Delhi, for the award of aJunior Research fellowship.


654 Model systems

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� of special interest

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Menger FM, Peresypkin AV: Strings of vesicles: flow behavior inan unusual type of aqueous gel. J Am Chem Soc 2003,125:5340-5345.

This paper describes the unusual properties of various unsymmetricalzwitterionic gemini lipids.

31. Masuda M, Shimizu T: Lipid nanotubes and microtubes:experimental evidence for unsymmetrical monolayermembrane formation from unsymmetrical bolaamphiphiles.Langmuir 2004, 20:5969-5977.



32. Ji Q, Iwaura R, Kogiso M, Jung JH, Yoshida K, Shimizu T: Directsol-gel replication without catalyst in an aqueous gel system:from a lipid nanotube with a single bilayer wall to a uniformsilica hollow cylinder with an ultrathin wall. Chem Mater 2004,16:250-254.

33. Tomohiro T, Ogawa Y, Okuno H, Kodaka M: Synthesis andspectroscopic analysis of chromophoric lipids inducingpH-dependent liposome fusion. J Am Chem Soc 2003,125:14733-14740.


34. Halter M, Nogata Y, Dannenberger O, Sasaki T, Vogel V:Engineered lipids that cross link the inner and outer leaflets oflipid bilayers. Langmuir 2004, 20:2416-2423.

35. Folgering JHA, Kuiper JM, de Vries AH, Engberts JBFN,Poolman B: Lipid-mediated light activation of amechanosensitive channel of large conductance.Langmuir 2004, 20:6985-6987.


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Recent advances in lipid molecular design