University of Groningen Nucleic acid amphiphiles Kwak ... · Nucleic acid amphiphiles: synthesis and self-assembled nanostructures w Minseok Kwak and Andreas Herrmann* Received 24th

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Nucleic acid amphiphilesKwak, Minseok; Herrmann, Andreas; Clever, Guido; Mao, Chengde; Shionoya, Mitsuhiko;Stulz, EugenPublished in:Chemical Society Reviews

DOI:10.1039/c1cs15138j

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Citation for published version (APA):Kwak, M., Herrmann, A., Clever, G. (Ed.), Mao, C. (Ed.), Shionoya, M. (Ed.), & Stulz, E. (Ed.) (2011).Nucleic acid amphiphiles: synthesis and self-assembled nanostructures. Chemical Society Reviews,40(12), 5745-5755. DOI: 10.1039/c1cs15138j

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This journal is c The Royal Society of Chemistry 2011 Chem. Soc. Rev., 2011, 40, 5745–5755 5745

Cite this: Chem. Soc. Rev., 2011, 40, 5745–5755

Nucleic acid amphiphiles: synthesis and self-assembled nanostructuresw

Minseok Kwak and Andreas Herrmann*

Received 24th May 2011

DOI: 10.1039/c1cs15138j

This review provides an overview of a relatively new class of bio-conjugates, DNA amphiphiles,

which consist of oligonucleotides covalently bonded to synthetic hydrophobic units. The reader

will find the basic principles for the structural design and preparation methods of the materials.

Moreover, the self-assembly into superstructures of higher order will be highlighted. Finally, some

potential applications will be described.

1 Introduction

Five decades have passed since the discovery of the structure

of deoxyribonucleic acids (DNAs), ‘‘the secret of life’’, by

Watson, Crick and coworkers, key among them Franklin. This

elegant double helix has ever since fascinated researchers

throughout the natural and applied sciences. Thanks to the

invention of chemical DNA synthesis in the 1960s, broader

studies involving nucleic acids became possible, not only

in biological and medical fields but also beyond. From a chemical

point of view, the driving interest of DNA is its programmability

and self-recognition properties. These properties have been

utilized to particularly great effect in materials science to build

programmed architectures. As such, it is now recognized that

DNA is ‘‘not merely the secret of life’’.1

DNA nanotechnology is now a common term to describe

the use of DNA as a structural material rather than as a

medium for genetic information. Since Seeman’s artistic

Department of Polymer Chemistry, Zernike Institute for AdvancedMaterials, University of Groningen, Nijenborgh 4, 9747 AGGroningen, The Netherlands. E-mail: [email protected];Fax: +31 50 363 4400; Tel: +31 50 363 6318w Part of a themed issue on the advances in DNA-based nano-technology.

Minseok Kwak

Minseok Kwak studied

chemistry at the Ajou Univer-

sity in Suwon (South Korea)

and received his Master’s

degree in molecular science

and technology in 2006. He

started his PhD studies at the

Max-Planck Institute for

Polymer Research in Mainz

(Germany) under the supervi-

sion of Professor A. Herrmann

and Professor K. Müllen. In

2007, he moved to the Zernike

Institute for Advanced Materials

with the group of Andreas

Herrmann and obtained his

PhD in 2011 from the University of Groningen. He is currently

employed as a postdoctoral researcher in the group of Professor

W. M. Shih at Harvard Medical School in Boston with a Rubicon

fellowship from the Netherlands Organisation for Scientific

Research (NWO).

Andreas Herrmann

Andreas Herrmann studied

chemistry at the University of

Mainz (Germany). From 1997

to 2000 he pursued his graduate

studies at the Max-Planck

Institute for Polymer Research

in the group of Professor

K. Müllen. Then he was

employed as a consultant for

Roland Berger Management

Consultants in Munich (2001).

In the years 2002 and 2003 he

returned to academia working

on protein engineering at the

Swiss Federal Institute of Tech-

nology, Zurich, with Professor

D. Hilvert. In 2004 he was appointed as a head of a junior

research group at the Max-Planck Institute for Polymer

Research. In 2007 he moved to the Zernike Institute

for Advanced Materials at the University of Groningen,

The Netherlands, where he holds a chair for Polymer Chemistry

and Bioengineering. Andreas Herrmann was awarded the

Reimund-Stadler Prize (2008) and the Dr Hermann-Schnell

Prize (2009) from the German Chemical Society (GDCh).

Moreover, in 2009 and 2010, he received prestigious funds, the

ERC Starting Grant from the European Commission and the

Vici grant from NWO, respectively.

Chem Soc Rev Dynamic Article Links

www.rsc.org/csr TUTORIAL REVIEW

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5746 Chem. Soc. Rev., 2011, 40, 5745–5755 This journal is c The Royal Society of Chemistry 2011

building strategy for unusual DNA structures was reported

in 1991,2 countless beautiful DNA architectures have been

described—from intricate 2D patterns to highly precise nano-

scopic tubes, convex polyhedra, strings and 3D origami. These

new geometries, the increasingly sophisticated understanding

of assembly mechanisms they generated and the opportunities

for further manipulation which they revealed opened the door

to working with this material in multidimensional systems.3–8

The key structural property that makes these designs possible

is the persistence length of double-stranded (ds) DNA of 50 nm.

Qualifying it as a semi-rigid polymer, the double helix serves as a

rigid scaffold for short nucleic acid stretches.

At the same time, attempts have been made to develop

applications for DNA by incorporating functionalities and

utilizing its information-carrying capability. For instance,

fluorescently labeled DNAs can be used to detect particular

sequences or monitor the polymerase chain reaction (PCR).9

Today a range of modifications are commercially available for

daily laboratory use: chemical functionalities for covalent-

bond formation, optical/fluorescent labels for detection, and

others for further molecular recognition. While the above

modifications simply introduce an additional function, a

particular focus in materials science has been to chemically

couple nucleic acid strands with new moieties that alter the

molecule’s structural, morphological or self-assembly properties.

Such combinations of DNA with other classes of materials,

including chemical functional groups, (bio)polymers and

inorganic nanoobjects, are known as DNA hybrid materials.

This class of materials finds application in a wide range of

research fields, for instance diagnostics and electronics, as the

properties and advantages of each component can be tailored

to meet particular needs. This has been well demonstrated

and reviewed for hybrids incorporating gold nanoparticles10

and proteins.11

In this review, the class of amphiphilic DNA hybrids will be

covered in depth. Their amphiphilic nature arises from the

hydrophilicity of the DNA backbone containing charged

phosphodiester bonds, and chemical attachment of hydro-

phobic moieties. Here, amphiphilic structures with only a single

or very short nucleotides will be excluded. Such materials most

often lack the property of predetermined DNA hybridization

so that rarely more complex superstructures are formed. This

class of modified nucleic acids is covered in an excellent

review.12 First, the classification and techniques for the syn-

thesis of amphiphilic oligonucleotides (AONs) will be intro-

duced. Then their self-assembled structures and potential

applications will be described.

2 Structural classification and synthesis

Solid-phase synthesis (SPS) and solution coupling are two

general ways for the preparation of DNA (or RNA) modified

with functional groups.13–15 Short up to long fragments of

DNA (up to 200 mers), called oligonucleotides (ONs), can be

built up by iterative chemical synthesis on solid supports using

activated phosphoramidite building blocks. The four-step

cycle includes: (1) deblocking, (2) coupling, (3) capping and

(4) oxidation.16 The SPS technique makes it possible not only

to prepare pristine ONs but also to introduce functional

groups while the ONs are still present on the support. Solution

coupling is a more widely used method to make covalent

bonds between reaction-ready DNAs (e.g. amine- or thiol-

modified, prepared by SPS) that are available from commer-

cial suppliers and the complementary functionalities (e.g.

carboxylic acid, thiol or maleimide) of the target molecules.

However, solution coupling with hydrophobic molecules often

results in low yields due to the solvent incompatibility of the

two components. For this reason, solid-phase oligonucleotide

synthesis, which affords a wide choice of organic solvents and

restricts reactions to the solid supports, is more suitable for

preparing AONs. SPS methods can be further divided into two

classes: (1) fully automated synthesis within an ON synthesizer

and (2) modified techniques including syringe synthesis and

in-flask reactions utilizing DNA as synthesized on solid

supports. Fully automated synthesis offers precise control

and monitoring of the entire procedure, relatively large scales

and higher reproducibility despite of a few disadvantages such

as a high level of expertise and high investment costs for equip-

ment. Often the modified techniques can be used to mitigate some

of these difficulties, as well as to meet more specialized needs (i.e.

longer reaction times or solvents incompatible with a synthesizer).

This review will focus on the use of SPS methods to prepare

two structural classes of AONs. The first architecture contains

terminal hydrophobic moieties while the second type of structures

consists of a brush-configuration.

Terminally-functionalized AONs

Solution coupling has been used to prepare amphiphilic

DNAs with hydrophobic molecules at either terminus of the

DNA. While yields can often be low for the reasons discussed

above, the introduction of an oligoethyleneglycol linker

between the hydrophobic moiety and the DNA enhances

solvent compatibility, giving moderate coupling yields.15 SPS

represents the method of choice for the preparation of these

materials. Unlike solution coupling, though, the incorporation

of small hydrophobic moieties does not notably lower the

coupling yield. One classic and essential method to prepare

AONs using SPS with the hydrophobic moiety covalently

connected to the 50-end of the ONs is the use of 2-cyanoethyl-

N,N-diisopropylphosphoramidite (CEPA) groups.17 Here, a

hydrophobic molecule is functionalized with CEPA groups

and subsequently applied onto the detritylated 50-end of ONs

grown on solid supports (Fig. 1A). Introducing a hydrophobe

at the 30-end of the DNA requires different strategies. One

technique necessitates starting with custom solid supports which

already contain the desired hydrophobic moieties, connected via

a cleavable linker (e.g. carboxylic ester) (Fig. 1B).15 The other

method is reverse synthesis, in which the DNA sequence is

elongated in the opposite (i.e. from the 50- to 30-end) direction

with a final addition of the desired hydrophobe at the 30-end.

In this case, the CEPA group is located at the 50-end and the

4,40-dimethoxytrityl (DMT) group at the 30-end of each nucleo-

side, as opposed to conventional DNA synthesis (compare the

structures shown in Fig. 1B). Fig. 1C portrays a range of CEPA

compounds to introduce hydrophobicity for specific purposes.

In simple hydrophobic functionalities, linear lipophilic (or

aliphatic) chains are directly connected to CEPA (1 and 2)18,19

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Fig. 1 Synthetic schemes and precursors of DNA amphiphiles with terminal hydrophobic moieties. General solid-phase synthesis for amphiphilic

DNAs with hydrophobes at (A) 50- and (B) 30-end of the DNA; (a) deblocking of DMT; (b) coupling of activated CEPA to 50-end; (c) standard

synthesis with nucleoside phosphoramidite. After the synthesis, cleavage from the solid supports and removal of the 2-cyanoethyl group

on phosphorus yield amphiphilic DNAs. (C) Chemical structures of small hydrophobic compounds modified as CEPA. (D) Hydrophobic

CEPA-functionalized polymers. (E) Graphical representations of AONs with a hydrophobic functionality and polymer (DNA block copolymer),

left and right, respectively, at a terminus of DNA. Note that primary amines (–NH2) at nucleobases (denoted as N) are accordingly protected and

CEPA will be the linker to a DNA in AON products.

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or attached to the nucleobases of the phosphoramidite building

blocks (3 and 4).20,21 Hydrophobic moieties such as the fluorous

DMT group (FDMT) of 3 offer the additional advantage of fast,

highly efficient purification using a fluorous affinity column or

cartridge. In a similar synthetic manner, cholesterol derivatives

(5, 6 and 7)22 are introduced into DNA as terminal chain motifs.

For the synthesis of 30-end conjugated AONs, compounds 7a

and 7b are attached to the solid support via an ester bond at the

hydroxy groups. A useful means to tune the degree of hydro-

phobicity in these materials is by incorporating bis-adducts of

the hydrophobe connected to CEPA or altering the length of the

linear hydrophobic chain.23

Due to the high charge density of nucleic acids, it is often

desirable in AONs to have relatively large hydrophobic seg-

ments rather than small moieties (compare Fig. 1E, especially

when self-assembled nanostructures should be achieved.

Linear DNA block copolymers (DBCs) are good candidates

for attaining balanced amphiphilicity by changing the mole-

cular weight (Mw) of the polymer segments. In general, DBCs

consist of an ON covalently connected at either end to a

hydrophobic polymer or a block copolymer, yielding amphi-

philic diblock (Fig. 1E, right image) or multiblock structures.

Since Jeong and Park generated a polymeric AON with

poly(D,L-lactic-co-glycolic acid) (PLGA) as the hydrophobic

block using solution coupling,24 analogous routes were com-

monly used. Note that in these solution based methods, there

are always two or more reacting groups for the coupling of the

hydrophobes to DNA. Moreover, the coupling of highly

hydrophobic polymers to ONs entails very low yields due to

the incompatibility of solvents for hydrophobes and DNA.

To overcome solvent compatibility limitations on the choice of

polymers, solid-phase synthesis was also adopted to prepare

DBCs, yielding AONs with more hydrophobic polymers like

poly(styrene) (PS) (8).25 Here, the hydroxy-terminal group of

PS was converted to 2-cyanoethyl-N,N-diisopropylphosphor-

amidite (CEPA) and was subsequently applied onto the

detritylated 50-end of elongated ONs on solid supports

(Fig. 1A and D). Nowadays, fully automated SPS is optimized

and thus commonly used for large-scale preparation of DBCs

in DNA synthesizers with several different hydrophobic

polymers including poly(propyleneoxide) (PPO) (9)26 and

poly(9,9-di-n-octylfluorene) (PFO) (10) (Fig. 1D and E, right

image).27 The reader is directed to two recent reviews for more

comprehensive information about other polymer hybrids of

biomolecules, including DNA.28,29

Brush-type AONs

Brush-type is a structural term for macromolecules consisting

of a linear backbone onto which multiple oligomer or polymer

segments are grafted. Such macromolecular architectures

containing DNA can be generated through SPS. As shown

in the general scheme of DNA synthesis (Fig. 1B), the presence

of CEPA and DMT groups is critical for performing the

reaction cycle. Thus both groups need to be present in a

molecule if it is to be incorporated within the DNA sequence.

To build up brush-type AONs, monomers must contain either

protruding hydrophobic moieties or functional groups which

can be converted into hydrophobic units through additional

transformations. One such building block (11) fulfilling the

former requirement was recently reported,30 resulting in lipid-

grafted ONs (Fig. 2A, left). Here, a C10-alkyl chain was

introduced at C5 of the uracil nucleobase via an ethynyl group

Fig. 2 Brush-type AONs. (A) Chemical structures of nucleoside- and polyaza crown ether monomers (11 and 12, respectively) bearing CEPA and

DMT to yield hydrophobe(s)-grafted AONs. (B) Three-dimensional representation of modified uracil nucleotide (precursor: 11) base-pairing. The

hydrophobic chain (white) does sterically not interfere with the hydrogen bond formation between modified-U and A nucleobases. Side (left) and

top view (right). (C) Brush-type 12 mer AONs containing the hydrophobic (Uracil) building block (11) at varying positions (Middle or Termini)

and in different numbers (2 or 4). (D) Representation of DNA-grafted polymers in homopolymer (left, precursor: 14a) and block copolymer motifs

(right, precursors: 14b and 15; see Fig. 3C for the chemical structures). Each sphere represents a monomer unit and red strings are grafted-ONs.

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Fig. 3 Post-DNA-synthesis preparation of AONs. (A) After SPS, hydrophobes in organic solvents are attached to the 50-end of the ribose (*) or

at the nucleobase (**) of nucleotides on the solid support. After the coupling, liberation from the resin and deprotection of primary amines of

nucleobases are performed in concentrated ammonia to yield AON products. (B) List of reactions that allow functionalization of the DNA with

hydrophobic units. (a) Chemical functionalities (R1 and R2) can be exchanged with each other in a particular case. (b) The CEPA group is only

introduced in the hydrophobes (R2). (c) Reaction conditions may vary. (C) Hydrophobic moieties for the attachment on the solid support after

DNA synthesis. (D) Synthetic route for the on-resin-modification of ONs with hydrophobes by Huisgen cycloaddition.

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using Sonogashira–Hagihara coupling. This 5-(dodec-1-ynyl)-

uracil-containing nucleoside phosphoramidite has both DMT

and CEPA at the 50- and 30-ends, respectively. This structure

allows multiple addition of the modified nucleobases at precise

positions in the target ON.31 Moreover, the relatively small

hydrophobic functional group does sterically not hinder

duplex formation with its complementary nucleobase, in this

case adenine (Fig. 2B). In spite of the short alkyl chain, the

morphological behavior of the hybrids confirms their classifi-

cation as brush-type AONs. Due to the fact that the alkyl-

modification does not lower the coupling yield compared to

commercial reagents during SPS, virtually no additional

synthetic effort is needed to include the desired number of this

modified nucleotide in the desired positions (Fig. 2C). Using

this strategy, 12 mer DNA amphiphiles with two or four lipid

tails positioned in the middle or terminus (U2M, U2T and

U4T) could be isolated with reasonable yields of 60 to 91%,

based on analytical HPLC. As such, this method represented

a facile means to tune the hydrophobicity of AONs in a fully

controlled, automated manner. In an analogous strategy, a non-

nucleoside building block (12) is also capable of linking two

nucleotides in SPS. These azacrown derivatives possess varied

hydrophobic segments in two aza-N positions.32 The duplexes

formed from such compounds exhibited tolerable stability.

Just as hydrophobic functional groups can be introduced

along a DNA chain, one can imagine a structure in which

DNAs are grafted onto a hydrophobic polymer backbone

(Fig. 2D). The first such reported hybrid was prepared via

SPS exhibiting a norbornene polymer (PNB) backbone.33

Therein, two types of brush macromolecules were introduced:

DNA and DNA/ferrocene (14a and b respectively, see

Fig. 2D). Recently, Gianneschi et al. reported an analogous

brush block copolymer (15), in which one block contained

carboxylic acid in each repeating unit, which could be con-

jugated to amino-modified DNA, while in the other block

methylbenzene was incorporated as a hydrophobic function-

ality.34 Here, amino-modified DNA on solid-supports was

reacted with the diblock copolymers to realize an amide bond

between the DNA and the polymer backbone.

Preparation of AONs without a DNA synthesizer

This ex situ conjugation method, entailing post-DNA-synthesis

reactions while still on solid supports, particularly helps to

achieve couplings in cases of incompatible solvents or catalysts,

longer reaction times or more extreme reaction conditions than

are accessible with a DNA synthesizer. This strategy can be

used to prepare both brush-type (14 and 15) and linear (13 and

16) AONs (see Fig. 3A–C). An emerging synthetic method

along these lines is the Huisgen cycloaddition, the so-called

‘‘Click chemistry’’,35 employing either azide- or acetylene-

modified DNA that is reacted with the correspondingly

functionalized hydrophobic moieties (Fig. 3D).36 However,

the conditions for this ex situ method vary depending on the

chemical structure, catalyst and chemostability and thus need

to be optimized separately for each reactant.37–39

Regardless of the type of SPS method used for synthesis, the

resulting AONs offer additional advantages in the purification

stage compared to pristine ODNs. When hydrophobic units

are introduced, the AON materials interact strongly with

chromatographic stationary phases. Thus, high performance

liquid chromatography (HPLC) with affinity columns, such

as reverse-phase or anion exchange resins, can be used to

efficiently isolate target AONs.40

3 Self-assembled structures of AONs

DNA amphiphiles on their own generally self-assemble into

structures with simple geometries: spherical or cylindrical micelle

aggregates or vesicles. In addition, these structures can be altered

by mixing in other materials of interest, by hybridization or by

enzymatic reactions, as will be discussed below.

In aqueous media, the hydrophobic units of AONs tend to

undergo microphase separation, to minimize the exposure to

water. The linear DBC with poly(butadiene), DNA-b-PB,

formed vesicles of about 80 nm in diameter (Fig. 4A).41

Thereby, the isolation of the vesicular interior from the

surrounding medium by a DBC double-layer was demon-

strated using fluorescence probes. Although the material

stability and duplex formation capability have not yet been

studied, the novel behavior of this DNA hybrid suggests

further investigations of such AON structures.42 Another

vesicular structure involving AONs used terminal bilipid

moieties to form the hydrophobic core of the bilayer.43

Through the hybridization of fluorescently labelled comple-

mentary DNAs (cDNAs), the reversible decoration of the

surface of the self-assembled aggregates by hybridization was

demonstrated. Instead of constructing vesicle structures from

Fig. 4 Microscopic images and illustrations of self-assembled

amphiphilic DNAs. (A) A TEM image (top) of PB-b-DNA (from

precursor: 16, italicized b such as X-b-Y denotes a block copolymer

composed of polymer segments X and Y that are covalently

connected) vesicles. Reproduced from ref. 41 with permission of the

Royal Society of Chemistry. (B) An AFM image (top) of PS-b-DNA

spherical micelles (unpublished). Analogous aggregates were also

formed with single-stranded DBCs (precursors: 8–10) and lipid-DNAs

(see Fig. 2C, precursor: 11) with 4–10 nm height. Scale bars: 100 nm;

height color scale: 10 nm.

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AONs exclusively, it is much easier to incorporate AONs into

the membrane of artificial liposomes fabricated from lipids or

polymers.42

Simpler and more extensively studied systems are DNA

micelles (Fig. 4B). Many AONs have been observed to form

spherical micelles with a diameter range of 5 to 12 nm, as

measured by dynamic light scattering (DLS) and atomic force

microscopy (AFM).18,26,31 These AFM measurements further

revealed that deformation of such micelles on the surface is

depending on the hydrophobic segments. AONs containing

hydrophobic segments with higher glass transition tempera-

tures (Tg), in particular PS and PFO, endure the mechanical

forces, during the AFM measurement, more than those with

lower-Tg segments like PPO, PLGA and lipids.

One big advantage of constructing nanostructures with

DNA is that once assembled, the architectures can be further

manipulated by enzymatic reactions. Indeed, enzymatic

manipulations were also applied to linear AONs and DNA

brushes. For instance, micelles consisting of a DNA diblock

copolymer, DNA-b-PPO, were treated with the enzyme,

terminal deoxynucleotidyl transferase (TdT), which catalyzes

nucleotidic elongation of the terminal 30-end of single-stranded

(ss) DNA in the presence of deoxyribonucleoside triphosphate

(dNTP) under isothermal conditions at 37 1C. In this experi-

ment, over the course of 16 hours, the sequence-independent

DNA polymerase added approximately 60 T nucleotides to the

termini of DNA chains in the corona of the micelles (Fig. 5A),

which resulted in a height increase from 5 to 11 nm on a mica

surface.44,45 This method offers a convenient post-synthesis size

control of nucleic acid nanoobjects. Precise post-synthesis

shape control has also been demonstrated with such materials

through the addition of ssDNA: AON micelles were trans-

formed into rod-shaped aggregates through hybridization with

a long cDNA template (Fig. 5B).46 The sequence of the long

DNA template was designed to contain five repeats of the

complementary sequence of the DNA corona of spherical

micelles. Alignment of five AONs along the template, after

disaggregation of spherical micelles, resulted in rod-like aggre-

gates, where the hydrophobic polymer units were uniformly

placed between two long dsDNAs glueing the two duplexes

together. Another example of changing supramolecular AON

structures by very mild external stimuli was realized with the

enzyme, phosphodiesterase (Fig. 5C). Starting from a spherical

micelle consisting of brush-type polymeric AONs, digestion

of the DNA segments reduced the volume occupied by the

grafted nucleotides. The resulting change in the hydrophilic/

hydrophobic volume ratio induced a transformation of the

spherical nanoobjects into long cylindrical aggregates. The

second stimulus applied on the AON tube was hybridization

of longer ONs with the remaining segments of the DNA brush.

This lengthening restored the initial structural parameters,

producing spherical aggregates again.34 Such reversible tech-

niques for structural manipulation should eventually produce

potential applications of AONs in the biomedical field with

possibly the same impact as peptide amphiphiles.47

4 Applications of AONs and their nanocomposites

Utilization of pristine AONs

Many advances of AON-micellar systems in the last five years

were presented in the fields of DNA detection,25 templated

reactions,26 and drug delivery due to their self-recognition

properties and the presence of a hydrophobic core to serve as a

carrier unit.24 In particular, an AON micelle has shown great

potential in cancer therapy.48–50 PPO-b-DNA micelles were

equipped both with a hydrophobic anticancer drug and a

targeting unit. Therby, doxorubicin accumulated in the core

of the AON aggregates by simple mixing while the folic acid

targeting units were incorporated into the carrier system by

hybridization (Fig. 6A, top). These aggregates were taken up

by CaCo-2 cancerous cells through receptor mediated endo-

cytosis (Fig. 6A, bottom) and, as anticipated, resulted in

efficient cytotoxicity and high mortality.48 In a different

approach, Tan et al. demonstrated that RNA aptamers,

ONs that can specifically bind to a target molecule, can be

conjugated to lipids, resulting in micelle formation and

efficient targeting ability to a specific cancerous cell line

Fig. 5 Engineering self-assembled structures of AONs. (A) Isothermal enzymatic growth of DNA-b-PPO (precursor: 9) micelles incubated

with TdT and dTTP at 37 1C (top). AFM images of growing nanoparticles with increasing reaction times (bottom). (B) DNA-templated shape

transition from spherical micelles to rod-like aggregates (top) and an AFM image of rod-like structures (bottom). (C) Enzyme induced reversible

transformation of a DNA-brush block copolymer (top, precursor: 15) and its TEM images (bottom). Note that the outer-segments of

DNA-brushes in both spherical aggregates (top left and right of the representation) have ethylene glycol chains to lower electrostatic repulsion

between the DNA brushes. Reproduced from ref. 44, 46 and 34, respectively, with permission of Wiley-VCH Verlag GmbH & Co KGaA.

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(Ramos) (Fig. 6B).50 The multimerization of the aptamer unit

at the surface of the AON aggregates significantly increased the

binding of the nanoobjects compared to the pristine nucleic

acid sequences. Although these are powerful new tools for

cancer therapy, there is an inherent limitation to the use of

micellar carriers in vivo: upon dilution below the critical micelle

concentration (CMC), they tend to disassemble. One potential

solution to this issue involves an additional nanocontainer, a

virus capsid.30 In addition to the advantages of micellar

delivery described above, it was demonstrated that micelles

of DNA amphiphiles can act as a template for the self-

assembly of Cowpea Chlorotic Mottle Virus capsids with

T = 1 and 2 geometry at neutral pH (Fig. 7A). The resulting

structures were then stable against dilution. At the same time,

this encapsulation around micelles of DNA amphiphiles

represented a general and facile supramolecular loading strategy

for hydrophobic or hydrophilic small molecules within the protein

nanocontainer, an essential process for the application of these

nanoobjects in biomedicine. The virus encapsulation of AONs is a

good example of how the properties, in this case the micellar

stability, can be greatly improved by combining AONs with other

materials.

AONs employed together with other materials

Composites are made from two or more materials to achieve

desired synergic properties out of the individual constituents.

Although the synthesis and designed self-assembly of a single

material is one of the beauties and goals of fundamental

research, more focused applications can be realized through

combination with other materials of interest. Since the essence

of DNA nanotechnology is the precise programmed assembly

of DNAs through Watson–Crick basepairing, the other com-

ponent of AONs, the hydrophobic moieties, can play an

important role as well by interacting with other hydrophobic

materials to produce versatile composites for particular

applications.

Fig. 6 Medical applications of micellar AONs in cancer therapy.

(A) A multifunctional micellar drug-carrier consisting of a DBC

(precursor: 9). The targeting unit, folic acid (FA), to cancerous cells

is attached to the outer surface of the DNA corona through hybridiza-

tion while a drug, doxorubicin (Dox), is loaded into a hydrophobic

core of the micelle (top). Fluorescence microscopy image of CaCo-2

cells that have taken up the micellar vehicle (bottom). Reproduced

from ref. 49 with permission of Wiley-VCH Verlag GmbH & Co

KGaA. (B) Graphical representation of a targeting micelle (precursor:

11) with an RNA aptamer as the corona (top). The aptamer micelle

exhibited a high cell-specific affinity to lymphoma cells (Ramos) as

shown in the fluorescence micrograph (bottom). Reproduced from

ref. 50 with permission of the National Academy of Sciences.

Fig. 7 Composite micelles consisting of AONs and viral capsids or synthetic polymers, respectively. (A) Micelles of DNA amphiphiles

(precursors: 9 and 11) loaded with either small hydrophobic compounds (top left) or with hydrophilic compounds by hybridization (top right)

templated virus capsid formation at neutral pH. TEM images of micelles incorporated in virus capsids with T = 1 or 2 geometry (bottom) and an

empty capsid formed at pH 5.0 as control (inset). Scale bars: 40 nm (adapted from ref. 30). (B) Graphical representation of a blend micelle.

A diblock DNA copolymer, PPO-b-DNA (precursor: 9), was mixed with a triblock copolymer Pluronic (PEO-b-PPO-b-PEO) that exhibits the same

hydrophobic block, PPO. Both block copolymers form mixed micelles. The hydrophobic core was further stabilized through UV-induced semi-

interpenetrating network formation, which inhibits disaggregation or precipitation under dilution or low temperature, respectively. In a similar

manner as shown in (A), the core and corona could be equipped with desired functionalities also with distance-control (adapted from ref. 53).

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With regard to micellar aggregates, this principle has

resulted in doping electrostatically or magnetically active

materials in the hydrophobic core.51,52 In a more elegant

example, DNA diblock copolymers (DNA-b-PPO) formed

mixed micelles with Pluronict triblock architectures (PEO-b-

PPO-b-PEO) (Fig. 7B).53 This polymer–AON composite, with

a DNA/PEO corona and a PPO core, could be loaded with

hydrophobic molecules and stabilized against dissociation by

the formation of a semi-interpenetrating network, resulting in

highly stable soft particles. Furthermore, the potential of the

DNA for further self-assembly remained unchanged—the

corona could be conveniently modified by hybridization either

with dye-modified complementary DNA, demonstrating dis-

tance controlled functionalization, or with cDNA-labelled

gold nanoparticles. This composite is an excellent candidate

for a smart drug delivery vehicle, with possibly reduced

immunotoxicity due to the presence of the PEO chains on

the surface.

Vesicles or liposomes have been intensively investigated to

understand and manipulate biological events and processes.42,54

Due to the fact that their bilayer is composed of amphiphiles,

it is no surprise that AONs can also play a role in decorating

these nanocontainers with DNA. More precisely, the hydro-

phobic components of AONs can be tailored to anchor into

liposomes, leaving the DNA strands available for subsequent

supramolecular events, whether for functionalizing the surface

(Fig. 8A), anchoring the liposome or even tethering vesicles

together through hybridization (Fig. 8B. The AONs described

above, in which the hydrophobes are conjugated to the DNA

and peptide nucleic acid (PNA)55 termini, are most commonly

combined with phospholipid bilayers. Thus AONs have been

used to achieve liposome tagging,21,56,57 intervesicular

fusion,19,58 the assembly of larger containers59 and attachment

to lipid bilayers, mimicking cellular systems.22,60 With regard

to applications of AONs in animal experiments, lipophilic

units and cholesterol-conjugated small interfering (si) RNA

have been utilized to study siRNA-AON uptake into cells and

gene silencing in vivo.61

A more integrated application of AON composites was

reported with single-walled carbon nanotubes (SWNTs). In

the study, a single polymeric AON was demonstrated to be an

all-in-one solution for SWNT technology.27 The hydrophobic

segment of the AON, PFO (11), was covalently connected to a

short 22 mer via a phosphodiester bond and interacted

strongly with SWNT sidewalls by p–p interactions. This

allowed highly diameter-selective dispersion (0.8–1.1 nm) of

SWNT species out of as-produced HiPCO SWNTs (Fig. 9A).

The dispersion selected for a relatively small subset of chiral

indices, which determine the electronic properties of the

materials. In addition, the ssDNA block provided solubility

in aqueous media and, most importantly, remained available

for straightforward duplex formation with its cDNA (Fig. 9B).

Through base-pairing between the free DNA block and cDNA

conjugated to a gold nanoparticle, alignment of the metallic

particles along the SWNT was demonstrated (Fig. 9C).

A similar procedure allowed attachment of the dispersion to

a cDNA-functionalized surface. The same surface immobiliza-

tion onto lithographically prepared electrodes (Fig. 9D)

resulted in 98% fabrication efficiency for SWNT field effect

transistors. The entire process proved highly selective for

semiconducting SWNT species and represented a solution-

based, scalable method achieved purely by self-assembly. This

composite powerfully combined all the advantageous proper-

ties of the individual polymer, SWNT and DNA constituents.

5 Conclusions and outlook

Synthetic methods, chemical variety, structural parameters

and outlined functions of AONs are summarized in Table 1

for the reader’s convenience. These AONs are indeed a new

Fig. 8 AONs incorporated into lipid bilayers of liposomes.

(A) Hydrophobic parts (orange, precursors: 1–2, 4–7, 13) of AONs

could be used as anchors (left) to bilayers of liposomes. Simple tagging

of the liposomes was realized by hybridizing fluorescently labeled

cDNA (blue string, right) to the DNA segment (red string) of the

AON. (B) AONs could induce moderate vesicular fusion via duplex

formation of AONs anchored in liposomes.

Fig. 9 Utilization of AONs in a SWNT composite. (A) A polymeric

AON (precursor: 10), PFO-b-DNA, was used to disperse HiPCO

SWNTs as produced. (B) Resulting dispersions were enriched in

semiconducting SWNT species with narrow diameter distribution

due to the strong and specific interaction between the PFO block

and the SWNT surface. The presence of the protruding DNA strand

was exploited to introduce functionalities by hybridization with

cDNA-modified (blue) Au-nanoparticles (yellow spheres) (C) and to

sequence-specifically immobilize SWNTs on defined cDNA surfaces,

such as electrodes of field-effect transistors (FETs). (D) The device

yield (98%) achieved exclusively by aqueous solution processing and

hybridization was extremely high (adapted from ref. 27).Dow

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class of materials that has seen rapid growth with great future

potential. Regarding the choice of synthetic methods, in

general coupling hydrophobic units to DNA in solution is a

difficult task mostly resulting in low overall yields. In contrast,

synthetic strategies based on SPS approaches are the preferred

route to fabricate AON materials. While preparing AONs

in-line guarantees good reproducibility and allows large scale

synthesis, the modification of ONs on solid supports with

hydrophobic moieties offers more flexibility regarding experi-

mental conditions and does not necessitate large equipment

costs. Within the context of polymeric AON synthesis, as of

yet no 30-amphiphilic DBCs have been reported using a fully

automated SPS approach showing that there are still synthetic

challenges to be overcome in the field. The same holds true for

the DNA part of AONs. ONs of up to hundred nucleotides,

as shown in Table 1, could be chemically synthesized. There

are still ongoing efforts to overcome this current limit, for

instance, by enzymatic reactions employing ss- and ds

ON-hybrids in combination with polymerases, ligases or

endonucleases to extend the size of nucleic acid segments.62–64

Another future task in AON synthesis is to incorporate

hydrophobic compounds that have interesting optoelectronic

properties like conjugated polymers, thereby widening the field

for potential applications in diagnostics and (nano)electronics.

The amphiphilicity of AONs allows them to aggregate into

superstructures, mostly micelle aggregates or vesicles. Thereby,

well established strategies for structure formation of small

molecule amphiphiles and block copolymers can be adopted

for AONs and their composites with other amphiphiles. And

indeed those methods are much simpler than the sophisticated

design and annealing techniques known for pristine DNA

nanoconstruction. Moreover, self-assembled nanostructures

of AONs consist of a very limited set of building blocks

compared to complex DNA nanoobjects.65,66 The aggregation

behavior of AONs can be conveniently controlled by adjusting

the molecular parameters like the length of the DNA segment

and the molecular weight or the nature of the hydrophobic

unit. Additional opportunities for manipulating their self-

assembly properties are hybridization and enzymatic modi-

fications. From another point of view, introducing amphiphilic

properties into the already well-developed field of pristine

DNA nanostructures should greatly enhance their appli-

cability. This can range from simply depositing them on

hydrophobic surfaces or generating well defined compartments

of different polarities.

Regarding applications, great potential of AONs can be

foreseen for the biomedical field. Promising examples have

demonstrated basic functions such as targeted-drug delivery or

transfection with AON nanoobjects in vitro. However, the

cytotoxicity, immunogenicity and uptake of AON nano-

structures are far from being well understood. In the future,

elucidating these issues will bring advances with AONs in the

pharmaceutical sector especially in regard to stability and

delivery of biologicals. Those challenges can only be mastered

in a multidisciplinary effort, especially with input from medical

and clinical researchers. In this respect, one can be excited

about the future demonstrations of AON nanostructures

in vivo.

Acknowledgements

We thank the EU (ERC starting grant, ECCell), the Netherlands

Organization for Scientific Research (NWO-Vici), the German

Research Foundation (DFG), and the Zernike Institute for

Advanced Materials for financial support.

References and notes

1 This quote is Nadrian C. Seeman’s, the founder of DNA nano-technology, title of his lecture since a decade.

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Table 1 Summary of AONs covered in this review

No. Hydrophobea Func. ONb ON-Fuct. ON lengthc Couplingd Ref.

AONs terminally functionalized with a hydrophobic unit1 Lipid CEPA D, R 50-OH 20–81 SPS 18,502 Bislipid CEPA D 30-/50-OH 24–48 SPS 193 FDMT CEPA D 50-OH 30–100 SPS 204 Bislipid CEPA D 50-OH 15 SPS 215–7 Mono-/bischol CEPA D, R, P 30-/50-OH 12–42 SPS 22,56,588 PS (10K) CEPA D 50-OH 20, 25 postSPS 25,51,529 PPO (7K) CEPA D 50-OH 11, 22 SPS 26,30,4810 PFO (6K) CEPA D 50-OH 22 SPS 2713 Bislipid COOH D 50-OH 9 postSPS 4316 PB (2K) NH2 D 5

0-COOH 12 postSPS 41N/A PLGA (10K) COOH D 50-NH2 15 Solution 24AONs with DNA chains attached to a hydrophobic polymer backbone14a–b PNB (-b-Fc) CEPA D 50-OH 18, 22 postSPS 3315 PNB COOH D 50-NH2 19 postSPS 34AONs with DNA hydrophobic units attached to a DNA backbone11 Lipid CEPA/DMT D N/A 11, 12 (2, 4) SPS 30,31AONs containing a hydrophobic unit within the nucleic acid structure12 Azacrown ether CEPA/DMT D N/A 9–17 (1–3) SPS 32,60

a Numbers in parentheses represent number-averaged molecular weight (g molÿ1) of the polymers. b D: DNA, R: RNA, P: PNA. c Unit: number

of nucleotides. Numbers in parentheses represent the number of hydrophobes included in the AON. d SPS: solid-phase synthesis, postSPS: post-

synthesis after SPS of ONs.

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University of Groningen Nucleic acid amphiphiles Kwak ... · Nucleic acid amphiphiles: synthesis and self-assembled nanostructures w Minseok Kwak and Andreas Herrmann* Received 24th