University of Groningen DNA nanotechnology as a tool to manipulate lipid bilayer membranes Meng, Zhuojun IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2017 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Meng, Z. (2017). DNA nanotechnology as a tool to manipulate lipid bilayer membranes. [Groningen]: University of Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 21-05-2020
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University of Groningen
DNA nanotechnology as a tool to manipulate lipid bilayer membranesMeng, Zhuojun
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.
Document VersionPublisher's PDF, also known as Version of record
Publication date:2017
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):Meng, Z. (2017). DNA nanotechnology as a tool to manipulate lipid bilayer membranes. [Groningen]:University of Groningen.
CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.
dimethylaminopropylacrylamide (P(NIPAAm-co-DMAPAAm)) was
synthesized and used for liposome modification. This research showed that
the polymer underwent dehydration and aggregation above 40 °C and that
temperature-responsive polymer-modified liposomes had faster cellular
uptake and release compared to non-modified liposomes (Fig. 1.9).74
Chapter 1
22
Fig. 1.9 Liposomes modified with temperature-responsive polymers are used for cellular
uptake. The copolymer displayed a thermosensitive transition at a lower critical solution
temperature (LCST) that is higher than body temperature. Above the LCST, the temperature-
responsive liposomes started to aggregate and release their content. The liposomes showed a
fixed aqueous layer thickness (FALT) at the surface below the LCST, and the FALT decreased
with increasing temperature. Above 37°C, cytosolic release from the temperature-responsive
liposomes was higher than that from the PEGylated liposomes, indicating intracellular
uptake.74 (This figure was adapted from reference 74)
1.3.2.3 Magnetic responsive vesicle systems
Magnetoliposomes are composed of a lipid bilayer surrounding
superparamagnetic iron oxide nanoparticles. Due to the biocompatibility,
size, material-dependent physicochemical properties and potential
applications as alternative contrast enhancing agents for magnetic
resonance imaging, magnetoliposomes are ideal candidates to achieve a
spatial and temporal control over drug release.75,76 Superparamagnetic iron
oxide nanoparticles (SPION) can be guided to their site of action using an
externally applied magnetic field. The subsequent accumulation of SPION
in the target site can be exploited for simultaneous drug delivery, MR
imaging or hyperthermia therapy of cancer (Fig. 1.10).
Functionalization of Lipid Bilayer Membranes
23
Fig. 1.10 Superparamagnetic iron oxide nanoparticles can be guided to the site of action using
an externally applied magnetic field.77 (This figure was adapted from reference 77)
In the beginning, liposomes were studied only for their physicochemical
properties as models of membrane morphology. Today, they are used as
delivery devices to encapsulate cosmetics, drugs, fluorescent detection
reagents, and as vehicles to transport nucleic acids, peptides, and proteins
to specific cellular sites in vivo. Advances in therapeutic applications of
liposomes have been achieved through surface modifications. With these
surface modifications, their biological stability could be increased, which
includes reduced constituent exchange and leakage as well as reduced
unwanted uptake by cells of the mononuclear phagocytic system.78
Targeting components such as antibodies can be attached to liposomal
surfaces and were used to create large antigen-specific complexes. In this
sense, liposomal derivatives are being used to target cancer cells in vivo, to
enhance detectability in immunoassay systems.
Chapter 1
24
1.4 Motivation and Thesis Overview
The overall goal of the work described in this thesis was to use DNA
nanotechnology as a tool to manipulate lipid bilayer surfaces. Our group
synthesized and characterized a new family of DNA amphiphiles containing
modified nucleobases. The modification is introduced in uracil and consists
of hydrophobic moieties. Through solid phase synthesis, the modified
nucleotides can be incorporated in any desired position and several
modifications per DNA strands can be introduced.79 The resulting DNA
sequences still undergo specific Watson-Crick base pairing. This property
combined with the amphiphilic nature of this lipid-DNA qualifies the
material as appealing candidate to interact with and manipulate biological
membrane structures.
In chapter 2, a powerful new approach was introduced by modifying DNA
with lipid chains at four nucleobases to tightly anchor the nucleotide to the
lipid membrane. This strategy allows highly stable incorporation of DNA
into the liposomal bilayer, thereby limiting dissociation. Several assays
were employed proving the incorporation and stable anchoring in the
phospholipid bilayer. These measurements involve small vesicles and
fluorescence energy transfer. These experiments allow to measure how
long the DNA amphiphiles remain in the bilayer.
In chapter 3, efficient fusion of liposomes was studied using lipid-DNA
introduced in the chapter before. While the orientation of DNA
hybridization played a significant role in the efficacy of full fusion of DNA-
grafted vesicles, the number of anchoring units was found to be a crucial
factor as well. As compared to vesicles functionalized with single-anchored
or double-anchored DNA, liposomes containing quadruple-anchored
oligonucleotides were found to be highly fusogenic, achieving considerable
full fusion of up to 29% without notable leakage. This study demonstrates
the importance of the DNA-anchoring strategy in hybridization-induced
vesicle fusion, as not only the structural properties of the unit itself, but
also the number of anchoring units determines its favorable fusion-
inducing properties. Several fluorescence assays, dynamic light scattering
and cryogenic transmission electron microscopy were utilized to prove
these results.
Functionalization of Lipid Bilayer Membranes
25
In chapter 4, we expand the functionality of DNA encoded vesicles
significantly. It was demonstrated that strand replacement can be carried
out. In this chapter it will be outlined what sequences and what DNA
amphiphiles are needed to reach this goal, i.e. changing the surface
functionalities of liposomes by the simple addition of oligonucleotides.
Moreover, it will be detailed how such a surface modification can be
amplified by a simple DNA-triggered supramolecular polymerization.
In chapter 5, we investigated whether it is possible to insert the lipid-
modified DNA sequences into the membrane of live zebrafish to function as
artificial receptor. We demonstrate that oligonucleotides functionalized
with a membrane anchor can be immobilized on a zebrafish. Protruding
single-stranded DNA atop the fish was functionalized by Watson-Crick base
pairing employing complementary DNA sequences. In this way, small
molecules and liposomes were guided and attached to the fish surface. The
anchoring process can be designed to be reversible allowing exchange of
surface functionalities by simple addition of DNA sequences. To achieve
this on a fish surface, the strand exchange experiments established in
chapter 4 on simple vesicles as model were crucial. Finally, a DNA based
amplification process was performed atop of the zebrafish enabling the
multiplication of surface functionalities from a single DNA anchoring unit.
Chapter 1
26
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