Nanostructures with improved stability for the development of more
effective cancer nanomedicine

Date:
April 20, 2022
Source:
Aarhus University
Summary:
Most drugs used today have only one mechanism of action and it is
both difficult and expensive to manufacture drugs with multiple
functions.

Researchers have recently found a way to create more stable
nanostructures that can assemble biomolecules with different
functions, which in combination e.g., can provide more effective
cancer medicine.



FULL STORY ==========================================================================
Most drugs used today have only one mechanism of action and it is both difficult and expensive to manufacture drugs with multiple functions.

Researchers at Aarhus University have recently found a way to create
more stable nanostructures that can assemble biomolecules with different functions, which in combination e.g., can provide more effective cancer medicine.


==========================================================================
For millennia, DNA has played a central role in storing each cell's
genetic information and consists of strands with a specific sequence
of four different building blocks. These DNA strands are copied by the
cell at each cell division in an extremely well-orchestrated way, but amazingly, this sophisticated machinery is governed by very simple rules.

In recent years, it has been found to utilize these simple rules not only
in the context of genetic engineering, but also to construct useful DNA nanostructures by designing DNA strands. These DNA nanostructures have
been shown to have a number of useful biomedical functions such as to be
able to transport cancer drugs to exact places in the body where they
are needed. This can increase the effect of the medication as well as
provide fewer side effects compared to conventional cancer treatment.

DNA nanostructures are also increasingly used as a tool to bind and
assemble biomolecules, into multifunctional structures. One of these
DNA nanostructures used forms a branched structure with four ends
(see illustration), called 4-way junctions (4WJ), which are also found naturally.

With specially designed versions of these 4WJ structures, for example,
Harvard Medical School in Boston has managed to bind and collect various antibodies, which in combination ensured that T cells attacked aggressive cancer cells more intensively and thus killed tumors.

Enhanced DNA nanostructures with artificial building blocks Researchers
who are part of the Center for Multifunctional Biomolecular Drug Design (CEMBID) at Aarhus University are also working on finding new ways to link different drugs to achieve more and more effective mechanisms of action.

The research group, led by Professor Kurt Gothelf, has just published
an article in the acclaimed journal Angewandte Chemie Int. Ed. with
results involving above mentioned 4WJ structures, but in an improved
version. The work was performed in collaboration with the groups of
Jo/rgen Kjems and Ken Howard who are also part of CEMBID.



========================================================================== Admittedly, these DNA nanostructures (4WJ) are smart, but there is the disadvantage of DNA structures that DNA is de facto a biodegradable
polymer.

This means that the structures are broken down faster in the blood than desired. In addition, the structures can be so large that they themselves activate the immune system. In order for the structures to be used for diagnostics or in medicine, it is crucial that the structures are very
stable, non-toxic and do not themselves trigger an immune reaction in
the patient.

Anders Ma"rcher, a postdoc in Kurt Gothelf's research group and part
of CEMBID, has, together with his research colleagues, now found a way
to increase the stability of these nanostructures. They have achieved
this by using small chains, called oligonucleotides, of artificial
and modified building blocks to form the nanostructure. The artificial oligonucleotides, Ma"rcher et al. use is called acyclic L-threoninol
nucleic acid (aTNA) and work in the same way and just as well as the
natural building blocks of DNA. Here, the sugar molecule (deoxyribose)
in the natural building blocks is replaced with an artificial sugar
molecule (acyclic L-threoninol), which strengthens the overall structure.

The positive results showed that 4WJ structures with the artificial
building block, aTNA, are very stable, do not degrade in the blood, have
been shown to be non-toxic to cells, and do not elicit a nonspecific
immune response. When the researchers coupled a particular type of
biomolecule, which is known to bind to a biomarker in high-specificity
breast cancer cells, to the new 4WJ structure, it turned out that the
4WJ structure may prove effective in directing cancer drugs to the
desired cells. In addition, by making further modifications to the new
4WJ structure, they could extend its lifetime in the bloodstream and thus
also the effect of the drug that may be coupled to the DNA nanostructure.

The researchers imagine that their 4WJ structure built with artificial
building blocks can both be used as a tool to transport drugs to the right position in a patient's body. In addition, they see that it can serve
as a valuable tool in research. For example, researchers imagine that
the effects of different combinations of cancer-degrading biomolecules
can be screened faster and more efficiently, so that the most effective
cancer treatment can be found more quickly.

Center for Multifunctional Biomolecular Drug Design (CEMBID) The Center
for Multifunctional Biomolecular Drug Design (CEMBID) was funded by the
Novo Nordisk Foundation with DKK 60 million in 2018 and runs until 2024.

Professor Kurt V. Gothelf heads the center with a background in
organic chemistry, bioconjugation and DNA nanotechnology, but the interdisciplinary team of researchers at CEMBID works in the fields of chemistry, molecular biology, pharmacology and medicine. The colleagues
from iNANO: Professor Jo/ rgen Kjems and Associate Professor Ken Howard
help lead the center, where Jo/ rgen Kjems has great expertise in nucleic
acid nanotechnology and drug delivery, while Associate Professor Ken
Howard is an expert in drug delivery and pharmacokinetics. Also, from
Vrije Universiteit in Brussels is Professor Tony LaHoutte, who through
his extensive experience with clinical trials of bioconjugates contributes
in connection with testing of the new coupled drugs.


========================================================================== Story Source: Materials provided by Aarhus_University. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Anders Ma"rcher, Vipin Kumar, Veronica L. Andersen, Kassem
El‐Chami, Thuy J. D. Nguyen, Mads K. Skaanning, Imke
Rudnik‐Jansen, Jesper S. Nielsen, Kenneth A. Howard,
Jo/rgen Kjems, Kurt V. Gothelf. Functionalized Acyclic ( l
)‐Threoninol Nucleic Acid Four‐Way Junction with High
Stability In Vitro and In Vivo.

Angewandte Chemie International Edition, 2022; DOI: 10.1002/
anie.202115275 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220420092132.htm

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