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@PHDTHESIS{Ishaqat:987345,
author = {Ishaqat, Aman Aref Mousa},
othercontributors = {Herrmann, Andreas and De Laporte, Laura},
title = {{N}ucleic acid delivery : from ultrasound-triggered release
to autonomous systems},
school = {RWTH Aachen University},
type = {Dissertation},
address = {Aachen},
publisher = {RWTH Aachen University},
reportid = {RWTH-2024-05609},
pages = {1 Online-Ressource : Illustrationen},
year = {2024},
note = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
University; Dissertation, RWTH Aachen University, 2024},
abstract = {Drug delivery plays a crucial role in effectively managing
diverse medical conditions. However, conventional systemic
drug delivery methods face challenges related to maintaining
precise drug concentrations and minimizing side effects.
These hurdles can be addressed through the design and
refinement of smart responsive drug delivery systems that
can be controlled by different types of endogenous and
exogenous stimuli.In this work, we present two innovative
strategies for achieving controlled on-demand drug delivery,
employing ultrasound and enzymes as physical and chemical
triggers, respectively. Ultrasound emerges as a standout
trigger due to its deep tissue penetration and non-invasive
applicability in biological environments, surpassing other
physical triggers such as light, magnetic fields and
temperature. The unique ability of ultrasound to convert
mechanical energy into productive work at the molecular
level inspired us to adapt principles developed in the field
of polymer mechanochemistry and translate them into
biomedical applications. Overcoming the challenge associated
with the typically high energy levels of ultrasound in
polymer mechanochemistry, we develop a carrier that
inherently responds to low-intensity (i.e., spatial-peak
temporal-average intensity (IP) below 720 mW∙cm-2) and
high frequency (4 -12 MHz) medical imaging US.Our
mechanoresponsive drug delivery system, constructed from DNA
nanomaterial, serves as a versatile scaffold for delivering
various therapeutic nucleic acids, both DNA- and RNA-based.
We characterize our system extensively, investigate its
mechanical properties and evaluate the underlying mechanism
of ultrasound responsiveness. We demonstrate successful
delivery of CpG oligodeoxynucleotides leading to controlled
immunostimulation in different cell culture models.
Moreover, we validate our drug delivery system in healthy
animal immunostimulation model in vivo, marking an
unprecedented application of polymer mechanochemistry in
living organisms. Additionally, we demonstrate the delivery
of small interfering RNA oligonucleotides as a second cargo,
resulting in controlled gene knockdown in cell culture
experiments. We believe that this pioneering work positions
our mechanochemically responsive drug delivery system as a
universal platform, poised for loading other types of cargo,
such as small molecules and proteins, further expanding its
potential applications in fundamental and therapeutic
research. In the second strategy, our focus is to design DNA
circuits that can be activated by the enzymatic activity of
exonucleases, facilitating a precise control over the
delivery of CpG oligodeoxynucleotides in vitro. These
DNA-based nanosystems are pre-programmed to achieve distinct
pharmacokinetic profile, characterized with an acute and
robust immunostimulatory response, in contrast to a system
lacking controlled drug release, which exhibited a slow and
delayed response. Furthermore, we transformed the DNA
circuit into a dissipative system, characterized by multiple
cycles of activation/deactivation, operating
out-of-equilibrium. Such systems are envisioned to achieve
autonomous control, allowing it to seamlessly interact with
and respond to the biological milieu, requiring minimal
external intervention. We believe this approach paves the
path for tailored drug delivery systems, in which a
harmonious interplay between activation and inhibition
responses becomes paramount.},
cin = {155910 / 150000},
ddc = {540},
cid = {$I:(DE-82)155910_20190516$ / $I:(DE-82)150000_20140620$},
pnm = {DFG project 464121872 - Ultraschallkontrollierte
Krebsimmuntherapie mit DNA-Nanostrukturen (464121872)},
pid = {G:(GEPRIS)464121872},
typ = {PUB:(DE-HGF)11},
doi = {10.18154/RWTH-2024-05609},
url = {https://publications.rwth-aachen.de/record/987345},
}
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