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@PHDTHESIS{Schfer:1014255,
author = {Schäfer, Laura},
othercontributors = {Schillberg, Stefan Johannes and Herrmann, Andreas},
title = {{A}uger electron-emitting nanotheranostics for image-guided
radio-chemotherapy against triple-negative breast cancer},
school = {RWTH Aachen University},
type = {Dissertation},
address = {Aachen},
publisher = {RWTH Aachen University},
reportid = {RWTH-2025-05979},
pages = {1 Online-Ressource : Illustrationen},
year = {2025},
note = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
University; Dissertation, RWTH Aachen University, 2025},
abstract = {Radio-nanomedicine, the combination of radiation technology
or nuclear medicine with nanomedicine, is an emerging and
promising field in nuclear imaging and therapy. BRCA-mutated
(BRCAmut) triple-negative breast cancer (TNBC), the most
aggressive form of breast cancer that is often treated with
poly(ADP-ribose) polymerase inhibitors (PARPi) has been
evaluated as a potential tumor entity using
radio-nanomedicine. While PARPi can prolong survival, they
do not provide a curative effect. Auger electron-emitting
radiotherapeutics have shown promise for radionuclide
therapy of BRCAmut TNBC by effectively inducing DNA
double-strand breaks, when located in close proximity to the
DNA. In this context, an Auger-electron emitting therapeutic
based on [123/125I]I-PARPi-01 was recently developed and
evaluated for BRCAmut TNBC. However, as many other
radiotracers, it presented several drawbacks when
administered in vivo, particularly low water-solubility, a
rapid enzymatic degradation, rapid clearance, and low tumor
accumulation, thereby resulting in suboptimal therapeutic
performance. To overcome these issues, encapsulating drugs
within nanocarriers has shown promise. Nanoscale drug
delivery systems have proven effective in enhancing drug
stability and improving biodistribution and tumor targeting,
together potentiating anticancer therapy performance. Among
the different drug delivery systems, polymeric micelles are
widely used for hydrophobic drug delivery and hold high
promise as modular platforms for multidrug delivery, thus
enabling drug combination nanotherapies. In this thesis, a
theranostic polymeric micelle co-formulation of Auger
electron-emitting and SPECT-imageable 123/125I-PARPi with
the non-radioactive counterpart was developed for improved
radio-chemotherapy combination in BRCAmut TNBC. For that
purpose, physically stabilized micelles have been employed
based on mPEG-b-p(HPMAm-Bz) block copolymers to
co-encapsulate the hydrophobic radiolabeled poly
(ADP-ribose) polymerase inhibitor [123/125I]I-PARPi-01 and
the non-radioactive counterpart I-PARPi-01. The co-loaded
micelles showed diameters around 70 nm, with homogeneous
size distribution and spherical morphology. Both drugs were
efficiently encapsulated and effectively co-delivered by the
micelles. The micelle formulation improved the PARPi tracer
stability in biological media. In vivo SPECT/CT measurements
using 123I corroborated these findings and demonstrated
prolonged circulation times, enhanced tumor accumulation,
and slowed tracer degradation when encapsulated in polymeric
micelles as compared to the free tracer. The double (Auger
electron-emitting 125I-radioactive and non-radioactive
PARPi) drug-loaded micelles showed improved antitumor
efficacy after a single intravenous administration, with a
50 $\%$ reduction in tumor volume observed after 14 days of
treatment, in comparison to the co-administration of the
free drugs (also confirmed via ex vivo immunohistochemical
analysis), while being well-tolerated. Taken together, this
newly developed Auger electron emitting co-loaded micelle
formulation demonstrated enhanced in vivo tracer stability,
prolonged blood circulation, and improved tumoral uptake,
together potentiating PARPi therapeutic performance in
BRCAmut TNBC and underscoring the potential of
radio-nanomedicine combinations in difficult-to-treat
cancers, including beyond TNBC and towards eventual clinical
investigations.},
cin = {162910 / 160000},
ddc = {570},
cid = {$I:(DE-82)162910_20140620$ / $I:(DE-82)160000_20140620$},
pnm = {GRK 2375 - GRK 2375: Tumor-Targeted Drug Delivery
(331065168)},
pid = {G:(GEPRIS)331065168},
typ = {PUB:(DE-HGF)11},
doi = {10.18154/RWTH-2025-05979},
url = {https://publications.rwth-aachen.de/record/1014255},
}
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