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TY - THES AU - Schäfer, Laura TI - Auger electron-emitting nanotheranostics for image-guided radio-chemotherapy against triple-negative breast cancer PB - RWTH Aachen University VL - Dissertation CY - Aachen M1 - RWTH-2025-05979 SP - 1 Online-Ressource : Illustrationen PY - 2025 N1 - Veröffentlicht auf dem Publikationsserver der RWTH Aachen University N1 - Dissertation, RWTH Aachen University, 2025 AB - 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 LB - PUB:(DE-HGF)11 DO - DOI:10.18154/RWTH-2025-05979 UR - https://publications.rwth-aachen.de/record/1014255 ER -