Targeted therapies for the treatment of triple-negative breast cancer
| Autor: | Karolin, Römhild |
|---|---|
| Přispěvatelé: | Knüchel-Clarke, Ruth, Lammers, Twan |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Nanomedizin
Makrophagenpolarisierung Tumormikroumgebung doxorubicin prodrugs macrophage polarization Eisenstoffwechsel tumor microenvironment iron metabolism ddc:610 Doxorubicin Pro-Pharmaka Tumormikroumgebung Makrophagenpolarisierung Nanomedizin Eisenstoffwechsel Doxorubicin Pro-Pharmaka tumor microenvironment macrophage polarization nanomedicine iron metabolism doxorubicin prodrugs nanomedicine |
| Zdroj: | Aachen : RWTH Aachen University 1 Online-Ressource : Illustrationen, Diagramme (2022). doi:10.18154/RWTH-2022-09080 = Dissertation, Rheinisch-Westfälische Technische Hochschule Aachen, 2022 |
| DOI: | 10.18154/rwth-2022-09080 |
| Popis: | Dissertation, Rheinisch-Westfälische Technische Hochschule Aachen, 2022; Aachen : RWTH Aachen University 1 Online-Ressource : Illustrationen, Diagramme (2022). = Dissertation, Rheinisch-Westfälische Technische Hochschule Aachen, 2022 Triple-negative breast cancer (TNBC) has very limited treatment options. Novel targeted treatment strategies and combinations of already established modalities for the treatment of TNBC are investigated in this thesis. Macrophages (MΦ) play a key role in cancer development and progression, and are promising targets for TNBC therapy. Iron metabolism in tumor-associated macrophages was targeted by elevating the iron level with iron oxide nanoparticles (NP) to induce a pro-inflammatory and anti-tumor macrophage phenotype. Several iron oxide NP formulations were tested. In vitro, only the clinically used formulation ferumoxytol polarized primary human macrophages towards a pro-inflammatory phenotype. In vivo, we studied whether ferumoxytol has anti-cancer properties and is able to enhance drug delivery in a TNBC mouse model. Even though high levels of iron accumulation were observed upon i.v. ferumoxytol therapy, no effect on tumor progression, macrophage polarization and the tumor microenvironment (TME) were observed. Furthermore, the impact of macrophage cell culture conditions in dependence of iron was investigated. To this end, we used both serum-free conditions and fetal bovine serum alternatives, and found that both had no significant impact on pro-inflammatory macrophage polarization upon iron treatment. Iron depletion was investigated by using the iron chelator deferoxamine (DFO). DFO showed a reduction in viability in various TNBC cell lines and was able to polarize macrophages towards a pro-inflammatory phenotype in vitro. DFO-containing polymeric micelles (PMs) were synthesized to promote DFO’s circulation time and tumor accumulation upon i.v. application. DFO-loaded PMs were tested in vitro and in vivo versus free DFO regarding tumor growth inhibition and macrophage polarization. Unlike previously published results, no effect of iron depletion was observed on tumor growth inhibition and macrophage polarization. However, DFO-loaded PM could be successfully co-loaded with doxorubicin prodrugs, to serve as an image-guided nanomedicine formulation for cancer therapy. For the latter purpose, doxorubicin (DOX) prodrugs were developed, to reduce off-target toxicity. We designed DOX prodrugs containing a beta-glucuronidase-sensitive capping group with different spacer lengths. Spacer elongation increased the enzyme conversion rate and improved the uptake and activity of the prodrug. A prodrug with two aromatic spacer units was chosen and was successfully combined with focused ultrasound to enable. To conclude, both iron metabolism targeting strategies did not affect the tumor growth and TME. However, ferumoxytol and DFO PM can serve as image-guided drug delivery systems. Published by RWTH Aachen University, Aachen |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|