Galal, Salma Tarek Rafik AbdELKhalek; (2025) Pharmacological and therapeutic studies using a bioengineered 3D breast cancer model. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The breast tumour microenvironment comprises specific biophysical, biochemical, and ‎cellular facets, which include a collagen-rich extracellular matrix and a mixture of tumour cells ‎and stromal cells. The interactions between tumour cells and their microenvironment alter ‎tumour behaviour and impact response to therapies. Despite their common use in breast ‎cancer studies, in vitro 2D cell cultures exhibit limited biomimicry of breast cancer complexity. ‎‎3D cell culture models are more biomimetic as they recapitulate the physiological 3D tissue ‎architecture of the tumour microenvironment. In this study, a biomimetic 3D in vitro breast ‎tumour model, termed ‘tumouroid’, was developed by incorporating breast tumour cells within ‎a complex stroma to mimic the physiological tumour microenvironment. This model was used ‎to investigate the therapeutic effects of targeted nano-delivery systems, combined ultrasound ‎with chemotherapy and photodynamic therapy in the treatment of breast cancer. ‎ A novel 3D multi-compartment dense collagen I gel was engineered, where either MCF-7 or ‎MDA-MB-231 breast cancer cells were embedded within a central artificial tumour mass ‎surrounded by a stromal compartment composed of stromal cells with various extracellular ‎matrix proteins. The impact of the stromal compartment on cancer cell growth and invasion, ‎along with changes in oxygen levels, was evaluated in 3D tumouroids. The response to ‎different therapies, including doxorubicin, liposomal doxorubicin, hyaluronic nanoparticles ‎encapsulating doxorubicin, and photoactivatable drugs, was assessed in 3D tumouroids via ‎imaging, cell viability assay, and real-time monitoring of oxygen gradient levels. Finally, the ‎effect of ultrasound application on the uptake of previously drug-treated tumouroids was ‎investigated. ‎ ‎3D breast tumouroids were successfully established where the presence of adipose tissue-‎derived mesenchymal stem cells and extracellular matrix proteins in the stromal ‎compartment influenced vascular network formation, hypoxia development, cancer cell ‎growth, invasion, as well as response to therapies. The stromal compartment significantly ‎enhanced the tumourigenic potential of the less metastatic MCF-7 breast cancer cells ‎compared to the highly metastatic MDA-MB-231. Direct killing of tumour cells was observed ‎in addition to disruption of vascular networks and alleviation of hypoxia, in response to ‎doxorubicin‎, hyaluronic nanoparticles encapsulating doxorubicin, and combined ‎doxorubicin/photoactivatable drug treatments. MCF-7 breast cancer cells showed higher drug ‎therapeutic responses compared to MDA-MB-231 breast cancer cells. Ultrasound application ‎improved the cell-killing effects of doxorubicin and liposomal doxorubicin in MDA-MB-231 3D ‎tumouroids. ‎ In conclusion, 3D breast tumouroids display biomimicry of the in vivo breast tumour ‎microenvironment and the ability to distinguish between different drug responses, which ‎support their suitability as a platform for mechanistic studies of tumour biology and ‎therapeutic screening. ‎

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