Development of a novel targeted therapy using gold nanoparticles for dose enhancement of X-ray irradiation for the treatment of triple-negative breast cancer (Acronym: TaGoNaX)

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Gold nanoparticles show potential as radiosensitizers in radiation therapy. The first successful experiment using gold nanoparticles to increase the radiosensitivity of tumours in mice after irradiation with X-rays stimulated extended experimental and theoretical investigations. One of the major challenges in this research field is the limited availability of target structures that enables a selective uptake of gold nanoparticles into tumour cells. In this proposal, we will investigate the role of membrane heat shock protein 70 (Hsp70) on tumour cells as a target for an enhanced and selective uptake of gold nanoparticles to enhance the efficacy of X-ray based radiation therapy. The research results can provide quantitative information for the decision of using gold nanoparticle as sensitizers in preclinical and clinical radiation therapy settings. In a first step, the Hsp70-specific antibody cmHsp70.1 will be conjugated to gold nanoparticles with different sizes and shapes (AuNP-cmHsp70.1). The coupling of the cmHsp70.1 antibody to AuNPs should enable a tumour-specific targeting of gold nanoparticles into tumorigenic mouse mammary gland cells (4T1) and primary breast cancer cell cultures derived from patients, as Hsp70 is exclusively expressed on the surface of cancer cells, but not on normal cells. Transmission electron microscopy and dynamic light scattering imaging will image the location and distribution of gold nanoparticles inside the cells. In a second step, an X-ray irradiation of the cells with and without gold nanoparticles will be performed at the radiation facilities at the Klinikum rechts der Isar, Technical University of Munich. In a third step, DNA damage and cell survival will be determined comparatively in irradiated cancer cells with and without AuNPs-cmHsp70.1 and the enhanced physical and biological effects induced by gold nanoparticles and X-rays will be determined quantitatively. The most promising AuNP-cmHsp70.1 conjugates will be tested in orthotopic breast cancer mouse models with respect to their radiosensitizing effects. Parallel to the biological experimental investigations, Monte Carlo radiation transport simulations of dose enhancement of gold nanoparticles irradiated by X-rays provide a quantitative cellular dose in the cancer cells. A mathematical model will be developed to analyse the relationship between the enhanced biological endpoints, such as DNA strand breaks and cell survival fractions and physical radiation doses deposited in the cellular level and in tumour mouse-models. Finally, the radiation dose-response relationship can provide basic information for a better understanding of the mechanisms of gold nanoparticles as sensitizers in radiation therapy of breast cancer.