These DSBs are caused by the energy deposition events happening at two close positions when an ionizing particle passes through a DNA strand; + means the average probability for a DSB to induce cell death. program which applied AuNP-conjugates in preclinical modeling of radiotherapy at the Klinikum rechts der Isar, Technical University of Munich and Helmholtz Zentrum Mnchen. A pharmacokinetic model of superparamagnetic iron oxide nanoparticles was developed in preparation for a model simulating the uptake and distribution of AuNPs in mice. Multi-scale Monte Cucurbitacin B Carlo simulations were performed on a single AuNP and multiple AuNPs in tumor cells at cellular and molecular levels to determine enhancements in the radiation dose and generation of chemical radicals in close proximity to AuNPs. A biologically based mathematical model was developed to predict the biological response of AuNPs in radiation enhancement. Although simulations of a single AuNP demonstrated a clear dose enhancement, simulations relating to the generation of chemical radicals and the Cucurbitacin B induction of DNA strand breaks induced by multiple AuNPs showed only a minor dose enhancement. The differences in the simulated enhancements at molecular and cellular levels indicate that further investigations are necessary to better understand the impact of the physical, chemical, and biological parameters in preclinical experimental settings prior to a translation of these AuNPs Cucurbitacin B models into targeted cancer radiotherapy. and mice (in vivousing different radiation beams have reported an enhanced biological efficacy Cucurbitacin B [17,37,38,39,40,41,42,43,44,45,46,47]. In general, irradiation induced effects, such as DNA damage and apoptosis, are enhanced by the application of AuNPs, and the overall survival of tumor-bearing mice has been shown to be improved. In addition to kV X-rays, other radiation types, such as megavoltage X-rays, protons, and heavy ions, have also been applied in combination with AuNPs [48,49,50]. However, a number of factors, such as the shape, size, precise location of AuNPs, and their biodistribution in different cell types, are known to affect the dose enhancement effect, and as a consequence the DEF has to be determined for each individual experimental setup individually [35,38,48,51]. Furthermore, potential toxic side effects of different types of nanoparticles have to be considered before they can be applied in clinical practice [52]. However, the translation of AuNPs as radiosensitizers into clinical cancer radiotherapy is limited by the lack of tumor-specific targets which enable the selective uptake of AuNPs into tumor cells. In this regard, the Multhoff laboratory at the Klinikum rechts der Isar, Technical University of Munich (TUM) has previously reported that the major stress-inducible heat shock protein 70 (Hsp70) is selectively expressed on the membrane of a large range of different tumor cells, but not on cells in the surrounding healthy tissues [53,54]. Furthermore, standard treatment procedures, such as radiotherapy and chemotherapy, selectively further increase the manifestation denseness of membrane Hsp70 on tumor cells, but not on normal cells [55]. Moreover, an elevated Hsp70 membrane denseness has also been recognized on relapsed tumors, metastases, and Rabbit Polyclonal to MRPL47 highly aggressive tumors such as triple bad breast tumor cells [56]. The unique monoclonal antibody (mAb) cmHsp70.1 is able to detect membrane-bound Hsp70 on viable tumor cells and recent work has indicated that following binding, cmHsp70.1 antibody conjugated AuNPs are rapidly taken up into membrane Hsp70-positive tumor cells by endocytosis [57]. Furthermore, stressed glioma cells exhibiting an increased manifestation of membrane Hsp70 preferentially take up superparamagnetic iron oxide nanoparticles (SPIONs) that are coupled to the cmHsp70.1 antibody [58]. Membrane indicated Hsp70 consequently provides an ideal tumor-specific antigen for focusing on cmHsp70.1 mAb coupled AuNPs into triple negative breast cancer cells. Targeted and non-targeted AuNPs have been used as an X-ray contrast agent for molecular computed tomography (CT) imaging of malignancy [59,60,61], for X-ray fluorescence computed tomography (XFCT) [61,62,63,64,65] of tumors in mice, as well as for cone-beam XFCT simulations and experimental studies [66,67,68]. A high-sensitivity benchtop X-ray fluorescence imaging platform for detecting.