The existence of therapy resistant glioma stem cells is responsible for the high recurrence rate and incurability of glioblastomas. The Hedgehog pathway activity plays an essential role for self-renewal capacity and survival of glioma stem cells. We examined the potential of the Sonic hedgehog ligand for sensitizing of glioma stem cells to endogenous nano-irradiation. We demonstrate that the Sonic hedgehog ligand preferentially and efficiently activats glioma stem cells to enter the radiation sensitive G2/M phase. Concomitant inhibition of de novo thymidine synthesis with fluorodeoxyuridine and treatment with the Auger electron emitting thymidine analogue 5-[I-125]-Iodo-4’-thio-2’-deoxyuridine ([I-125]ITdU) leads to a fatal nano-irradiation in sensitized glioma stem cells. Targeting of proliferating glioma stem cells with DNA-incorporated [I-125]ITdU efficiently invokes the intrinsic apoptotic pathway despite active DNA repair mechanisms. Further, [I-125]ITdU completely inhibits survival of glioma stem cells in vitro. Analysis of non-stem glioblastoma cells and normal human astrocytes reveals that glioma stem cells differentially respond to Sonic hedgehog ligand. These data demonstrate a highly efficient and controllable single-cell kill therapeutic model for targeting glioma stem cells.

PARP1 inhibitors (PARPi) are currently approved for BRCA^mut metastatic breast cancer, but they have shown limited response in triple negative breast cancer (TNBC) patients. Combination of an Auger emitter with PARPis enables PARP inhibition and DNA strand break induction simultaneously. This will enhance cytotoxicity and additionally allow a theranostic approach. This study presents the radiosynthesis of the Auger emitter [¹²⁵I] coupled olaparib derivative: [¹²⁵I]-PARPi-01, and its therapeutic evaluation in a panel of TNBC cell lines. Specificity was tested by a blocking assay. DNA strand break induction was analysed by γH2AX immunofluorescence staining. Cell cycle analysis and apoptosis assays were studied using flow cytometry in TNBC cell lines (BRCA^wt/mut). Anchorage independent growth potential was evaluated using soft agar assay. [¹²⁵I]-PARPi-01 showed PARP1-specificity and higher cytotoxicity than olaparib in TNBC cell lines irrespective of BRCA their status. Cell lines harbouring DNA repair deficiency showed response to [¹²⁵I]-PARPi-01 monotherapy. Combined treatment with Dox-NP further enhanced therapeutic efficiency in metastatic resistant BRCA^wt cell lines. The clonogenic survival was significantly reduced after treatment with [¹²⁵I]-PARPi-01 in all TNBC lines investigated. Therapeutic efficacy was further enhanced after combined treatment with chemotherapeutics. [¹²⁵I]-PARPi-01 is a promising radiotherapeutic agent for low radiation dosages, and mono/combined therapies of TNBC.

Given the high sensitivity and specificity of sodium [¹⁸F]Fluoride (Na[¹⁸F]F) for vascular calcifications and positive emerging data of vitamin K on vascular health, the aim of this study is to assess the ability of Na[¹⁸F]F to monitor therapy and disease progression in a unitary atherosclerotic mouse model. ApoE^−/− mice were placed on a Western-type diet for 12-weeks and then split into four groups. The early stage atherosclerosis group received a chow diet for an additional 12-weeks, while the advanced atherosclerosis group continued the Western-type diet. The Menaquinone-7 (MK-7) and Warfarin groups received MK-7 or Warfarin supplementation during the additional 12-weeks, respectively. Control wild type mice were fed a chow diet for 24-weeks. All of the mice were scanned with Na[¹⁸F]F using a small animal positron emission tomography (PET)/computed tomography (CT). The Warfarin group presented spotty calcifications on the CT in the proximal aorta. All of the spots corresponded to dense mineralisations on the von Kossa staining. After the control, the MK-7 group had the lowest Na[¹⁸F]F uptake. The advanced and Warfarin groups presented the highest uptake in the aortic arch and left ventricle. The advanced stage group did not develop spotty calcifications, however Na[¹⁸F]F uptake was still observed, suggesting the presence of micro-calcifications. In a newly applied mouse model, developing spotty calcifications on CT exclusively in the proximal aorta, Na[¹⁸F]F seems to efficiently monitor plaque progression and the beneficial effects of vitamin K on cardiovascular disease.

Over the past 20 years, ⁶⁸Ga-labelled radiopharmaceuticals have become an important part in clinical routine. However, the worldwide supply with ⁶⁸Ge/⁶⁸Ga generators is limited as well as the number of patient doses per batch of ⁶⁸Ga radiopharmaceutical. In the recent years, a new technique appeared, making use of the ease of aqueous labelling via chelators as with ⁶⁸Ga but using ¹⁸F instead. This technique takes advantage of the strong coordinative bond between aluminium and fluoride, realized in the aqueous cation [Al¹⁸F]²⁺. Most applications to date make use of one-pot syntheses with free Al(III) ions in the system. In contrast, we investigated the labelling approach split into two steps: generating the Al-bearing precursor in pure form and using this Al compound as a precursor in the labelling step with aqueous [¹⁸F]fluoride. Hence, no free Al³⁺ ions are present in the labelling step. We investigated the impact of parameters: temperature, pH, addition of organic solvent, and reaction time using the model chelator NH₂-MPAA-NODA. With optimized parameters we could stably achieve a 80% radiochemical yield exerting a 30-min reaction time at 100 °C. This technique has the potential to become an important approach in radiopharmaceutical syntheses.

Tissue engineering as a multidisciplinary field enables the development of living substitutes to replace, maintain, or restore diseased tissue and organs. Since the term was introduced in medicine in 1987, tissue engineering strategies have experienced significant progress. However, up to now, only a few substitutes were able to overcome the gap from bench to bedside and have been successfully approved for clinical use. Substantial donor variability makes it difficult to predict the quality of tissue-engineered constructs. It is essential to collect sufficient data to ensure that poor or immature constructs are not implanted into patients. The fulfillment of certain quality requirements, such as mechanical and structural properties, is crucial for a successful implantation. There is a clear need for new nondestructive and real-time online monitoring and evaluation methods for tissue-engineered constructs, which are applicable on the biomaterial, tissue, cellular, and subcellular levels. This paper reviews current established nondestructive techniques for implant monitoring including biochemical methods and noninvasive imaging.