Boron neutron capture therapy (BNCT) for cancer is on the rise worldwide due to recent developments of in-hospital neutron accelerators which are expected to revolutionize patient treatments. There is an urgent need for improved boron delivery agents, and herein we have focused on studying the biochemical foundations upon which a successful GLUT1-targeting strategy to BNCT could be based. By combining synthesis and molecular modeling with affinity and cytotoxicity studies, we unravel the mechanisms behind the considerable potential of appropriately designed glucoconjugates as boron delivery agents for BNCT. In addition to addressing the biochemical premises of the approach in detail, we report on a hit glucoconjugate which displays good cytocompatibility, aqueous solubility, high transporter affinity, and, crucially, an exceptional boron delivery capacity in the in vitro assessment thereby pointing toward the significant potential embedded in this approach.

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Boron Neutron Capture Therapy (BNCT) is a non-invasive binary therapeutic modality applicable to the treatment of cancers. While BNCT offers a tumor-targeting selectivity that is difficult to match by other means, the last obstacles preventing the full harness of this potential come in the form of the suboptimal boron delivery strategies presently used in the clinics. To address these challenges, we have developed delivery agents that target the glucose transporter GLUT1. Here, we present the chemical synthesis of a number of ortho-carboranylmethyl substituted glucoconjugates and the biological assessment of all positional isomers.Altogether, the study provides protocols for the synthesis and structural characterization of such glucoconjugates and insights on their essential properties e.g. cytotoxicity, GLUT1-affinity, metabolism and boron delivery capacity. In addition to solidifying the biochemical foundations of a successful GLUT1-targeting approach to BNCT, we identify the most promising modification sites in Dglucose which are critical in order to further develop this strategy towards clinical use.

To study the role of metallothioneins (MTs) in Zn accumulation, the expression of TcMT2a, TcMT2b, and TcMT3 was analysed in three accessions and 15 F3 families of two inter-accession crosses of the Cd/Zn hyperaccumulator Thlaspi caerulescens, with different degrees of Zn accumulation. The highest expression levels were found in the shoots of a superior metal-accumulating calamine accession from St Laurent le Minier, with >10-fold TcMT3 expression compared with another calamine accession and a non-metallicolous accession. Moreover, F3 sibling lines from the inter-accession crosses that harboured the MT2a or MT3 allele from St Laurent le Minier had higher expression levels. However, there was no co-segregation of TcMT2a or TcMT3 expression and Zn accumulation. To examine the functions of TcMTs in plants, TcMT2a and TcMT3 were ectopically expressed in Arabidopsis. The transformant lines had reduced root length in control medium but not at high metal concentrations, suggesting that the ectopically expressed proteins interfered with the physiological availability of essential metals under limited supply. The Arabidopsis transformant lines did not show increased tolerance to Cd, Cu, or Zn, nor increased Cd or Zn accumulation. Immunohistochemical analysis indicated that in roots, MT2 protein is localized in the epidermis and root hairs of both T. caerulescens and Arabidopsis thaliana. The results suggest that TcMT2a, TcMT2b, and TcMT3 are not primarily involved in Zn accumulation as such. However, the elevated expression levels in the metallicolous accessions suggests that they do contribute to the metal-adapted phenotype, possibly through improving Cu homeostasis at high Zn and Cd body burdens. Alternatively, they might function as hypostatic enhancers of Zn or Cd tolerance.

Porous silicon (PSi) has attracted wide interest as a potential material for various fields of nanomedicine. However, until now, the application of PSi in photothermal therapy has not been successful due to its low photothermal conversion efficiency. In the present study, biodegradable black PSi (BPSi) nanoparticles were designed and prepared via a high-yield and simple reaction. The PSi nanoparticles possessed a low band gap of 1.34 eV, a high extinction coefficient of 13.2 L/g/cm at 808 nm, a high photothermal conversion efficiency of 33.6%, good photostability, and a large surface area. The nanoparticles had not only excellent photothermal properties surpassing most of the present inorganic photothermal conversion agents (PCAs) but they also displayed good biodegradability, a common problem encountered with the inorganic PCAs. The functionality of the BPSi nanoparticles in photothermal therapy was verified in tumor-bearing mice in vivo. These results showed clearly that the photothermal treatment was highly efficient to inhibit tumor growth. The designed PCA material of BPSi is robust, easy to prepare, biocompatible, and therapeutically extremely efficient and it can be integrated with several other functionalities on the basis of simple silicon chemistry.

Several populations with diVerent metal tolerance, uptake and root-to-shoot transport are known for the metal hyperaccumulator plant Thlaspi caerulescens. In this study, genes diVerentially expressed under various Zn exposures were identiWed from the shoots of two T. caerulescens accessions (calaminous and non-calaminous) using Xuorescent diVerential display RT-PCR. cDNA fragments from 16 Zn-responsive genes, including those encoding metallothionein (MT) type 2 and type 3, MRP-like transporter, pectin methylesterase (PME) and Ole e 1-like gene as well as several unknown genes, were eventually isolated. The fulllength MT2 and MT3 sequences diVer from those previously isolated from other Thlaspi accessions, possibly representing new alleles or isoforms. Besides the diVerential expression in Zn exposures, the gene expression was dependent on the accession. Thlaspi homologues of ClpP protease and MRP transporter were induced at high Zn concentrations. MT2 and PME were expressed at higher levels in the calaminous accession. The MTs and MRP transporter expressed in transgenic yeasts were capable of conferring Cu and Cd tolerance, whereas the Ole e 1-like gene enhanced toxicity to these metals. The MTs increased yeast intracellular Cd content. As no signiWcant diVerences were found between Arabidopsis and Thlaspi MTs, they apparently do not diVer in their capacity to bind metals. However, the higher levels of MT2 in the calaminous accession may contribute to the Zn-adapted phenotype.

Aminobisphosphonates, e.g., alendronate and neridronate, are a well known class of molecules used as drugs for various bone diseases. Although these molecules have been available for decades, a detailed understanding of their most important physicochemical properties under comparable conditions is lacking. In this study, ten aminobisphosphonates, H2N(CH2)nC(OH)[P(O)(OH)2]2, in which n = 2–5, 7–11 and 15 have been synthesized. Their aqueous solubility as a function of temperature and pH, pKa-values, thermal stability, IR absorptions, and NMR spectral data for both liquid (1H, 13C, 31P-NMR) and solid state (13C, 15N and 31P-CPMAS NMR) were determined.

A Novel approach to remove metals from aqueous solutions has been developed. The method is based on a resin free, solid, non-toxic, microcrystalline bisphosphonate material, which has very low solubility in water (59 mg/l to ion free Milli-Q water and 13 mg/l to 3.5% NaCl solution). The material has been produced almost quantitatively on a 1 kg scale (it has been prepared also on a pilot scale, ca. 7 kg) and tested successfully for its ability to collect metal cations from different sources, such as ground water and mining process waters. Not only was this material highly efficient at collecting several metal ions out of solution it also proved to be regenerable and reusable over a number of adsorption/desorption, which is crucial for environmental friendliness. This material has several advantages compared to the currently used approaches, such as no need for any precipitation step.