Addressing the Biochemical Foundations of a Glucose-Based "Trojan Horse"-Strategy to Boron Neutron Capture Therapy: From Chemical Synthesis to In Vitro Assessment

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

Retention of metals in periprosthetic tissues of patients with metal-on-metal total hip arthroplasty is reflected in the synovial fluid to blood cobalt transfer ratio in the presence of a pseudotumour

Abstract Background: Modern metal-on-metal (MOM) arthroplasties were performed for over a decade before alarming reports of adverse metal reactions dramatically reduced their use. Failures are seen more often with high-wearing implants, but also well-positioned components with more favourable wear patterns can cause problems. There are no specific clinical indicators that could help us to predict the prognosis of these implants. For this reason, we still need more information on the effect of underlying factors that contribute to this process. Methods: In this prospective cohort study, we investigated how cup orientation and type of pseudotumour determined by the Hart classification effect the distribution of metals in blood, synovial fluid and tissues surrounding the metal-on-metal hip prosthesis in revision surgery patients. One thousand two hundred twenty-nine metal-on-metal hip patients were screened and of those, 60 patients that had a revision surgery due to adverse metal reaction were included. Whole blood, synovial fluid and synovial/pseudotumour tissue samples were analysed for metal ion concentrations (Co, Cr, Mo and Ti). Results: The lowest metal concentrations were found when both cup anteversion and inclination were optimal, and the highest when both were suboptimal. Suboptimal anteversion alone raised Cr-ion concentrations more than suboptimal inclination. The concentrations of metals in blood, synovial fluid or synovial soft tissue were the same in patients with and without a pseudotumour, but the relative transfer percentage of cobalt from synovial fluid to blood was higher in patients with a pseudotumour. Conclusions: The implant orientation alone does not explain the metal concentrations found in tissues or distribution of metals between different tissues. The accumulation of metals in periprosthetic soft tissues increase the total metal load, and in the presence of a pseudotumour this is reflected in the transfer ratio of Co from synovial fluid to the blood. The total metal load of the pseudotumour tissue should be defined in future studies to determine if this will provide new insights for clinical practice

In utero deposition of trace elements and metals in tissues

Abstract Introduction: All animals, including humans, are exposed to heavy metals which are known to accumulate in different tissues, especially in bone. During pregnancy, the maternal bone turnover is increased and the metals in the mother’s body can be mobilized into the bloodstream. Heavy metals in maternal blood are known to pass through the placenta to the fetal blood and finally, deposited to bone tissue. However, there are no studies on the concentration of metals in the fetal solid tissues and until now, the rate of metal transfer from mother to fetus is not exactly known. Materials and methods: Samples of the blood, liver, placenta, and three different bones were collected from 17 pregnant ewes and their 27 fetuses. The animals had no known exposure to heavy metals. The concentrations of Al, As, Ba, Ca, Cd, Co, Cr, Cu, Fe, Hg, K, Mg, Mn, Mo, Na, Ni, P, Pb, Rb, Sb, Sn, Sr, Te, Ti, Tl, V, and Zn were analyzed using ICP-MS. Results and discussion: The concentration of Sb, Sn, Te, and Tl were under the detection limit in all the samples. The other metals were found in all maternal and fetal tissues, suggesting that all detectable metals cross the placenta. Blood concentrations were low compared to solid tissue concentrations. The concentrations of essential elements varied between maternal and fetal tissues, which could be explained by biological differences. The differences in concentrations of non-essential elements between the ewe and fetuses were smaller. The most significant differences were between maternal and fetal concentrations of Ba and Sr, which is at least partly explained by the mineralization degree of the bone. Conclusion: Heavy metals accumulate in fetal solid tissues in sheep that are not directly exposed to heavy metals. Because of the differences in anatomy between human and sheep placenta, the accumulation in the tissue of human fetuses should be extrapolated cautiously. However, there might be some clinical relevance for fertile aged women who are exposed to heavy metals, such as women who work in the metal industry or who have undergone joint replacement surgery

Addressing the Biochemical Foundations of a Glucose-Based "Trojan Horse"-Strategy to Boron Neutron Capture Therapy : From Chemical Synthesis to In Vitro Assessment

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.Peer reviewe