Towards New Delivery Agents for Boron Neutron Capture Therapy: Synthesis and In Vitro Evaluation of a Set of Fluorinated Carbohydrate Derivatives.

Boron Neutron Capture Therapy (BNCT) is a cancer treatment which combines tumor-selective boron delivery agents with thermal neutrons in order to selectively eradicate cancer cells. In this work, we focus on the early-stage development of carbohydrate delivery agents for BNCT. In more detail, we expand upon our previous GLUT-targeting approach by synthesizing and evaluating the potential embedded in a representative set of fluorinated carbohydrates bearing a boron cluster. Our findings indicate that these species may have advantages over the boron delivery agents in current clinical use, e.g., significantly improved boron delivery capacity at the cellular level. Simultaneously, the carbohydrate delivery agents were found to bind strongly to plasma proteins, which may be a concern requiring further action before progression to in vivo studies. Altogether, this work brings new insights into factors which need to be accounted for if attempting to develop theranostic agents for BNCT based on carbohydrates in the future.

Sweet Battle of the Epimers─Continued Exploration of Monosaccharide-Derived Delivery Agents for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is a cancer therapy in which boron delivery agents play a crucial role. In theory, delivery agents with high tumor targeting capabilities can lead to selective eradication of tumor cells without causing harmful side effects. We have been working on a GLUT1-targeting strategy to BNCT for a number of years and found multiple promising hit compounds which outperform the clinically employed boron delivery agents in vitro. Herein, we continue our work in the field by further diversification of the carbohydrate scaffold in order to map the optimal stereochemistry of the carbohydrate core. In the sweet battle of the epimers, carborane-bearing d-galactose, d-mannose, and d-allose are synthesized and subjected to in vitro profiling studies─with earlier work on d-glucose serving as the reference. We find that all of the monosaccharide delivery agents display a significantly improved boron delivery capacity over the delivery agents approved for clinical use in vitro, thus providing a sound foundation for advancing toward in vivo preclinical assessment studies.

Synthesis and In Vitro Evaluation of a Set of 6-Deoxy-6-thio-carboranyl d-Glucoconjugates Shed Light on the Substrate Specificity of the GLUT1 Transporter.

Glucose- and sodium-dependent glucose transporters (GLUTs and SGLTs) play vital roles in human biology. Of the 14 GLUTs and 12 SGLTs, the GLUT1 transporter has gained the most widespread recognition because GLUT1 is overexpressed in several cancers and is a clinically valid therapeutic target. We have been pursuing a GLUT1-targeting approach in boron neutron capture therapy (BNCT). Here, we report on surprising findings encountered with a set of 6-deoxy-6-thio-carboranyl d-glucoconjugates. In more detail, we show that even subtle structural changes in the carborane cluster, and the linker, may significantly reduce the delivery capacity of GLUT1-based boron carriers. In addition to providing new insights on the substrate specificity of this important transporter, we reach a fresh perspective on the boundaries within which a GLUT1-targeting approach in BNCT can be further refined.

Exploring the Biochemical Foundations of a Successful GLUT1-Targeting Strategy to BNCT: Chemical Synthesis and In Vitro Evaluation of the Entire Positional Isomer Library of ortho-Carboranylmethyl-Bearing Glucoconjugates.

Boron neutron capture therapy (BNCT) is a noninvasive 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 into their essential properties, for example, 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 d-glucose, which are critical in order to further develop this strategy toward clinical use.

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.

Screening of undiagnosed depression among elderly primary care patients: a cross-sectional study from the Republic of Srpska, Bosnia and Herzegovina.

Aim To examine the prevalence of undiagnosed depression among primary care elderly patients in the entity of the Republic of Srpska (Bosnia and Herzegovina) as well as the sociodemographic and clinical risk factors associated with depression. Methods A cross-sectional study was conducted between April and June 2019 in nine towns of the Republic of Srpska. The study sample included 1,198 primary care patients older than 65 years of age. Research instruments included a sociodemographic questionnaire and Geriatric Depression Scale - Short Form (GDS-SF). Results Positive screening test (GDS-SF score > 5), which indicates depression was found in 484 (40.4%) participants. Multivariate regression analysis showed that lower education levels [OR = 1.565, 95% CI (1.13-2.17)], divorced and widowed [OR = 1.366, 95% CI (1.16-1.62)], poor financial situation [OR = 1.690 , 95% CI (1.25-2.29)], non-home residents [OR = 2.200, 95% CI (1.41- 3.44)], non-hobby patients [OR = 2.115, 95% CI (1.54-2.91) ], non-friends [OR = 3.881, 95% CI (2.70-5.57)], patients suffering from chronic pain [OR = 2.414, 95% CI (1.72-3.39)], patients with daily life limitation activities [OR = 1.415, 95% CI (1.03-1.95)], patients with three or more chronic diseases [OR = 1.593, 95% CI (1.12-2.27)], patients using five or more drugs [OR = 1.425. 95% CI (1.00-2.03)], and patients with history of previous depression [OR = 2.858, 95% CI (1.94-4.21)] were at higher risk for depression. Conclusion The prevalence of undiagnosed depression in the elderly in Republic of Srpska is high. Future strategies are needed to strengthen screening of geriatric depression in primary health care.

Comprehensive geriatric assessment: comparison of elderly hemodialysis patients and primary care patients.

BACKGROUNDS: The quality of life and survival of elderly depend not only on their age but on many social and health factors. In the present study, comprehensive geriatric assessment (CGA) was made in elderly patients on regular hemodialysis (HD) and those without chronic kidney disease recruited in primary health care in order to compare their sociodemographic characteristics, physical health, functional ability and social support. METHOD: The 106 HD patients and 300 primary care patients aged 70 years and more were studied. Data on sociodemographic characteristics, neurosensory deficits, pain, falls, polypharmacy, basic activities of daily living (ADL) questionnaire, instrumental activities of daily living (IADL) questionnaire were obtained during interview. The Timed Up and Go, Nutritional Health Checklist, Two Question Instrument for depression and Charlson comorbidity index (CCI) were applied. RESULTS: No significant differences were found for age, gender, education level and dwelling between the two groups. A lower percentage of HD patients lived alone when compared with controls. BMI >25 kg/m(2) had 43.4% of HD patients and 49.3% of controls. CCI differed significantly between HD and primary care patients (median: 6 vs. 4) and significantly more HD patients reported depression. No significant difference was found between groups for cognitive dysfunction and ADL, but HD patients had significantly lower IADL scores than controls. The mobility of HD patients was worse; 45.7% of them reported falls in the previous year but only 9.7% from the controls. CONCLUSIONS: CGA revealed that HD patients had significantly higher CCI, worse IADL score, mobility and reported more frequent falls, depression and impaired vision than primary care patients.