The Generation of Novel Metal-Folate- Phenanthroline Complexes and Phenanthroline-Folate Conjugates with Potential as Chemotherapeutic Agents

The folate receptor (FR) was identified in 1986 and has been established as a ‘molecular Trojan Horse’ target for the uptake of folate-conjugated organic molecules into cells. The FR is overexpressed in many malignancies, including those of the ovary, uterus, breast, cervix, and prostate, yet it is reportedly under-expressed in normal healthy cells. This difference in expression and the high affinity/specificity of folate towards the folate receptor presents a promising drug delivery system. The aim of this research was to utilise folic acid as a targeting moiety and generate simple metal folate and novel folate-phenanthroline complexes with cytotoxic properties. A challenging set of chemical objectives were set and resulted in the successful generation of simple metal-folate and metal-folate-phen complexes (metal = Cu2+, Mn2+, Fe3+ and Zn2+). In contrast to reports in the literature, NMR and IR evidence indicates that the folate ligand coordinates the metal centre via a tridentate ONO {α-COO-, γ-COO-, and Namide} binding mode. A challenging six-stage synthetic route yielded the novel folate-ethylenediamine-imidazole-phen (FIMP-et) ligand and the novel complexes [Cu(FIMP-et)2(H2O)2].(ClO4)2.4.5H2O and [Mn(FIMP-et)3].(ClO4)2.9H2O were subsequently isolated in high yield and purity. The complexes generated were then utilised in a series of biological studies using cellular models expressing the folate receptor. Our results suggest that the effects mediated by these complexes are not dependent on folate receptor expression. Western blot analysis and live cell analysis identified that [Cu(fol)(phen)(H2O)].3H2O, with or without the inclusion of folic acid, induced expression of proteins associated with proteasomal inhibition and apoptosis. In contrast, [Mn(fol)(phen)(H2O)].4H2O was ineffective in inducing proteasomal inhibition. Interestingly [Mn(fol)(phen)(H2O)].4H2O induces cell death through a mechanism independent of proteasomal inhibition, which may involve ROS-induced autophagy. This work advances the field of medicinal inorganic chemistry and has identified novel mechanisms of action for metal folate targeted inorganic complexes as potential chemotherapeutic agents, through proteasomal inhibition and ROS-induced autophagy

Targeting the folate receptor: Improving efficacy in inorganic medicinal chemistry

The discovery of the high-affinity, high-specificity folate receptor in mamalian kidney cells, coupled with the ability of folate to enter cells by folate receptor-mediated endocytosis and the subsequent elucidation of the folate receptor’s overexpression in specific cancer cell types; heralded the arrival of the area of chemotherapeutic folate targeting. The application of purely organic folate-based small-molecule drug conjugates that selectively target the folate receptor, which is over expressed in several diseases such as cancer, is well established. The application of inorganic folate-targeted drugs offers significant potential to expand and enhance this therapeutic approach. From the data made available to date, it is apparent that this aspect of inorganic medicinal chemistry is in its youth but has the capability to contribute greatly to cancer research, both in therapy and diagnosis. The union of folate-receptor targeting and inorganic medicine may also lead to the development of treatments for disorders such as chronic-inflammation, tuberculosis, neurodegenerative disease and leishmaniasis. In this review, we summarize what is known about the coordination chemistry of folic acid and the therapeutic potential of such complexes. We also describe approaches adopted to conjugate platinum drugs to folate- or folate-carrier- systems and their prospective ability to overcome problems associated with unwanted side-effects and resistance by improving their delivery and/or selectivity. The literature pertaining to non-platinum metal complex conjugates with folic acid is also reviewed revealing that this is an area that offers significant potential to develop targeted therapeutic approaches in areas such as chemotherapy and molecular imaging for diagnostics

Pharmacy students' experience of technology-enhanced learning during the COVID-19 pandemic

With the advent of the COVID-19 pandemic, pharmacy students and educators experienced an abrupt shift as programmes that were previously taught exclusively in-person were then predominantly taught online. This sudden change provided little time for students to prepare for the new learning environment. The study objective was to explore pharmacy students' experiences of technology-enhanced learning during the COVID-19 pandemic. A cross-sectional survey was developed and distributed by email to all 3rd year (N = 76) and 4th year (N = 68) pharmacy students undertaking an MPharm programme in an Irish university. A total of 32 responses were collected, including 20 third year and 12 fourth year pharmacy students (response rates of 26.3% and 17.6%, respectively). The majority of respondents reported good or very good internet speed (71%) and stability (59%). Almost all were confident or very confident using Canvas (97%) prior to the onset of online learning. Respondents preferred engaging with other students in-person rather than online for coursework (68.8%) and learning new material (56.3%). Students favoured face-to-face delivery, with a recording of the session available online afterwards, for lectures (68.8%), workshops (50%) and tutorials (56.3%). Analysis of free-text comments indicates that respondents used recorded content to support exam revision and that a key drawback of online learning was social isolation. Pharmacy students favoured a blended learning approach, with in-person learning being recorded to support study and revision. Students' experience of TEL during the pandemic should be considered in the development and ongoing review of pharmacy programmes

Increased rates of invasive bacterial disease in late 2022

Invasive bacterial disease is associated with significant morbidity and mortality. In winter 2022, there was an apparent increased rate of invasive bacterial disease compared to preceding years. Cross-site retrospective analysis of the three Children's Health Ireland (CHI) hospitals looking at children admitted between 1st October 2022-31st December 2022 (Q4) with community-acquired invasive bacterial disease, defined as an abscess in a normally sterile site in the head, neck and chest or isolation or PCR detection of Streptococcus pneumoniae, Neisseria meningitidis, Streptococcus pyogenes (Group A streptococcus) or Haemophilus influenzae from a normally sterile site. Case numbers were compared to Q4 in each of 2018-2021. Eighty-two children met the case definition in Q4 2022 vs 97 (Q4 2018-2021). In 2022, 42/82 (51%) were female, median age 3.75 years (1.5-8.25 years). Only 2 (2%) were immunosuppressed and 2 others (2%) had underlying neurodisability. Fifty (61%) were admitted on second or subsequent presentation to a healthcare setting. Fifty-six (68%) had an abscess in a sterile site. Bloodstream infection (positive blood culture or PCR: 24 (29%)) was the most common site of infection, followed by neck 22 (27%) and intracranial 12 (15%). Group A streptococcus (GAS) 27 (33%) was the most common organism isolated. Seven cases (9%) died in 2022 compared to 2 patients (2%) from 2018 to 2021 (p 1 in 2022 than 2018-2021 (p = 0.003). Conclusion: Invasive bacterial diseases increased in Q4 2022 with higher morbidity and mortality than in the preceding 4 years. Group A streptococcal infection was the most significant organism in 2022.  What is known: • Invasive bacterial disease is the leading cause of childhood mortality globally. • There was an increase in cases of invasive Group A streptococcus infections reported in many countries (including Ireland) during the winter of 2022/23.  What is new: • Head, neck and chest abscesses increased in Q4 of 2022 compared to the previous 4 years combined. • Invasive bacterial infections in Q4 of 2022 were associated with higher rates of mortality (9%), paediatric intensive care unit (PICU) admission (24%) and requirement for surgical drainage or intervention (67%) than in the preceding years.</p