ItemNebulised delivery of RNA formulations to the lungs: From aerosol to cytosol(Elsevier, 2024-11-25) Neary, Michael T.; Mulder, Lianne M.; Kowalski, Piotr S.; MacLoughlin, Ronan; Crean, Abina M.; Ryan, Katie B.; Science Foundation Ireland; Health Research Board; European Research Council; Irish Research CouncilIn the past decade RNA-based therapies such as small interfering RNA (siRNA) and messenger RNA (mRNA) have emerged as new and ground-breaking therapeutic agents for the treatment and prevention of many conditions from viral infection to cancer. Most clinically approved RNA therapies are parenterally administered which impacts patient compliance and adds to healthcare costs. Pulmonary administration via inhalation is a non-invasive means to deliver RNA and offers an attractive alternative to injection. Nebulisation is a particularly appealing method due to the capacity to deliver large RNA doses during tidal breathing. In this review, we discuss the unique physiological barriers presented by the lung to efficient nebulised RNA delivery and approaches adopted to circumvent this problem. Additionally, the different types of nebulisers are evaluated from the perspective of their suitability for RNA delivery. Furthermore, we discuss recent preclinical studies involving nebulisation of RNA and analysis in in vitro and in vivo settings. Several studies have also demonstrated the importance of an effective delivery vector in RNA nebulisation therefore we assess the variety of lipid, polymeric and hybrid-based delivery systems utilised to date. We also consider the outlook for nebulised RNA medicinal products and the hurdles which must be overcome for successful clinical translation. In summary, nebulised RNA delivery has demonstrated promising potential for the treatment of several lung-related conditions such as asthma, COPD and cystic fibrosis, to which the mode of delivery is of crucial importance for clinical success. ItemComparison of fenofibrate-mesoporous silica drug-loading processes for enhanced drug delivery(Elsevier, 2013-08-24) Ahern, Robert J.; Hanrahan, John P.; Tobin, Joseph M.; Ryan, Katie B.; Crean, Abina M.; Science Foundation IrelandLoading a poorly water-soluble drug onto a high surface area carrier such as mesoporous silica (SBA-15) can increase the drug's dissolution rate and oral bioavailability. The loading method can influence subsequent drug properties including solid state structure and release rate. The objective of this research was to compare several loading processes in terms of drug distribution throughout the mesoporous silica matrix, drug solid state form and drug release properties. A model poorly water-soluble drug fenabrate was loaded onto SBA-15 using; (i) physical mixing, (ii) melt, (iii) solvent impregnation, (iv) liquid CO2 and (v) supercritical CO2 methods. Physical mixing resulted in heterogeneous drug-loading, with no evidence of drug in the mesopores and the retention of the drug in its crystalline state. The other loading processes yielded more homogeneous drug-loading; the drug was deposited into the mesopores of the SBA-15 and was non-crystalline. All the processing methods resulted in enhanced drug release compared to the unprocessed drug with the impregnation, liquid and SC-CO2 producing the greatest increase at t=30 min. (C) 2013 Elsevier B.V. All rights reserved. ItemSynthesis and evaluation of aromatic BDSF bioisosteres on biofilm formation and colistin sensitivity in pathogenic bacteria(Elsevier, 2023-09-23) Gómez, Andromeda-Celeste; Horgan, Conor; Yero, Daniel; Bravo, Marc; Daura, Xavier; O'Driscoll, Michelle; Gibert, Isidre; O'Sullivan, Timothy P.; Irish Research Council; Ministerio de Ciencia e Innovación; Agència de Gestió d'Ajuts Universitaris i de RecercaThe diffusible signal factor family (DSF) of molecules play an important role in regulating intercellular communication, or quorum sensing, in several disease-causing bacteria. These messenger molecules, which are comprised of cis-unsaturated fatty acids, are involved in the regulation of biofilm formation, antibiotic tolerance, virulence and the control of bacterial resistance. We have previously demonstrated how olefinic N-acyl sulfonamide bioisosteric analogues of diffusible signal factor can reduce biofilm formation or enhance antibiotic sensitivity in a number of bacterial strains. This work describes the design and synthesis of a second generation of aromatic N-acyl sulfonamide bioisosteres. The impact of these compounds on biofilm production in Acinetobacter baumannii, Escherichia coli, Burkholderia multivorans, Burkholderia cepacia, Burkholderia cenocepacia, Pseudomonas aeruginosa and Stenotrophomonas maltophilia is evaluated, in addition to their effects on antibiotic tolerance. The ability of these molecules to increase survival rates on co-administration with colistin is also investigated using the Galleria infection model. ItemOrganocatalytic asymmetric peroxidation of g,d-unsaturated ß-keto esters - A novel route to chiral cycloperoxides(2023-05-24) Hennessy, Mary C.; Hirenkumar, Gandhi; O'Sullivan, Timothy P.; Irish Research Council; Science Foundation IrelandA methodology for the asymmetric peroxidation of g,d-unsaturated ß-keto esters is presented. Using a cinchona-derived organocatalyst, the target d-peroxy-ß-keto esters were obtained in high enantiomeric ratios of up to 95:5. Additionally, these d-peroxy esters can be readily reduced to chiral d-hydroxy-ß-keto esters without impacting the ß-keto ester functionality. Importantly, this chemistry opens up a concise route to chiral 1,2-dioxolanes, a common motif in many bioactive natural products, via a novel P2O5-mediated cyclisation of the corresponding d-peroxy-ß-hydroxy esters. ItemLeveraging the use of in vitro and computational methods to support the development of enabling oral drug products: An InPharma commentary(Elsevier B.V., 2023-07-13) Reppas, Christos; Kuentz, Martin; Bauer-Brandl, Annette; Carlert, Sara; Dallmann, André; Dietrich, Shirin; Dressman, Jennifer; Ejskjaer, Lotte; Frechen, Sebastian; Guidetti, Matteo; Holm, René; Holzem, Florentin Lukas; Karlsson, Εva; Kostewicz, Edmund; Panbachi, Shaida; Paulus, Felix; Senniksen, Malte Bøgh; Stillhart, Cordula; Turner, David B.; Vertzoni, Maria; Vrenken, Paul; Zöller, Laurin; Griffin, Brendan T.; O'Dwyer, Patrick J.; Horizon 2020Due to the strong tendency towards poorly soluble drugs in modern development pipelines, enabling drug formulations such as amorphous solid dispersions, cyclodextrins, co-crystals and lipid-based formulations are frequently applied to solubilize or generate supersaturation in gastrointestinal fluids, thus enhancing oral drug absorption. Although many innovative in vitro and in silico tools have been introduced in recent years to aid development of enabling formulations, significant knowledge gaps still exist with respect to how best to implement them. As a result, the development strategy for enabling formulations varies considerably within the industry and many elements of empiricism remain. The InPharma network aims to advance a mechanistic, animal-free approach to the assessment of drug developability. This commentary focuses current status and next steps that will be taken in InPharma to identify and fully utilize 'best practice' in vitro and in silico tools for use in physiologically based biopharmaceutic models.