Showing papers by "Caitriona M. O'Driscoll published in 2012"
TL;DR: In vivo, utilising a mouse model grafted with prostate carcinoma, significant tumour suppression was achieved using PEGylated complexes without marked toxicity or undesirable immunological response, this was accompanied by a simultaneous reduction in target mRNA levels.
76 citations
TL;DR: The transfection efficiency of the cationic vector was lowered by co-formulation with the PEGylated cyclodextrin, requiring future surface modification of particles with targeting ligands for effective siRNA delivery.
Abstract: A new approach to the synthesis of amphiphilic β-cyclodextrins has used ‘click’ chemistry to selectively modify the secondary 2-hydroxyl group. The resulting extended polar groups can be either polycationic or neutral PEGylated groups and these two amphiphile classes are compatible in dual cyclodextrin formulations for delivery of siRNA. When used alone with an siRNA, a cationic cyclodextrin was shown to have good transfection properties in cell culture. Co-formulation with a PEGylated cyclodextrin altered the physicochemical properties of nanoparticles formed with siRNA. Improved particle properties included lower surface charges and reduced tendency to aggregate. However, as expected, the transfection efficiency of the cationic vector was lowered by co-formulation with the PEGylated cyclodextrin, requiring future surface modification of particles with targeting ligands for effective siRNA delivery.
66 citations
TL;DR: This is the first time that a modified β-cyclodextrin vector has been used as a safe and efficacious vector for siRNA delivery into neuronal cells.
Abstract: RNA interference (RNAi) holds great promise as a strategy to further our understanding of gene function in the central nervous system (CNS) and as a therapeutic approach for neurological and neurodegenerative diseases. However, the potential for its use is hampered by the lack of siRNA delivery vectors which are both safe and highly efficient. Cyclodextrins have been shown to be efficient and low toxicity gene delivery vectors in various cell types in vitro. However, to date, they have not been exploited for delivery of oligonucleotides to neurons. To this end, a modified β-cyclodextrin (CD) vector was synthesized, which complexed siRNA to form cationic nanoparticles of less than 200 nm in size. Furthermore, it conferred stability in serum to the siRNA cargo. The in vitro performance of the CD in both immortalized hypothalamic neurons and primary hippocampal neurons was evaluated. The CD facilitated high levels of intracellular delivery of labeled siRNA, while maintaining at least 80% cell viability. Significant gene knockdown was achieved, with a reduction in luciferase expression of up to 68% and a reduction in endogenous glyceraldehyde phosphate dehydrogenase (GAPDH) expression of up to 40%. To our knowledge, this is the first time that a modified CD has been used as a safe and efficacious vector for siRNA delivery into neuronal cells.
65 citations
TL;DR: Galactosylated amphiphilic cyclodextrins (CDs) were examined in terms of their ability to transfect asialoglycoprotein receptor-bearing HepG2 cells as discussed by the authors.
Abstract: Objectives Achieving targeted delivery of gene medicines is desirable to maximise activity. Here, galactosylated amphiphilic cyclodextrins (CDs) are examined in terms of their ability to transfect asialoglycoprotein receptor-bearing HepG2 cells.
Methods Cationic amphiphilic CDs were synthesised as well as amphiphilic CDs bearing galactose-targeting ligands with different linker lengths. Binding of galactosylated CDs to a galactose-specific lectin was examined by surface plasmon resonance. CDs were formulated with and without the helper lipid DOPE and complexed with plasmid DNA. Transfection was evaluated by luciferase assay. Intracellular trafficking was assessed by confocal microscopy.
Key findings Binding of targeted CDs to a galactose-specific lectin was achieved. Binding decreased with linker length between the galactosyl group and the CD core. Contrary to the lectin binding results, transfection levels increased with an increase in linker length from 7 atoms to 15. Compared to non-targeted formulations, a significant increase in transfection was observed only in the presence of the helper lipid DOPE. Confocal microscopy revealed that DOPE caused a pronounced effect on cellular distribution.
Conclusions The galactose-targeting ligand induced substantial increases in transfection over non-targeted formulations when DOPE was included, indicating the potential for targeted gene delivery using CD-based delivery systems.
44 citations
TL;DR: Despite the suitability of both CDs as siRNA delivery vectors in terms of their ability to complex siRNA and the properties of the complexes yielded, only one CD achieved good transfection efficiency, likely due to the differences in their chemical structures.
26 citations
31 Dec 2012
TL;DR: This paper aims to demonstrate the efforts towards in-situ applicability of EMMARM, as to provide real-time information about concrete mechanical properties such as E-modulus and compressive strength.
Abstract: Science Foundation Ireland (grant no. 07/SRC/B1154); Irish Research Council for Science Engineering and Technology (Embark initiative)
19 citations
30 Jun 2012
TL;DR: The oral route is the preferred route for drug administration especially in the case of chronic therapies because of its convenience and wide patient acceptance and there are many challenges associated with orally delivering drugs that have sub-optimal biophysicochemical properties.
Abstract: The oral route is the preferred route for drug administration especially in the case of chronic therapies because of its convenience and wide patient acceptance. There are many challenges associated with orally delivering drugs that have sub-optimal biophysicochemical properties. Two major physiolog...
6 citations
30 Jun 2012
TL;DR: The synthetic V2 receptor agonist, desmopressin, is exceptionally potent, stable and relatively cheap to synthesize, and thus its oral bioavailability of 0.16% is still commercially acceptable.
Abstract: Only two peptides have been licensed to date for oral delivery, desmopressin and cyclosporine (CsA). The synthetic V2 receptor agonist, desmopressin, is exceptionally potent, stable and relatively cheap to synthesize, and thus its oral bioavailability (F) of 0.16% is still commercially acceptable.1 ...
5 citations
18 Jun 2012
1 citations