Novel cationic liposome formulation for the delivery of an oligonucleotide decoy to NF-kappaB into activated macrophages.
ABSTRACT Nuclear factor-kappaB (NF-kappaB) is involved in several pathological processes, such as inflammation. Pro-inflammatory genes expression can be down-regulated by using an oligonucleotide (ODN) decoy to NF-kappaB. Cationic liposomes are largely used to improve ODN uptake into cells, although a higher transfection efficiency and a lower toxicity are required to use them in therapy. In this work, we investigated the potential of a novel liposome formulation, based on the recently synthesised cationic lipid (2,3-didodecyloxypropyl) (2-hydroxyethyl) dimethylammonium bromide (DE), as the delivery system for a double stranded ODN decoy to NF-kappaB. Liposomes composed of DE or DE mixed with 1,2-dioleyl-sn-glycero-3-phosphoethanolamine or cholesterol as helper lipids were complexed with ODN at different +/- charge ratios. In vitro uptake and the effect of ODN, naked or complexed with DE-containing liposomes, were evaluated in lipopolysaccharide-stimulated RAW 264.7 macrophages. The use of helper lipids increased liposome physical stability up to 1 year at 4 degrees C. ODN complexed with DE/cholesterol liposomes, at the +/- charge ratio of 8, showed a limited cytotoxicity and the highest inhibition of nitrite production, inducible nitric oxide synthase protein expression and NF-kappaB/DNA binding activity. Confocal microscopy confirmed a high ODN cell uptake obtained with DE/cholesterol liposomes at the highest +/- charge ratio.
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ABSTRACT: The current methods for treatment of cancers are inadequate and more specific methods such as gene therapy are in progress. Among different vehicles, cationic liposomes are frequently used for delivery of genetic material. This investigation aims to prepare and optimize DOTAP cationic liposomes containing an antisense oligonuclotide (AsODN) against protein kinase C alpha in non-small cells lung cancer (NSCLC). To perform this investigation, two different methods of ethanol injection and thin film hydration were used to prepare AsODN-loaded DOTAP liposomes. The formulated liposomes were then evaluated for their morphology, particle size, zeta potential and encapsulation efficiency, and the best formulation was chosen. In-vitro growth inhibitory effect of encapsulated ODN on A549 cells were evaluated by MTT and colonogenic assay. The physical and serum stability of liposomal ODN were also evaluated. Thin film hydration method resulted in large liposomes that required downsizing by extrusion with an encapsulation efficiency of 13%. Ethanol injection, in a single step gave liposomes with a small size of 115 nm and an encapsulation efficiency of around 90% which were physically stable for 6 months. The optimized liposome could protect oligonucleotides from degradation by nuclease. Cell studies showed a 20% sequence-specific inhibition of cell growth in MTT assay and revealed an LC50 of 103 nM in colonogenic studies. In conclusion, ethanol injection was able to provide suitable liposomes from the permanently charged DOTAP. Also the resulted liposomes were able to inhibit the growth of lung cancer cells.Iranian journal of pharmaceutical research (IJPR) 01/2013; 12(Suppl):3-10. · 0.54 Impact Factor
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ABSTRACT: Since the pioneering work dealing with the synthesis and physicochemical aspects of dendrimers, a predictable and tunable set of compositions for therapeutic, scaffolding and imaging systems has been reported. These are well documented, but many hot issues should be examined and reviewed. Herein, a review is given on dendritic nanopolymers and their applications that show promise in the field of regenerative medicine. This review begins with a brief overview on research merging nanotechnology and regenerative medicine. Fundamentals of the synthesis and macromolecular structure of dendritic polymers are provided. Dendrimers fulfill the requirements as carriers for gene, nucleic acids, bioactive molecules and peptide/protein delivery aimed at modulate the cells functions, in vitro and in vivo. However, to make use of this potential, toxicological, drug-loading capacity, surface engineering and host–guest chemistries in dendrimers must be addressed and thus are also discussed. We focus on recent work involving dendrimers with applications in tissue engineering and the central nervous system. Due to their innovative character, applications beyond drug delivery systems became possible, namely as scaffolding and chemoattractants for tissue regeneration, and implantable biodegradable nanomaterial-based medical devices integrated with drug delivery functions (theranostics). Finally, we highlight promising areas for further research and comment on how and why dendrimer and dendron technology should be viewed as the next generation of biomaterials for the 21st century.Progress in Polymer Science 09/2010; 35(9):1163-1194. · 26.38 Impact Factor
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ABSTRACT: The development of carbon nanotubes (CNTs) for biomedical and biotechnological applications has gained great promise recently, especially for their interesting use in the delivery of therapeutically active molecules to targeted cells. The interaction between cells and this nanomaterial is a critical feature that is responsible for the pharmacological effect as well as for any eventual toxicity. With respect to the latter aspect, in this manuscript we have evaluated a few parameters that seem to be involved in the cytotoxic profile of CNTs (both Single-walled (SWCNTs) and Multi-walled (MWCNTs) nanotubes), such as their sidewall functionalization, tubes' length, solubility, concentration and purity. Among them, we identified the last as the most crucial factor: we have shown that our ultrapure, totally dispersible, carbon nanotubes not only display lack of toxicity in the range of concentrations normally used (10-150 μg/ml), but they also pave the way for an extensive use of this material for several biomedical purposes.Current Nanoscience 03/2010; 6(2):141-154. · 1.36 Impact Factor