Browsing by Subject "Phospholipids"
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Item Development of an inhalational formulation of Coenzyme Q₁₀ to treat lung malignancies(2011-12) Carvalho, Thiago Cardoso; McConville, Jason ThomasCancer is the second leading cause of death in the United States and its onset is highly incident in the lungs, with very low long-term survival rates. Chemotherapy plays a significant role for lung cancer treatment, and pulmonary delivery may be a potential route for anticancer drug delivery to treat lung tumors. Coenzyme Q₁₀ (CoQ₁₀) is a poorly-water soluble compound that is being investigated for the treatment of carcinomas. In this work, we hypothesize that formulations of CoQ10 may be developed for pulmonary delivery with a satisfactory pharmacokinetic profile that will have the potential to improve a pharmacodynamic response when treating lung malignancies. The formulation design was to use a vibrating-mesh nebulizer to aerosolize aqueous dispersions of CoQ₁₀ stabilized by phospholipids physiologically found in the lungs. In the first study, a method was developed to measure the surface tension of liquids, a physicochemical property that has been shown to influence the aerosol output characteristics from vibrating-mesh nebulizers. Subsequently, this method was used, together with analysis of particle size distribution, zeta potential, and rheology, to further evaluate the factors influencing the capability of this nebulizer system to continuously and steadily aerosolize formulations of CoQ₁₀ prepared with high pressure homogenization. The aerosolization profile (nebulization performance and in vitro drug deposition of nebulized droplets) of formulations prepared with soybean lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC) were evaluated. The rheological behavior of these dispersions was found to be the factor that may be indicative of the aerosolization output profile. Finally, the pulmonary deposition and systemic distribution of CoQ₁₀ prepared as DMPC, DPPC, and DSPC dispersions were investigated in vivo in mice. It was found that high drug amounts were deposited and retained in the mouse lungs for at least 48 hours post nebulization. Systemic distribution was not observed and deposition in the nasal cavity occurred at a lower scale than in the lungs. This body of work provides evidence that CoQ₁₀ may be successfully formulated as dispersions to be aerosolized using vibrating-mesh nebulizers and achieve high drug deposition in the lungs during inhalation.Item Rapid remodeling of lipids and transcriptome in the diatom Phaeodactylum tricornutum in response to defense related decadienal(2016-06-15) Sabharwal, Tanya; Mehdy, Mona Cynthia, 1955-; Sathasivan, K. (Kanagasabapathi), 1957-; Roux, Stanley; Theriot, Edward; Huq, EnamulDiatoms rapidly release extracellular oxylipins (oxygenated lipids) including polyunsaturated aldehydes (PUAs) upon cell damage, as a defense response to inhibit reproduction in many herbivores. PUAs are synthesized from membrane phospholipids. In diatoms, PUAs rapidly increase intracellular Ca²⁺ and nitric oxide (NO) levels and affect gene expression and physiology. Treatment of the marine diatom Phaeodacylum tricornutum, with the PUA, decadienal (DD, 10 μM) altered lipid compositions. In cells treated for 3 hr, nine out of ten measured saturated and unsaturated fatty acids declined (range of 0.5-0.7 fold of solvent control levels). At 6 hr, most fatty acid species 14:0, 18:0, 20:5 remained at lower levels while 18:1 and 18:2 increased (1.12 fold and 1.46 fold respectively). Phospholipids in DD treated cells at 3 hr showed decline in PG¹ (0.69 fold) and PS¹ (0.36 fold) whereas PE¹ increased (1.79 fold). At 6 hr, PI¹ (0.79 fold), PS¹ (0.28 fold) and LPG¹ (0.56 fold) declined whereas PC¹ (1.21 fold) and PE¹ (2.7 fold) increased. There were no effects on abundant chloroplast glycolipids (DGDG/MGDG)¹. Molecular species composition of phospholipids showed a greater decline in polyunsaturated fatty acids than monounsaturated fatty acids and saturated fatty acids, which indicates a shift towards saturated fatty acids that may protect membranes from oxidative stress. C-28 brassicasterol declined 0.86 fold at 3hr whereas there was no change at 6hr. Non-polar lipids increased by 1.16 fold and 1.38 fold at 3hr and 6hr. Decreased membrane permeability in DD treated cells was suggested by reduced uptake of cytological dyes. To our knowledge, this is the first report documenting novel rapid (within 6 hr) phospholipid changes in response to PUA suggesting early membrane lipid remodeling to aid in adaptation to PUA stress in algae. Transcriptome analysis at 3hr and 6hr of DD treatment indicated differential regulation of a subset of genes in fatty acid metabolism pathway in co-ordination with genes in multiple metabolic pathways. This suggests that rapid lipid remodeling may be regulated at transcriptome levels to help adapt to decadienal stress.