Biodistribution and pharmacokinetics of a telodendrimer micellar paclitaxel nanoformulation in a mouse xenograft model of ovarian cancer

Wenwu Xiao1, Juntao Luo2, Teesta Jain3, John Riggs3, Harry P Tseng1, Paul T Henderson3, Simon R Cherry4, Douglas Rowland4, Kit S Lam1,31Department of Biochemistry and Molecular Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, CA; 2Department of Pharmacology, SUNY Upstate Cancer Research Institute, SUNY Upstate Medical University, Syracuse, NY; 3Department of Internal Medicine, Division of Hematology and Oncology, 4Department of Biomedical Engineering, UC Davis Cancer Center, University of California Davis, Davis, CABackground: A multifunctional telodendrimer-based micelle system was characterized for delivery of imaging and chemotherapy agents to mouse tumor xenografts. Previous optical imaging studies demonstrated qualitatively that these classes of nanoparticles, called nanomicelles, preferentially accumulate at tumor sites in mice. The research reported herein describes the detailed quantitative imaging and biodistribution profiling of nanomicelles loaded with a cargo of paclitaxel.Methods: The telodendrimer was covalently labeled with 125I and the nanomicelles were loaded with 14C-paclitaxel, which allowed measurement of pharmacokinetics and biodistribution in the mice using microSPECT/CT imaging and liquid scintillation counting, respectively.Results: The radio imaging data showed preferential accumulation of nanomicelles at the tumor site along with a slower clearance rate than paclitaxel formulated in Cremophor EL (Taxol®). Liquid scintillation counting confirmed that 14C-labeled paclitaxel sequestered in nanomicelles had increased uptake by tumor tissue and slower pharmacokinetics than Taxol.Conclusion: Overall, the results indicate that nanomicelle-formulated paclitaxel is a potentially superior formulation compared with Taxol in terms of water solubility, pharmacokinetics, and tumor accumulation, and may be clinically useful for both tumor imaging and improved chemotherapy applications.Keywords: telodendrimer, nanomicelle, paclitaxel, microSPECT/CT, imaging guided drug deliver

Plasma triglyceride concentrations are rapidly reduced following individual bouts of endurance exercise in women

It is known that chronic endurance training leads to improvements in the lipoprotein profile, but less is known about changes that occur during postexercise recovery acutely. We analyzed triglyceride (TG), cholesterol classes and apolipoproteins in samples collected before, during and after individual moderate- and hard-intensity exercise sessions in men and women that were isoenergetic between intensities. Young healthy men (n = 9) and young healthy women (n = 9) were studied under three different conditions with diet unchanged between trials: (1) before, during and 3 h after 90 min of exercise at 45% VO2peak (E45); (2) before, during and 3 h after 60 min of exercise at 65% VO2peak (E65), and (3) in a time-matched sedentary control trial (C). At baseline, high-density lipoprotein cholesterol (HDL-C) was higher in women than men (P < 0.05). In men and in women, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C, apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), and LDL peak particle size were unaltered by exercise either during exertion or after 3 h of recovery. In women, but not in men, average plasma TG was significantly reduced below C at 3 h postexercise by approximately 15% in E45 and 25% in E65 (P < 0.05) with no significant difference between exercise intensities. In summary, plasma TG concentration rapidly declines following exercise in women, but not in men. These results demonstrate an important mechanism by which each individual exercise session may incrementally reduce the risk for cardiovascular disease (CVD) in women

Molecular and functional characterization of polymorphisms in the secreted phospholipase A2 group X gene: relevance to coronary artery disease

Among secreted phospholipases A2 (sPLA2s), human group X sPLA2 (hGX sPLA2) is emerging as a novel attractive therapeutic target due to its implication in inflammatory diseases. To elucidate whether hGX sPLA2 plays a causative role in coronary artery disease (CAD), we screened the human PLA2G10 gene to identify polymorphisms and possible associations with CAD end-points in a prospective study, AtheroGene. We identified eight polymorphisms, among which, one non-synonymous polymorphism R38C in the propeptide region of the sPLA2. The T-512C polymorphism located in the 5′ untranslated region was associated with a decreased risk of recurrent cardiovascular events during follow-up. The functional analysis of the R38C polymorphism showed that it leads to a profound change in expression and activity of hGX sPLA2, although there was no detectable impact on CAD risk. Due to the potential role of hGX sPLA2 in inflammatory processes, these polymorphisms should be investigated in other inflammatory diseases

Increasing Compliance with Mass Drug Administration Programs for Lymphatic Filariasis in India through Education and Lymphedema Management Programs

Global elimination of lymphatic filariasis requires giving drugs at least annually to populations who live at risk of becoming infected with the parasite. At least 80% of people at risk need to take the drugs annually for 5 or more years to stop transmission of the infection. People suffering from the long-term effects of infection, such as swollen legs, benefit from programs that teach self-care of their affected limbs. In this study, we assessed the impact of an educational campaign that, after addressing previously identified predictors of compliance, significantly improved drug compliance. The specific factors improving compliance included knowing about the drug distribution in advance, knowing that everyone is at risk for acquiring the infection, knowing that the drug distribution was for lymphatic filariasis prevention, and knowing at least one component of leg care. We also found that areas with programs to assist people with swollen legs had greater increases in compliance. This research provides evidence that program evaluation can be used to improve drug compliance. In addition, our work shows for the first time that programs to benefit people with swollen legs caused by lymphatic filariasis also increase the participation of people without disease in drug treatment programs

Quantitative imaging of concentrated suspensions under flow

We review recent advances in imaging the flow of concentrated suspensions, focussing on the use of confocal microscopy to obtain time-resolved information on the single-particle level in these systems. After motivating the need for quantitative (confocal) imaging in suspension rheology, we briefly describe the particles, sample environments, microscopy tools and analysis algorithms needed to perform this kind of experiments. The second part of the review focusses on microscopic aspects of the flow of concentrated model hard-sphere-like suspensions, and the relation to non-linear rheological phenomena such as yielding, shear localization, wall slip and shear-induced ordering. Both Brownian and non-Brownian systems will be described. We show how quantitative imaging can improve our understanding of the connection between microscopic dynamics and bulk flow.Comment: Review on imaging hard-sphere suspensions, incl summary of methodology. Submitted for special volume 'High Solid Dispersions' ed. M. Cloitre, Vol. xx of 'Advances and Polymer Science' (Springer, Berlin, 2009); 22 pages, 16 fig

Local coexpression domains in the genome of rice show no microsynteny with Arabidopsis domains

Chromosomal coexpression domains are found in a number of different genomes under various developmental conditions. The size of these domains and the number of genes they contain vary. Here, we define local coexpression domains as adjacent genes where all possible pair-wise correlations of expression data are higher than 0.7. In rice, such local coexpression domains range from predominantly two genes, up to 4, and make up ∼5% of the genomic neighboring genes, when examining different expression platforms from the public domain. The genes in local coexpression domains do not fall in the same ontology category significantly more than neighboring genes that are not coexpressed. Duplication, orientation or the distance between the genes does not solely explain coexpression. The regulation of coexpression is therefore thought to be regulated at the level of chromatin structure. The characteristics of the local coexpression domains in rice are strikingly similar to such domains in the Arabidopsis genome. Yet, no microsynteny between local coexpression domains in Arabidopsis and rice could be identified. Although the rice genome is not yet as extensively annotated as the Arabidopsis genome, the lack of conservation of local coexpression domains may indicate that such domains have not played a major role in the evolution of genome structure or in genome conservation

Evidence of phonon-assisted tunnelling in electrical conduction through DNA molecules

We propose a phonon-assisted tunnelling model for explanation of conductivity dependence on temperature and temperature-dependent I-V characteristics in deoxyribonucleic acid (DNA) molecules. The capability of this model for explanation of conductivity peculiarities in DNA is illustrated by comparison of the temperature dependent I-V data extracted from some articles with tunnelling rate dependences on temperature and field strength computed according to the phonon-assisted tunnelling theory. PACS Codes: 87.15.-v, 71.38.-k, 73.40.GkComment: 6 pages, 3 figure