Nanomedicine approach for sustained release delivery of Avastin : treatment for PXE and AMD [abstract]

Gold nanoparticles possess unique properties including preferential binding to leaky blood vessels, ability to bind to a variety of ligands, with no evidence of cellular toxicity, making them an excellent platform for targeted sustained release of drugs. Avastin (Bevacizumab) is a humanized monoclonal antibody specifically targeting vascular endothelial growth factor (VEGF) that has found widespread use in inhibiting intraocular neovascularization manifested in macular degeneration and proliferative diabetic retinopathy. The conjugation of gold nanoparticles (AuNP) with Avastin (Av) yields AvAuNP nanoconjugates. Avastin conjugated gold nanoparticles (AvAuNP) can be used as therapeutic agents in the treatment of ophthalmic neovascular disorders, such as macular degeneration, PXE and proliferative diabetic retinopathy. AvAuNP nanoconjugate is a potential clinical therapeutic agent and has demonstrated excellent ability to deliver Avastin for sustained release of therapeutic dose within the eye. The design and development of AvAuNP conjugate would help in the initiation and completion of preclinical evaluations aimed at determining the ability to achieve long-term suppression of intraocular neovascularization in large animals. INVENTOR(S): Ravi Shukla; Kavita K. Katti; Raghuraman Kannan; Dean Hainsworth and Kattesh V. Katti CONTACT INFO: Paul Hippenmeyer, Ph.D., M.B.A.; [email protected]; (573)-882-047

Stability of Hill Slopes and Foundation Condition at Radio Astronomy Centre Ootacamand

Stability aspects of hill slopes and foundation considerations of Radio Astronomy Centre at Ootacamand are described. The analysis of slopes indicated that if joints are not covered, the material in joints may lose strength and the slopes may enter a state of instability. Footings with inclined legs were found to resist the horizontal forces, pull and overturning movements. Lime piles adopted for strengthening soft material at one of the tower locations were found to be effective

Green nanotechnology from cumin phytochemicals : generation of biocompatible gold nanoparticles

Published in final edited form as: Int J Green Nanotechnol Biomed. 2009 January 1; 1(1): B39-B52. doi:10.1080/19430850902931599.The powerful antioxidant characteristics of various phytochernicals within cumin prompted us to test their efficacy in reducing sodium tetrachloroaurate to corresponding gold nanoparticles. We, herein, report an unprecedented synthetic route that involves the production of well-defined spherical gold nanoparticles by simple mixing of cumin to an aqueous solution of sodium tetrachloro aurate. Production of gold nanoparticles in this cumin-mediated Green Nanotechnological process is achieved under biologically benign conditions. The gold nanoparticles generated through cumin-mediated process did not aggregate suggesting that the cocktail of phytochemicals including proteins serve as excellent coatings on nanoparticles and thus, provide robust shielding from aggregations. In addition, the phytochemical coatings on nanoparticles have rendered nontoxic features to these 'Green Gold Nanoparticles' as demonstrated through detailed MTT assays performed on 'normal fibroblast cells. Results of our studies presenting a new 'Nano-Naturo' connection for the production and utility of gold nanoparticles for potential applications in nanomedicine and nanotechnology are discussed in this paper.This work has been supported by the generous support from the National Institutes of Health/National Cancer Institute under the Cancer Nanotechnology Platform program (grant number: 5R01CA119412-01), NIH - 1R21CA128460-01 and University of Missouri-Research Board - Program C8761 RB 06-030

Agarose-stabilized gold nanoparticles for surface-enhanced Raman spectroscopic detection of DNA nucleosides

doi:10.1063/1.2192573 http://scitation.aip.org/getpdf/servlet/GetPDFServlet?filetype=pdf&id=APPLAB000088000015153114000001&idtype=cvips&prog=normal&doi=10.1063/1.2192573We present surface-enhanced Raman scattering (SERS) studies of DNA nucleosides using biologically benign agarose-stabilized gold nanoparticles (AAuNP). We compare the SERS activity of nucleosides with AAuNP to that of commercially obtained citrate-stabilized gold nanoparticles and find the SERS activity to be an order of magnitude higher with AAuNP. The higher SERS activity is explained in terms of the agarose matrix, which provides pathways for the gold nanoparticles to have distinct arrangements that result in stronger internal plasmon resonances.This work was supported through the University of Missouri Research Board grants URB04-023 (S.G.) and URB03-080 (M.C. and K.V.K.), NSF under Grant No. DMR-0413601and the NCI under Grant No. IR0ICA119412-01. The gold nanoparticles were produced and supplied by the University of Missouri Nanoparticle Production Core Facility

Green nanotechnology of MGF‑AuNPs for immunomodulatory intervention in prostate cancer therapy

Abstract Men with castration-resistant prostate cancer (CRPC) face poor prognosis and increased risk of treatment-incurred adverse effects resulting in one of the highest mortalities among patient population globally. Immune cells act as double-edged sword depending on the tumor microenvironment, which leads to increased infiltration of pro-tumor (M2) macrophages. Development of new immunomodulatory therapeutic agents capable of targeting the tumor microenvironment, and hence orchestrating the transformation of pro-tumor M2 macrophages to anti-tumor M1, would substantially improve treatment outcomes of CRPC patients. We report, herein, Mangiferin functionalized gold nanoparticulate agent (MGF-AuNPs) and its immunomodulatory characteristics in treating prostate cancer. We provide evidence of immunomodulatory intervention of MGF-AuNPs in prostate cancers through observations of enhanced levels of anti-tumor cytokines (IL-12 and TNF-α) with concomitant reductions in the levels of pro-tumor cytokines (IL-10 and IL-6). In the MGF-AuNPs treated groups, IL-12 was elevated to ten-fold while TNF-α was elevated to about 50-fold, while IL-10 and IL-6 were reduced by two-fold. Ability of MGF-AuNPs to target splenic macrophages is invoked via targeting of NF-kB signaling pathway. Finally, therapeutic efficacy of MGF-AuNPs, in treating prostate cancer in vivo in tumor bearing mice, is described taking into consideration various immunomodulatory interventions triggered by this green nanotechnology-based nanomedicine agent

Formation of regulatory modules by local sequence duplication

Turnover of regulatory sequence and function is an important part of molecular evolution. But what are the modes of sequence evolution leading to rapid formation and loss of regulatory sites? Here, we show that a large fraction of neighboring transcription factor binding sites in the fly genome have formed from a common sequence origin by local duplications. This mode of evolution is found to produce regulatory information: duplications can seed new sites in the neighborhood of existing sites. Duplicate seeds evolve subsequently by point mutations, often towards binding a different factor than their ancestral neighbor sites. These results are based on a statistical analysis of 346 cis-regulatory modules in the Drosophila melanogaster genome, and a comparison set of intergenic regulatory sequence in Saccharomyces cerevisiae. In fly regulatory modules, pairs of binding sites show significantly enhanced sequence similarity up to distances of about 50 bp. We analyze these data in terms of an evolutionary model with two distinct modes of site formation: (i) evolution from independent sequence origin and (ii) divergent evolution following duplication of a common ancestor sequence. Our results suggest that pervasive formation of binding sites by local sequence duplications distinguishes the complex regulatory architecture of higher eukaryotes from the simpler architecture of unicellular organisms

Comparative oncology and clinical translation of glyco protein conjugated gold nano therapeutic agent (GA-198AuNP) [abstract]

Nanoscience Poster SessionAs part of our efforts toward clinical translation of GA-198AuNP, our studies are focused on therapeutic efficacy of nanoparticulate GA198AuNP agent in dogs with prostatic carcinoma. The overall goal is to gain clinical insights on therapeutic efficacy of GA198AuNP in a large animal model. We have performed a phase I clinical trial using GA-AuNP administered intravenously or intratumorally by injection or infusion. CT scans were performed prior to injection and 24 hours post injection in 3 of the 4 dogs. Following injections, dogs were allowed further treatment as recommended by the primary attending clinician. Four dogs have been treated to date. Complications related to GA-AuNP treatment were not observed, and all 4 dogs received adjunctive treatment with radiation therapy and/ or chemotherapy. These preliminary studies have clearly provided compelling evidence on the therapeutic potential of biocompatible GA-AuNP for their utility as novel therapeutic agents in treating various types of inoperable solid tumors. Intra-tumoral and intravenous administration of GA-AuNP is safe in dogs with spontaneously occurring tumors. As further therapeutic efficacy studies continue, the outcome of this clinical trial in a large animal model will generate therapeutic efficacy data which will be used for filing IND application for Phase I clinical trial studies. This clinical translation effort provides significant advances in terms of delivering optimum therapeutic payloads into prostate cancers with subsequent reduction in tumor volume, thus may effectively reduce/eliminate the need for surgical resection. This presentation will include details of clinical translation of GA198AuNP in prostate tumor bearing dogs

Water-Soluble Mo3S4 Clusters Bearing Hydroxypropyl Diphosphine Ligands: Synthesis, Crystal Structure, Aqueous Speciation, and Kinetics of Substitution Reactions

The [Mo3S4Cl3(dhprpe)3]+ (1+) cluster cation has been prepared by reaction between Mo3S4Cl4(PPh3)3 (solvent)2 and the watersoluble 1,2-bis(bis(hydroxypropyl)phosphino)ethane (dhprpe, L) ligand. The crystal structure of [1]2[Mo6Cl14] has been determined by X-ray diffraction methods and shows the typical incomplete cuboidal structure with a capping and three bridging sulfides. The octahedral coordination around each metal center is completed with a chlorine and two phosphorus atoms of the diphosphine ligand. Depending on the pH, the hydroxo group of the functionalized diphosphine can substitute the chloride ligands and coordinate to the cluster core to give new clusters with tridentate deprotonated dhprpe ligands of formula [Mo3S4(dhprpe-H)3]+ (2+). A detailed study based on stopped-flow, 31P{1H} NMR, and electrospray ionization mass spectrometry techniques has been carried out to understand the behavior of acid−base equilibria and the kinetics of interconversion between the 1+ and the 2+ forms. Both conversion of 1+ to 2+ and its reverse process occur in a single kinetic step, so that reactions proceed at the three metal centers with statistically controlled kinetics. The values of the rate constants under different conditions are used to discuss on the mechanisms of opening and closing of the chelate rings with coordination or dissociation of chloride

Simple sequence repeats in Neurospora crassa: distribution, polymorphism and evolutionary inference

<p>Abstract</p> <p>Background</p> <p>Simple sequence repeats (SSRs) have been successfully used for various genetic and evolutionary studies in eukaryotic systems. The eukaryotic model organism <it>Neurospora crassa </it>is an excellent system to study evolution and biological function of SSRs.</p> <p>Results</p> <p>We identified and characterized 2749 SSRs of 963 SSR types in the genome of <it>N. crassa</it>. The distribution of tri-nucleotide (nt) SSRs, the most common SSRs in <it>N. crassa</it>, was significantly biased in exons. We further characterized the distribution of 19 abundant SSR types (AST), which account for 71% of total SSRs in the <it>N. crassa </it>genome, using a Poisson log-linear model. We also characterized the size variation of SSRs among natural accessions using Polymorphic Index Content (PIC) and ANOVA analyses and found that there are genome-wide, chromosome-dependent and local-specific variations. Using polymorphic SSRs, we have built linkage maps from three line-cross populations.</p> <p>Conclusion</p> <p>Taking our computational, statistical and experimental data together, we conclude that 1) the distributions of the SSRs in the sequenced N. crassa genome differ systematically between chromosomes as well as between SSR types, 2) the size variation of tri-nt SSRs in exons might be an important mechanism in generating functional variation of proteins in <it>N. crassa</it>, 3) there are different levels of evolutionary forces in variation of amino acid repeats, and 4) SSRs are stable molecular markers for genetic studies in <it>N. crassa</it>.</p