Fancy Thomas

Publications (6)21.38 Total impact

• Article: N-Aryl-substituted 3-(β-D-glucopyranosyloxy)-2-methyl-4(1H)-pyridinones as agents for Alzheimer's therapy

  Lauren E. Scott, Maria Telpoukhovskaia, Cristina Rodríguez-Rodríguez, Michael Merkel, Meryn L. Bowen, Brent D. G. Page, David E. Green, Tim Storr, Fancy Thomas, David D. Allen, Paul R. Lockman, Brian O. Patrick, Michael J. Adam, Chris Orvig
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  ABSTRACT: Molecules designed to sequester, redistribute and/or remove metal ions are attractive therapeutic agents in neurodegenerative diseases such as Alzheimer's disease. The multifactorial nature of the condition and the generally poor target specificity associated with metal ion-binding therapy has led to the development of multifunctional 3-hydroxy-4-(1H)-pyridinone pro-ligands. The excellent qualities of the basic 3-hydroxy-4-pyridinone framework as a low toxicity metal chelator and an antioxidant, as well as its antibacterial and analgesic properties among other functions, inspired us to functionalize it with a framework derived from thioflavin-T, the well-known traditional dye used as a marker to detect amyloid deposits in tissue sections. Thus 2-methyl-3-hydroxy-1-(4-dimethylaminophenyl)-4(1H)-pyridinone (HL1), 2-methyl-3-hydroxy-1-(4-methylaminophenyl)-4(1H)-pyridinone (HL2), 1-(4-aminophenyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL3), 1-(6-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL4), 1-(2-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL5) and 2-methyl-3-hydroxy-1-[4-(4-bromophenyl)-2-thiazolyl]-4(1H)-pyridinone (HL6) were obtained. Glycosylation, as well as incorporation of structures mimicking those of known amyloid imaging agents, may target drug action to the site of interest, the metal-overloaded amyloid plaques in the Alzheimer's brain. The pro-ligands were assessed for their antioxidant activity, cytotoxicity and ability to interfere with metal ion-induced amyloid peptide aggregation to screen promising lead compounds. Finally, in a brain uptake study with a radiolabeled glucoconjugate pyridinone, 3-(β-D-glucopyranosyloxy)-1-[4-(4-[125I]iodophenyl)-2-thiazolyl]-2-methyl-4(1H)-pyridinone ([125I]-GL7) was shown to cross the blood–brain barrier using an in situ rat brain perfusion technique.
  Chemical science. 12/2010; 2:642-648.
• Article: Uptake of ANG1005, a novel paclitaxel derivative, through the blood-brain barrier into brain and experimental brain metastases of breast cancer.

  Fancy C Thomas, Kunal Taskar, Vinay Rudraraju, Satyanarayana Goda, Helen R Thorsheim, Julie A Gaasch, Rajendar K Mittapalli, Diane Palmieri, Patricia S Steeg, Paul R Lockman, Quentin R Smith
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  ABSTRACT: We evaluated the uptake of angiopep-2 paclitaxel conjugate, ANG1005, into brain and brain metastases of breast cancer in rodents. Most anticancer drugs show poor delivery to brain tumors due to limited transport across the blood-brain barrier (BBB). To overcome this, a 19-amino acid peptide (angiopep-2) was developed that binds to low density lipoprotein receptor-related protein (LRP) receptors at the BBB and has the potential to deliver drugs to brain by receptor-mediated transport. The transfer coefficient (K(in)) for brain influx was measured by in situ rat brain perfusion. Drug distribution was determined at 30 min after i.v. injection in mice bearing intracerebral MDA-MB-231BR metastases of breast cancer. The BBB K(in) for (125)I-ANG1005 uptake (7.3 +/- 0.2 x 10(-3) mL/s/g) exceeded that for (3)H-paclitaxel (8.5 +/- 0.5 x 10(-5)) by 86-fold. Over 70% of (125)I-ANG1005 tracer stayed in brain after capillary depletion or vascular washout. Brain (125)I-ANG1005 uptake was reduced by unlabeled angiopep-2 vector and by LRP ligands, consistent with receptor transport. In vivo uptake of (125)I-ANG1005 into vascularly corrected brain and brain metastases exceeded that of (14)C-paclitaxel by 4-54-fold. The results demonstrate that ANG1005 shows significantly improved delivery to brain and brain metastases of breast cancer compared to free paclitaxel.
  Pharmaceutical Research 09/2009; 26(11):2486-94. · 4.09 Impact Factor
• Article: Carrier-mediated transport of the quaternary ammonium neuronal nicotinic receptor antagonist n,n'-dodecylbispicolinium dibromide at the blood-brain barrier.

  Paul R Lockman, Vamshi K Manda, Werner J Geldenhuys, Rajendar K Mittapalli, Fancy Thomas, Zaineb Fadhel Albayati, Peter A Crooks, Linda P Dwoskin, David D Allen
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  ABSTRACT: The quaternary ammonium compound N,N'-dodecyl-bispicolinium dibromide (bPiDDB) potently and selectively inhibits nicotinic receptors (nAChRs) mediating nicotine-evoked [(3)H]dopamine release and decreases nicotine self-administration, suggesting that this polar, charged molecule penetrates the blood-brain barrier (BBB). This report focuses on 1) BBB penetration of bPiDDB; 2) the mechanism of permeation; and 3) comparison of bPiDDB to the cations choline and N-octylnicotinium iodide (NONI), both of which are polar, charged molecules that undergo facilitated BBB transport. The BBB permeation of [(3)H]choline, [(3)H]NONI, and [(14)C]bPiDDB was evaluated using in situ rat brain perfusion methods. Cerebrovascular permeability surface-area product (PS) values for [(3)H]choline, [(3)H]NONI, and [(14)C]bPiDDB were comparable (1.33 +/- 0.1, 1.64 +/- 0.15, and 1.3 +/- 0.3 ml/s/g, respectively). To ascertain whether penetration was saturable, unlabeled substrate was added to the perfusion fluid. Unlabeled choline (500 microM) reduced the PS of [(3)H]choline to 0.15 +/- 0.06 microl/s/g (p < 0.01). Likewise, unlabeled bPiDDB (500 microM) reduced the PS of [(14)C]bPiDDB to 0.046 +/- 0.005 microl/s/g (p < 0.01), whereas unlabeled NONI reduced the PS for [(3)H]NONI by approximately 50% to 0.73 +/- 0.31 microl/s/g. The PS of [(14)C]bPiDDB was reduced (p < 0.05) in the presence of 500 microM choline, indicating that the BBB choline transporter may be responsible for the transport of bPiDDB into brain. Saturable kinetic parameters for [(14)C]bPiDDB were similar to those for [(3)H]choline. The current results suggest that bPiDDB uses the BBB choline transporter for approximately 90% of its permeation into brain, and they demonstrate the carrier-mediated BBB penetration of a novel bisquaternary ammonium nAChR antagonist.
  Journal of Pharmacology and Experimental Therapeutics 01/2008; 324(1):244-50. · 3.83 Impact Factor
• Article: Combating Alzheimer's disease with multifunctional molecules designed for metal passivation.

  Harvey Schugar, David E Green, Meryn L Bowen, Lauren E Scott, Tim Storr, Karin Böhmerle, Fancy Thomas, David D Allen, Paul R Lockman, Michael Merkel, Katherine H Thompson, Chris Orvig
  Angewandte Chemie International Edition 01/2007; 46(10):1716-8. · 13.45 Impact Factor
• Chapter: Nanoparticle Targeting for Drug Delivery Across the Blood–Brain Barrier

  James Egbert, Werner Geldenhuys, Fancy Thomas, Paul R. Lockman, Russell J. Mumper, David D. Allen
  06/2006: pages 160 - 169; , ISBN: 9780470097984
• Article: In vivo interactions of magnetic nanoparticles with the blood–brain barrier

  Patricia Stepp, Fancy Thomas, Paul R. Lockman, Haitao Chen, Axel J. Rosengart
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  ABSTRACT: Targeted drug delivery to the brain parenchyma, i.e., in brain tumor patients, by means of magnetically supported carrier delivery through the tight vascular endothelium of the blood–brain barrier is of critical biomedical importance. We were interested in delineating the first steps in successful brain drug delivery, which focuses on the interactions between magnetically guided yet freely blood circulating nanoparticles and the blood–brain barrier. We employed an in vivo model to quantitatively determine changes in cerebrovascular flow rate and volume during magnetically guided exposure of circulating nanoparticles.
  Journal of Magnetism and Magnetic Materials.