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  6. Eugene A. Cioffi, Ph.D.

Eugene A. Cioffi, Ph.D.

Eugene A Cioffi, Ph.D.Associate Professor Emeritus
USA Department of Pharmacology

Ph.D.: University of Connecticut
Post-doctoral: Yale University

eacioffi@southalabama.edu  

Research Interests

The study of carbohydrates within biological systems has illustrated that are involved in key biological functions such as cell-cell, cell-matrix, and cell-molecule interactions critical to the development and function of a complex multi-cellular organism. These glycans act as mediators in the interactions between different organisms (e.g., between a host and pathogen), and their high intra- and surficial cellular abundance denotes their key roles as recognition and regulatory molecular switches. An increasingly diverse and complete paradigm of molecular biology thus includes the glycans and covalently-linked glycoconjugates, in the context of proteoglycans, glycoproteins, and glycolipids. Our research studies are focused on two projects which involve glycochemistry and glycobiology. These projects are as follows:

A) Critical glycoconjugate interactions in the pulmonary vasculature.

The surface of vascular endothelium bears a glycocalyx comprised, in part, of a complex mixture of oligosaccharide chains attached to cell-surface proteins and membrane lipids. Due to its complexity, understanding of the structure and function of the endothelial glycocalyx is still in its infancy. Preliminary studies have demonstrated differences in the glycocalyx of pulmonary artery endothelial cells (PAECs) as compared to pulmonary microvascular endothelial cells (PMVECs). We observed that whilst pulmonary microvascular endothelial cells express similar amounts of total sialic acids as pulmonary artery endothelial cells, the intrinsic nature of the sialic acid linkages differs between the two cell types. Surficially, pulmonary artery endothelial cells express both α(2,3)- and α(2,6)-linked sialic acids, whereas microvascular endothelial cells principally express α(2,3)-linked sialic acids. To determine whether sialic acids play a role in endothelial barrier function, cells were treated with neuraminidases both in vitro and ex vivo to hydrolyze the specific sialic acid linkages. Pronounced disruption of cell-cell and cell-matrix adhesions were observed following in vitro neuraminidase treatment, suggesting that terminal sialic acids promote endothelial barrier integrity. When measuring transendothelial resistance (ECIS®), differential responses of pulmonary artery and micro-vascular endothelial cells to neuraminidase from Vibrio cholerae suggest that the molecular architecture of the α(2,3)-linked sialic acid species between these two cell types is different. Ex vivo, neuraminidase treatment resulted in alveolar-interstitial edema and formation of perivascular cuffs around the large vessels. Collectively, these observations reveal the structural and functional significance of sialic acids on the pulmonary endothelium, and are leading us to explore other potential glycan-mediated roles such as Ca+2 ion-channel signaling and response to pulmonary airway impairment.

B) Synthetic glycodendrimers for MRI enhancement and chemotherapeutic applications in oncology.

A common property of invasive primary and metastatic cancers is upregulation of glycolysis, with concomitant increased glucose consumption. Presumably, this constitutive upregulation of glycolysis is required for the vascular angiogenesis associated with the tumor growth. It has been widely reported that all invasive cancers avidly trap 2-18F-deoxyglucose (FdG), which is the most widely used PET imaging agent. FdG PET imaging affords quantitation of glucose uptake, and consistently correlates poor prognosis and increased tumor aggressiveness with increased glucose uptake. However, since the 18F- radionuclide is short-lived and emits both beta and gamma radiation [T½ = 1.8 hr.; β = 634keV; γ = 511 keV; (www.nchps.org)], both the medical staff and patient must be especially cautious in the use of FdG. But the avidity for glucose uptake by cancerous tissue can be exploited in a different way, using non-hydrolysable glucose-tethered dendrimers affixed to naturally abundant hydroxy-keto heterocycles which strongly and irreversibly bind M+2 and M+3 transition metals. Our prior work using isothermal titration calorimetry (ITC) has demonstrated that keto-hydroxy heterocycles show very strong binding to M+2 and M+3 transition metals. Furthermore, the parent O- or N- heterocycle itself may be "tuned" for enhanced binding to a specific metal by simple chemical modification (e.g., for Gd+3, the binding constant Ka (M-1) increased from 1.4 x 104 to 8.9 x 105 by a single ring-atom O → N substitution). The utility of non-radioactive nuclei such as Gd+3 as an MRI imaging agent (e.g., Gadovist® and Magnevist®) in clinical practice is well documented; however, anaphylactoid reactions may occur in patients with an allergic deposition to the macrocyclic azatetra-cyclododecane-triacetic acid tether, and is similarly contraindicated with patients with kidney insufficiency. Further, imaging and chemotherapeutic applications with "hot" isotopes such as 64Cu-ATSM [T½ = 12.7 hr.; β = 587 keV; positron = 653 keV; γ = 135 keV] and 67Ga [T½ = 3.3 days; γ = 185 keV] require direct tethering ligands [64Cu] or co-complexed ligands [67Ga] that may not readily select between target and non-target tissue, or is contraindicated by existing physiological conditions. The development of non-hydrolysable glucose-tethered heterocyclic dendrimers is a new unexplored class of agents, which take fully advantage of glucose avidity by a tumor. These custom-designed glycodendrimers show great potential for both MRI and radioimaging applications, and with sufficient development could become a central modality for both selective imaging and nuclear radiotherapy. 

Representative Publications

  1. Cioffi EA, Pyakurel S, Cioffi DL. (2011) Terminal sialic acids are an important determinant of pulmonary barrier integrity. Am J Phys-Lung Cell Mol Phys (accepted w/ revision).
  2. Cioffi EA, Stenson AL. (2011) Kojic acid M+2 metal complexation characterized via ESI ion-trap mass spectrometry; J Am Soc Mass Spectrom (submitted).  
  3. Cioffi EA, Stenson AL. (2011) Beryllium (Be+2) complexation avidity with hydroxy-keto heterocycles: an ESI-MS and Fourier transform ion-cyclotron mass spectrometry (FTIC-MS) investigation; J Am Soc Mass Spectrom (submitted).
  4. Cioffi EA, Thomley JK. (2011) Large-scale survey of aqueous and sedimentary mercury (Hg) contaminants in the Mobile-Tensaw River watershed”; J Water Research (submitted).
  5. Cioffi EA. (2008) High-energy glycoconjugates: Synthetic transformations of carbohydrates using microwave and ultrasonic energy. Current Topics in Medicinal Chemistry, 8(2), 152-158.
  6. Stenson AC, Cioffi EA. (2007) Speciation of M+3 –hydropyrone chelation complexes by electrospray ionization ion-trap and Fourier transform ion cyclotron resonance mass spectrometry. Rapid Communications in Mass Spectrometry, 21, 2594-2600.
  7. Bokatzian-Johnson SS, Maier ML, Bell RH, Alston KE, Le BY, Cioffi EA. (2007) Facile C-H bond activation for deuterium labelling of glycoconjugates conducted in ultrasonic and microwave fields: A review. Journal of Labelled Compounds and Radiopharmaceuticals, 50(5-6), 380-383.
  8. Sykora RE, Cioffi EA. (2007) A triphenylmethanol-pyridinium chloride adduct containing one-dimensional ionic substructure. Acta Crystallographica E, 63, o3148-o3149.
  9. Fox PA, Griffin ST, Reichert WM, Salter EA, Smith AB, Tickell MD, Wicker BF, Cioffi EA, Davis JH, Rogers RD, Wierzbicki A. (2006) Exploring Isolobal Relationships to Create New Ionic Liquids: Novel Room Temperature Ionic Liquids Based Upon (N-alkylimidazole)(amine)BH2+ "Boronium Ions. Chemical Communications, 3679-3681.
  10. Wu S, Cioffi EA, Alvarez D, Sayner S, Chen H, Cioffi DL, King JA, Creighton JR, Townsley M, Goodman SR, Stevens T. (2005) Essential Role of a Ca+2-Selective, Store-Operated Current (Isoc) in Endothelial Cell Permeability: Determination of the Vascular Leak Site. Circulation Research, 96, 856-863.
  11. Cioffi EA. (2005). Microwave Promoted C-H Bond Activation and Isotopic Exchange in Glycoconjugates. 2004 National High Magnetic Field Laboratory (NHMFL) Ann. Research Reviews, 71-72.
  12. Gross KL, Cioffi EA, Scammell JG. (2004).Increased activity of the calcineurin-nuclear factor of activated T cell pathway in squirrel monkey B-lymphoblasts identified by PowerBlot®. In Vitro Cellular and Developmental Biology- Animal, 40, 57-63.
  13. Cioffi EA, Cook ML, Alston KE, Le BY. (2004). Stereospecific C-H Bond Activation for Tritium Labeling of Glycoconjugates Conducted in Ultrasonic and Microwave Fields. "Synthesis and Applications of Isotopically Labelled Compounds", Volume 8, D. Filer and K. McCarthy, Ed., John Wiley & Sons, Ltd. (London), pp. 59-72.
  14. Musiyenko A, Kumar R, Cioffi EA, Oldenburg A, Adams B, Bitko V, Barik S. (2002). Reversible protein tyrosine phosphorylation in Plasmodium falciparum: Characterization of a dual-specificity YVH1- family phosphatase that contains a novel zinc-binding domains with distant similarity to RING-finger motifs. NCBI Protein Data Bank; gi:21311624; 02-Jun-2002.
  15. Jones PJ, Cioffi EA, Prestegard JH. (1997). {19F} –1H Heteronuclear NOE Studies of the Acyl Chain Binding Site of Acyl Carrier Protein. Journal of Biological Chemistry, 262, 8963-8965.