Coordinatore | BEN-GURION UNIVERSITY OF THE NEGEV
Organization address
address: Office of the President - Main Campus contact info |
Nazionalità Coordinatore | Israel [IL] |
Totale costo | 100˙000 € |
EC contributo | 100˙000 € |
Programma | FP7-PEOPLE
Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) |
Code Call | FP7-PEOPLE-2010-RG |
Funding Scheme | MC-IRG |
Anno di inizio | 2011 |
Periodo (anno-mese-giorno) | 2011-05-01 - 2015-04-30 |
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BEN-GURION UNIVERSITY OF THE NEGEV
Organization address
address: Office of the President - Main Campus contact info |
IL (BEER SHEVA) | coordinator | 100˙000.00 |
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'A molecular approach will be applied to mechanistically target drugs - by exploiting phospholipase A2 (PLA2) - to diseased tissues in inflammatory bowel disease (IBD). PLA2 hydrolyses the sn-2 fatty acyl bond of phospholipids (PL), liberating a fatty-acid and a lysophospholipid. We have shown that by substituting the sn-2 fatty-acid of the PL with a drug, PLA2 may be exploited as a prodrug activating enzyme, liberating the free drug from the PL-complex. Further, PLA2 affinity to the prodrug and the intestinal permeability of the whole prodrug can be manipulated by the conjugate design. PLA2 expression/activity has been shown to be significantly elevated in tissues of patients with IBD - both Crohn’s disease and ulcerative colitis. We posit that since the activation of the PL-drug conjugate is PLA2 mediated, increased PLA2 levels in the diseased tissue will lead to increased free drug in the actual diseased tissues, accompanied by decreased drug levels in non-diseased areas, resulting in extended therapeutic index and improved drug therapy. The proposed research will mechanistically facilitate specific targeting of 5-aminosalicylic acid (5ASA) for proof-of-concept. However, targeting of other drugs will be enabled by the core approach developed in this research. The specific aims are: 1) to design and synthesize a library of PL-5ASA conjugates with different linkers between the PL and the drug moiety; 2) to evaluate the PLA2-mediated activation and the intestinal permeability of the prodrugs (enabling the design/synthesis of optimal conjugates), thereby to identify the most promising prodrugs; and 3) to develop an IBD rat model, to quantify PLA2 expression/activity in diseased vs. control animals, and to evaluate the leading PL-5ASA conjugates for in-vivo drug targeting, pharmacokinetics and pharmacodynamics vis-à-vis other 5ASA products. The findings will significantly improve drug therapy in IBD patients, enabling higher efficacy and lower toxicity profiles.'
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