TARGETIBDBYPLA2 (277079)

  https://cordis.europa.eu/project/id/277079

  FP7 (2007-2013)

  A Novel Drug Targeting Strategy for the Treatment of Inflammatory Bowel Disease: A Molecular Biopharmaceutical Approach

  Marie Curie Action: "Reintegration Grants" (FP7-PEOPLE-2009-RG)

  inflammatory bowel disease  ·  pharmacokinetics  ·  enzymes

  2011-05-01 Start Date (YY-MM-DD)

  2015-04-30 End Date (YY-MM-DD)

  € 100,000 Total Cost

  Description

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.

  Complicit Organisations

1 Israeli organisation participates in TARGETIBDBYPLA2.