Phospholipid-drug conjugates as a novel oral drug targeting approach for the treatment of inflammatory bowel disease

Eur J Pharm Sci. 2017 Oct 15:108:78-85. doi: 10.1016/j.ejps.2017.06.022. Epub 2017 Jun 13.


The enzyme phospholipase A2 (PLA2) is overexpressed in the inflamed intestine in inflammatory bowel disease (IBD) patients, and in this work we aimed to exploit PLA2 as a prodrug-activating enzyme for a novel PL-drug conjugate, thereby liberating the free drug specifically in the targeted diseased tissue(s). The proposed prodrug contains a drug moiety covalently bound through a linker to the sn-2 position of a phospholipid (PL). The NSAID diclofenac was used as model molecule, and four different linker lengths (2, 4, 6 and 8 -CH2 units) were studied. The four PL-diclofenac conjugates were synthesized and characterized by LC/MS and NMR. PLA2-mediated activation of the prodrugs was analyzed in-vitro, and the remaining intact complex and free drug liberation were assessed after incubation with PLA2. The rate and degree of PLA2-mediated activation were highly dependent on the linker length; 2- and 4-carbon linker conjugates were activated to lower extent than the 6-carbon conjugate, and longer linker again decreased the affinity towards PLA2. The 6-carbon linker conjugate was found to be the optimal and released ~95% of the free drug after incubation with PLA2, whereas only ~20% were delivered by the 2-carbon linker prodrug. The 6-carbon linker conjugate was shown to be stable in intestinal perfusate, fresh plasma, and pH4.0 and 6.8 buffers, but not at pH1.0. In conclusion, the results of this work confirm the feasibility of our general aim to exploit PLA2 as a prodrug-activating enzyme of PL-drug conjugates. This may provide a novel oral drug targeting approach in IBD therapy.

Keywords: Drug targeting; Inflammatory bowel disease (IBD); Oral prodrug; Phospholipase A(2) (PLA(2)); Phospholipid–drug conjugate; Prodrug-activating enzyme.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry*
  • Bee Venoms
  • Chemistry, Pharmaceutical
  • Diclofenac / administration & dosage
  • Diclofenac / chemistry*
  • Drug Delivery Systems
  • Drug Liberation
  • Drug Stability
  • Excipients
  • Hydrogen-Ion Concentration
  • Inflammatory Bowel Diseases / drug therapy*
  • Jejunum / metabolism
  • Phospholipases A2 / chemistry*
  • Phospholipids / chemistry*
  • Prodrugs / administration & dosage
  • Prodrugs / chemistry*
  • Rats, Wistar
  • Solubility
  • Structure-Activity Relationship


  • Anti-Inflammatory Agents, Non-Steroidal
  • Bee Venoms
  • Excipients
  • Phospholipids
  • Prodrugs
  • Diclofenac
  • Phospholipases A2