The impact of conjugation position and linker chemistry on the lymphatic transport of a series of glyceride and phospholipid mimetic prodrugs

Sifei Han, Tim Quach, Luojuan Hu, Shea Fern Lim, Gracia Gracia, Natalie L. Trevaskis, Jamie S. Simpson, Christopher J.H. Porter

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7 Citations (Scopus)


Drug delivery to the lymphatic system is gaining increasing attention, particularly in fields such as immunotherapy where drug access to lymphocytes is central to activity. We have previously described a prodrug strategy that facilitates the lymphatic delivery of a model immunomodulator, mycophenolic acid (MPA) via incorporation into intestinal triglyceride transport pathways. The current study explored a series of structurally related glyceride and phospholipid mimetic prodrugs of MPA in an attempt to enhance lymph targeting and to better elucidate the design criteria for lipid mimetic prodrugs. MPA was conjugated to a glyceride or phospholipid backbone at various positions using different spacers employing ester, ether, carbonate and amide bonds. Patterns of prodrug hydrolysis were evaluated in rat digestive fluid, and lymphatic transport and plasma pharmacokinetics were assessed in lymph duct cannulated rats. Prodrugs with different spacers between MPA and the glyceride backbone resulted in up to 70-fold differences in gastrointestinal stability. MPA conjugation at the 2 position of the glyceride backbone and via an ester bond were most effective in promoting lymphatic transport. Phospholipid prodrug derivatives, or glyceride derivatives with MPA attached at the 1 position or when linked via ether, carbonate or amide bonds were poorly incorporated into lymphatic transport pathways.

Original languageEnglish
Pages (from-to)489-499
Number of pages11
JournalJournal of Pharmaceutical Sciences
Issue number1
Publication statusPublished - 1 Jan 2021


  • Biomimetic(s)
  • Conjugate(s)
  • Drug targeting
  • Immunotherapy
  • Lipid-based formulation(s)
  • Lipoprotein(s)
  • Lymphatic transport
  • Oral drug delivery
  • Phospholipid(s)
  • Prodrug(s)

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