The Impact of Conjugation Position and Linker Chemistry on the Lymphatic Transport of a Series of Glyceride and Phospholipid Mimetic Prodrugs
| Autor: | Jamie S. Simpson, Tim Quach, Christopher J.H. Porter, Gracia Gracia, Natalie L. Trevaskis, Shea Fern Lim, Luojuan Hu, Sifei Han |
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| Rok vydání: | 2021 |
| Předmět: |
Chemistry
Triglyceride transport Glyceride Phospholipid Pharmaceutical Science Ether 02 engineering and technology Prodrug 021001 nanoscience & nanotechnology 030226 pharmacology & pharmacy Combinatorial chemistry Glycerides Rats 03 medical and health sciences chemistry.chemical_compound Drug Delivery Systems 0302 clinical medicine Targeted drug delivery Drug delivery Animals Prodrugs Lymph 0210 nano-technology Linker Phospholipids |
| Zdroj: | Journal of Pharmaceutical Sciences. 110:489-499 |
| ISSN: | 0022-3549 |
| DOI: | 10.1016/j.xphs.2020.10.021 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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