Optimizing Triglyceride Prodrugs of a Model Immunomodulator: Conjugation through the Phenol of Mycophenolic Acid (MPA) Markedly Promotes Lymphatic Drug Transport.

Enhanced transport of immunomodulators via the lymphatics may increase drug exposure to therapeutic targets in the immune system. Our laboratory has demonstrated a triglyceride (TG) mimetic prodrug approach to enhance the lymphatic delivery of a model immunomodulator, mycophenolic acid (MPA), via conjugation of the carboxylic acid of MPA to a TG backbone, where the so formed prodrug is able to incorporate into intestinal TG deacylation-reacylation and lymph lipoprotein transport pathways (up to 37% of the administered dose being absorbed via the lymphatics). In the current study, another conjugation site in the molecule of MPA, i.e., the phenolic group, was explored for its potential to optimize the lymphatic transport profiles of TG mimetic prodrugs of MPA. This offers an unusual opportunity to directly compare the utility of TG prodrugs formed via conjugation to an acid versus a phenol in the same core molecule, which has not been examined previously for other parent drugs. A series of linkers were examined to connect the MPA moiety with the TG backbone. Lymphatic transport was assessed in mesenteric lymph duct cannulated rats, and drug exposure in the mesenteric lymph nodes was examined following oral administration to mice. Compared to the data observed previously for MPA prodrugs conjugated via the carboxylic acid, the new phenol-conjugated prodrugs showed clearly different profiles in terms of the linker chemistry. Prodrugs with shorter chain alkyl spacers (e.g., C4 and C6) supported minimal lymphatic transport (<3% of the dose recovered in lymph). When the chain lengths were longer (≥C10), the prodrugs demonstrated much higher potential for lymphatic transport (up to approximately 55% of dose). Although effectively promoting lymphatic transport, TG mimetic prodrugs with alkyl chain linkers did not necessarily result in marked increases in the exposure of MPA in the mesenteric lymph nodes in mice. Subsequently a number of self-immolative linkers conjugated via the phenol were explored to promote MPA liberation from the prodrugs, and these constructs demonstrated enhanced lymph node exposure. This study provides further insight into structure-lymphatic transport relationships for lymph-directing lipid mimetic prodrugs.