A facile di-acid mono-amidation strategy to prepare cyclization-activating mono-carboxylate transporter 1-targeting gemcitabine prodrugs for enhanced oral delivery.

Intestinal mono-carboxylate transporter 1 (MCT1) plays an important role in the oral absorption of short-chain fatty acids that were used as oxidative metabolite. However, the prodrug strategy targeting intestinal MCT1 for oral delivery is rarely exploited. The oral bioavailability of Gemcitabine (Gem) is low mainly due to its poor intestinal permeability and rapid metabolism. Herein, a facile di-acid mono-amidation strategy was firstly developed to target MCT1 for oral chemotherapy. The N4-amino group of Gem is mono-amidated with di-acids containing different carbon chain lengths, which could recognize intestinal MCT1 and are bio-activated at physiological pH independent of the hydrolysis enzymes. The adipic acid-Gem shows higher MCT1 affinity, better gastrointestinal tract stability (3-fold), improved oral bioavailability (8.8-fold), and less gastrointestinal toxicity in comparison to Gem. Moreover the bio-activation rate of the prodrugs decreases with the increased fatty acid chain length of the linkage under physiological conditions. In summary, we present the first evidence that MCT1 could act as a new target for oral prodrug delivery, and that the linkage could modify the bio-activation rate for achieving optimal oral bioavailability. Our findings provide novel knowledge to rationally design intestinal transporter-targeting oral carrier prodrug.