(T1530-04-20) Oral Drug Delivery Strategy Using Bile Acid Decorated Nanoparticles

Purpose: Oral delivery of nanomedicine has the constitutive complexity of the harsh gastrointestinal environment (pH and digestive enzymes) including physical state, degree of receptor exposure, particle instability, and transit time in the gastrointestinal tract (GIT). These factors make it difficult to identify the absorption and transport efficiencies and mechanisms of nanomedicine, especially in vivo. In this study, I used bile acid-conjugated solid fluorescent probe nanoparticles (BANP) to observe the transport pathways in the GIT of nanomedicine and rule out potential artifacts and instability issues when measuring oral bioavailability (oBA).

Methods: Fluorescent, carboxylic polystyrene nanoparticles (100 and 250 nm) are employed as probe nanoparticles (PN). For chemical conjugation of bile acid (BA) to PN, the carboxyl group in BA (glycocholic acid) was pre-modified to primary amine, and the aminated BA was bonded to the PN surface via simple carbodiimide chemistry under aqueous conditions. The apical sodium dependent bile acid transporter (ASBT)-specific cellular uptake efficiency and transport pathways of BAPN were evaluated in ASBT expressing SK-BR-3 cells. The oral bioavailability and absorption routes were evaluated in Balb/c nude mice and Sprague-Dawley (SD) rats. Microscopic observation and inhibition study were conducted for delivery pathways.

Results: The BANP (100 nm) exhibited oBA as high as 47 % in SD rats after oral dosing. Area under the curve (AUC) was dose-dependent up to 20 mg/kg. The pharmacokinetic profile was sustained. The oBA was influenced by degree of BA conjugation and nanoparticle size. The oBA was sharply declined when the rats were pretreated with cycloheximide that inhibits chylomicron export from enterocyte, which is a part of fat digestion/transport pathways. This pretreatment did not influence the uptake rate of PN without BA. When BAPN interacted with SK-BR-3 cells, the nanoparticle was internalized and located in endoplasmic reticulum and possibly in Golgi body, but neither in early endosome nor in lysosome. The GCA-PN was observed in lymph fluid collected from the thoracic duct, a central lymphatic duct, by TEM.

Conclusion: The evidences obtained from this study support massive uptake of intact nanoparticle in the ileum via ASBT mediated endocytosis. Intracellular pathway seems to follow the way of chylomicron transportation. The nanoparticles are, most probably, transported to the lymphatic system first, rather than portal circulation, as chylomicron does. This may provide us a new oral delivery route directly to the lymphatic system at high bioavailability.

Acknowledgments: This work was supported by the Basic Science Research Program (NRF-2021R1C1C2093337) through the National Research Foundation of Korea funded by the Ministry of Science and ICT (MSIT).