Enhanced Oral Absorption and Liver Distribution of Polymeric Nanoparticles through Traveling the Enterohepatic Circulation Pathways of Bile Acid

Abstract

The intestinal epithelium is known to be a main hindrance to oral delivery of nanoparticles. Even though surface ligand modification can enhance cellular uptake of nanoparticles, the “easy entry and hard across” was frequently observed for many active targeting nanoparticles. Here, we fabricated polymeric nanoparticles relayed by bile acid transporters with monomethoxy poly­(ethylene glycol)-poly­(D,l-lactide) and deoxycholic acid-conjugated poly­(2-ethyl-2-oxazoline)-poly­(D,l-lactide) based on structural characteristics of intestine epithelium and the absorption characteristics of endogenous substances. As anticipated, deoxycholic acid-modified polymeric nanoparticles featuring good stability in simulated gastrointestinal fluid could notably promote the internalization of their payload by Caco-2 cells through mediation of apical sodium-dependent bile acid transporter (ASBT) and transmembrane transport of the nanoparticles across Caco-2 cell monolayers via relay-guide of ASBT, ileal bile acid-binding protein, and the heteromeric organic solute transporter (OSTα-OSTβ) along with multidrug resistance-associated protein 3 (MRP3) evidenced by competitive inhibition and fluorescence immunoassay, which was further visually confirmed by the stronger fluorescence from C6-labeled nanoparticles inside enterocytes and the basal side of the intestinal epithelium of mice. The transcellular transport of deoxycholic acid-modified nanoparticles in an intact form was mediated by caveolin/lipid rafts and clathrin with intracellular trafficking trace of endosome-lysosome-ER-Golgi apparatus and bile acid transport route. Furthermore, the increased uptake by HepG2 cells compared with unmodified nanoparticles evidenced the target ability of deoxycholic acid-modified nanoparticles to the liver, which was further supported by ex vivo imaging of excised major organs of mice. Thus, this study provided a feasible and potential strategy to further enhance transepithelial transport efficiency and liver-targeted ability of nanoparticles by means of the specific enterohepatic circulation pathways of bile acid.

Hepatic‐Accumulated Obeticholic Acid and Atorvastatin Self‐Assembled Nanocrystals Potentiate Ameliorative Effects in Treatment of Metabolic‐Associated Fatty Liver Disease

“…[15] Given the enterohepatic recycling process of bile acids, utilizing bile acid transporter-mediated oral drug delivery has been acknowledged as a practical and promising strategy for enhancing oral bioavailability. [16] Considering these findings, we postulate that OCA (a bile acid derivative) might be considered a promising candidate for bile acid transportermediated oral drug delivery, which has not been reported yet.…”

Ursodeoxycholic Acid‐Decorated Zwitterionic Nanoparticles for Orally Liver‐Targeted Close‐Looped Insulin Delivery

“…[38,39] As reported, bile acids can be effectively transported through the intestinal epithelium via the basal lamina pathway mediated by the heteromeric organic solute transporter (OST𝛼-OST𝛽), ultimately reaching the liver through the portal vein and completing the enterohepatic cycle. [30] Herein, we developed UDCA-decorated zwitterionic nanoparticles (UC-CMs@ins) to address GI barriers for livertargeted insulin delivery, achieving excellent glucose control and bioavailability (Scheme 1). The phenyl borate ester structure endowed UC-CMs@ins to release insulin in a close-looped manner and the crosslinked structure prevented insulin degradation in the gastrointestinal tract.…”

“…Nonetheless, the limited absorption of carriers mediated by certain substrates results in suboptimal serum drug concentrations, challenging the attainment of the desired therapeutic window. [ 30 ] To enhance absorption, it is necessary to tailor the intestinal absorption properties of substrates to the structure of the small intestinal epithelial cells. Bile acids, such as deoxycholic acid (DA), [ 31 ] ursodeoxycholic acid (UDCA), [ 32 ] and obeticholic acid (OCA) [ 33 ] can be delivered via apical sodium‐dependent bile acid transporter (ASBT)‐mediated endocytosis and cytosolic ileal bile acid‐binding protein (IBABP)‐mediated intracellular transport.…”