Procedurally Targeted Delivery of Antitumor Drugs Using FAPα-Responsive TPGS Dimer-Based Flower-like Polymeric Micelles.

To overcome the intestinal epithelium barrier and achieve a better antitumor effect, the procedurally targeting flower-like nanomicelles for oral delivery of antitumor drugs were designed based on FAPα-responsive TPGS1000 dimer (TPGS-Gly-Pro-TPGS) and L-carnitine linked poly(2-ethyl-2-oxazoline)-b-poly(D, l-lactide) (Car-PEOz-b-PLA). As expected, compared with unmodified polymeric micelles (TT-PMs) composed of TPGS-Gly-Pro-TPGS, L-carnitine conjugated polymeric micelles (CTT-PMs) formed from both TPGS-Gly-Pro-TPGS and Car-PEOz-b-PLA with favorable stability in simulated gastrointestinal fluid and FAPα-dependent release capability exhibited remarkably enhanced cellular uptake and transmembrane transport through OCTN2 mediation confirmed by fluorescence immunoassay, which was intuitively evidenced by stronger fluorescence within epithelial cells, and the basal side of small intestinal epithelium of mice being given intragastric administration of DiI-labeled micelles. The transport of CTT-PMs across the intestinal epithelium in an intact form was mediated by clathrin along the intracellular transport pathway of endosome-lysosome-ER-Golgi apparatus. Furthermore, both the increased uptake by FAPα-positive U87MG cells and unchangeable uptake by FAPα-negative C6 cells for coumarin-6 (C-6)/CTT-PMs compared with C-6/TT-PMs evidenced the targeting ability of CTT-PMs to FAPα-positive tumor cells. Both OCTN2-mediation and FAPα-responsiveness were beneficial for polymeric micelles to improve the delivery and therapeutic efficiency of antitumor agents, which was further supported by the remarkable enhancement in in vivo antitumor efficacy via promoting apoptosis of tumor cells for paclitaxel (PTX)-loaded CTT-PMs (PTX/CTT-PMs) with low toxicity compared with PTX/TT-PMs. Our findings offered an alternative design strategy for procedurally targeted delivery of chemotherapeutics by an oral route.

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

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-OSTß) 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.