Procedurally Targeted Delivery of Antitumor Drugs Using FAPa-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 FAPa-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 FAPa-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 FAPa-positive U87MG cells and unchangeable uptake by FAPa-negative C6 cells for coumarin-6 (C-6)/CTT-PMs compared with C-6/TT-PMs evidenced the targeting ability of CTT-PMs to FAPa-positive tumor cells. Both OCTN2-mediation and FAPa-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.