OCTN2-targeted and ROS-responsive hybrid polymeric micelles for oral delivery of docetaxel

Our previous research identified that an oral mPEG-b-PCL polymeric micelle (PM) maintained satisfactory integrity but exhibited limited transcytosis efficiency. To enhance transcytosis and enable ROS-responsive release, we developed a series of hybrid PMs by blending a synthesized L-carnitine-grafted, thioketal-linked LC-PEG_5k-TK-PCL_7k polymer with mPEG_5k-PCL_7k. These hybrid PMs, similar in particle size (120 nm) and drug loading (10%) to the PM composed of pure mPEG_5k-PCL_7k (5-7E), retained good stability in SGF and SIF. However, the hybrid PM with a 40% LC-PEG_5k-TK-PCL_7k proportion showed reduced integrity and penetration in mucus layer. In Caco-2/E12 (7:3) cells, the hybrid PM with a 20% LC-PEG_5k-TK-PCL_7k proportion (20%Hybrid 5-7E) demonstrated superior uptake, low cytotoxicity, and a 3.37-fold higher transcytosis than that of 5-7E. In 4T1 cells, prepared PMs exhibited similar uptake but hybrid PMs showed obvious ROS-responsive dissociation and cytotoxicity. The in vivo integrity and biocompatibility of 20%Hybrid 5-7E were confirmed by plasma concentration and hemolysis test, and the bio-distribution results demonstrated its tumor accumulation. Pharmacokinetics revealed a 10-fold increase in docetaxel (DTX) bioavailability due to the 20%Hybrid 5-7E encapsulation. Consequently, orally administered 20%Hybrid 5-7E (DTX 40 mg/kg) achieved comparable antitumor activity but reduced systemic toxicity relative to intravenously injected DTX solution (10 mg/kg) in 4T1 tumor-bearing BALB/c mice.