A glutathione-responsive L-carnitine-modified camptothecin oral nano-prodrug for cancer therapy

A glutathione (GSH)-responsive amphiphilic camptothecin (CPT) prodrug, Lc-ss-CPT, was synthesized by conjugating hydrophobic CPT with hydrophilic L-carnitine (Lc) via a disulfide carbonate linker. The prodrug self-assembled into spherical nanoparticles (Lc-ss-CPT NPs, hydrodynamic diameter: ∼180 nm). In simulated gastrointestinal fluids and FBS-containing PBS, the NPs maintained stability over 24 h, with <10 % CPT leakage after 8 h. In vitro transcytosis studies using Caco-2 monolayers revealed an 188.5-fold higher apparent permeability coefficient for Lc-ss-CPT NPs than free CPT. The confocal fluorescence imaging studies demonstrated that the specific affinity between L-carnitine and organic cation transporter 2 (OCTN2) enhanced intestinal absorption of Lc-ss-CPT NPs and then transported into the bloodstream through transcytosis, facilitated by the Golgi apparatus and endoplasmic reticulum, enabling tumor accumulation. Pharmacokinetic analysis in rats showed oral administration of Lc-ss-CPT NPs achieved a higher bioavailability of 49.6 %. In HCT-116 cells, Lc-ss-CPT NPs reduced intracellular GSH to 5.4 % of baseline at 6 h, elevated ROS levels by 4.2-fold, and induced 71.2 % apoptosis. In MC38 tumor-bearing mice, oral Lc-ss-CPT NPs suppressed tumor growth by 86 % (vs. 12 % for free CPT). These data demonstrate the potential of Lc-ss-CPT NPs as an orally administrable platform for targeted CPT delivery.