DON encapsulated carbon dot-vesicle conjugate in therapeutic intervention of lung adenocarcinoma by dual targeting of CD44 and SLC1A5

Abstract

Lung adenocarcinoma, recognized as one of the most formidable malignancies with a dismal prognosis and low survival rates, poses a significant challenge in its treatment. This article delineates the design and development of a carbon dot-vesicle conjugate (HACD-TMAV) for efficient cytotoxicity towards lung cancer cells by target selective delivery of the glutamine inhibitor 6-diazo-5-oxo-L-norleucine (DON) within CD44-enriched A549 cancer cells. HACD-TMAV is composed of hyaluronic acid-based carbon dots (HACDs) and trimesic acid-based vesicles (TMAV), which are bound via electrostatic interactions. TMAVs are formed by positively charged trimesic acid-based amphiphiles through H-type aggregation in water. HACDs were synthesized through a one-step hydrothermal route. The blue-emitting HACD-TMAV conjugate demonstrated selective bioimaging in CD44-overexpressed A549 lung cancer cells due to specific ligand-receptor interactions between HA and CD44. HACD-TMAV exhibited notably improved DON loading efficiency compared to individual nano-vehicles. HACD-TMAV-DON exhibited remarkable (∼6.0-fold higher) cytotoxicity against CD44-overexpressing A549 cells compared to CD44^- HepG2 cells and HEK 293 normal cells. Also, DON-loaded HACD-TMAV showed ∼2.0-fold higher cytotoxicity against A549 cells compared to individual carriers and ∼4.5-fold higher cytotoxicity than by DON. Furthermore, HACD-TMAV-DON induced a ∼3.5-fold reduction in the size of 3D tumor spheroids of A549 cells. The enhanced anticancer effectiveness was attributed to starvation of the A549 cells of glutamine by dual targeting of glutamine metabolism and solute linked carrier family 1 member A5 (SLC1A5) through HA-linked CD44-mediated targeted delivery of DON. This led to over-production of reactive oxygen species (ROS) that induced apoptosis of cancer cells through downregulation of the PI3K/AKT/mTOR signaling cascade.