Improving lung cancer treatment: Hyaluronic acid‑modified and glutathione‑responsive amphiphilic TPGS‑doxorubicin prodrug‑entrapped nanoparticles.

Lung cancer nanotherapeutics aim to overcome the limitations of conventional therapeutic methods. In the present study, a self‑assembled amphiphilic prodrug‑based nanocarrier delivery system was developed that exhibited high therapeutic efficiency. D‑alpha‑tocopheryl polyethylene glycol 1000 succinate (TPGS) conjugated to doxorubicin (DOX) through disulfide (S‑S) bonds to constitute TPGS‑S‑S‑DOX was synthesized; furthermore, hyaluronic acid (HA) was conjugated to TPGS to obtain HA‑TPGS. TPGS‑S‑S‑DOX prodrug‑based and HA‑TPGS ligand‑modified nanoparticles (HA‑TPGS DOX‑NPs) were prepared for the treatment of lung cancer. In vitro and in vivo evaluation of the system was performed on lung cancer cell lines and lung tumor‑bearing mice. HA‑TPGS DOX‑NPs had a uniformly spherical shape with a white core and grey shell, with a size of 172.3 nm and a polydispersity index of 0.16. All of the NPs exhibited a drug encapsulation efficiency of >90%. The blank NPs exhibited low toxicity to all the tested cell lines, resulting in viabilities of >85%. HA‑TPGS DOX‑NPs had a more prominent in vitro antitumor effect than the other NPs tested, with cell viabilities of 80.2, 73.4, 57.8, 39.1, 28.3 and 10.9% observed after 72 h of incubation with 0.01, 0.05, 0.1, 0.5, 1 and 5 µM, respectively. The in vivo results demonstrated that HA‑TPGS DOX‑NPs had the highest antitumor efficacy, with 10.5% tumor inhibition efficiency after 28 days of injection. Overall, HA‑TPGS DOX‑NPs had significant antitumor effects and minimal systemic toxicity, and their application may be a promising strategy for the treatment of lung cancer.