Hypoxia-Responsive Golgi-Targeted Prodrug Assembled with Anthracycline for Improved Antitumor and Antimetastasis Efficacy

• Published in: ACS nano 2023-12, Vol.17 (24), p.24972-24987
• Main Authors: Guo, Chenqi, Wu, Mengying, Guo, Zhaofei, Zhang, Rongping, Wang, Zijun, Peng, Xiong, Dong, Jianxia, Sun, Xun, Zhang, Zhirong, Xiao, Peihong, Gong, Tao
• Format: Article
• Language: English
• Subjects: Anthracyclines - metabolism; Anthracyclines - pharmacology; Antibiotics, Antineoplastic - pharmacology; Cell Line, Tumor; Drug Delivery Systems; Golgi Apparatus; Humans; Hypoxia - drug therapy; Nanoparticles - chemistry; Prodrugs - chemistry
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.3c07183

Tumor metastasis is an intricate multistep process regulated via various proteins and enzymes modified and secreted by swollen Golgi apparatus in tumor cells. Thus, Golgi complex is considered as an important target for the remedy of metastasis. Currently, Golgi targeting technologies are mostly employed in Golgi-specific fluorescent probes for diagnosis, but their applications in therapy are rarely reported. Herein, we proposed a prodrug (INR) that can target and destroy the Golgi apparatus, which consisted of indomethacin (IMC) as the Golgi targeting moiety and retinoic acid (RA), a Golgi disrupting agent. The linker between IMC and RA was designed as a hypoxia-responsive nitroaromatic structure, which ensured the release of the prototype drugs in the hypoxic tumor microenvironment. Furthermore, INR could be assembled with pirarubicin (THP), an anthracycline, to form a carrier-free nanoparticle (NP) by emulsion-solvent evaporation method. A small amount of mPEG2000-DSPE was added to shield the positive charges and improve the stability of the nanoparticle to obtain PEG-modified nanoparticle (PNP). It was proved that INR released the prototype drugs in tumor cells and hypoxia promoted the release. The Golgi destructive effect of RA in INR was amplified owing to the Golgi targeting ability of IMC, and IMC also inhibited the protumor COX-2/PGE2 signaling. Finally, PNP exhibited excellent curative efficacy on 4T1 primary tumor and its pulmonary and hepatic metastasis. The small molecular therapeutic prodrug targeting Golgi apparatus could be adapted to multifarious drug delivery systems and disease models, which expanded the application of Golgi targeting tactics in disease treatment.