A Pioglitazone Nanoformulation Designed for Cancer-Associated Fibroblast Reprogramming and Cancer Treatment

• Published in: Nano letters Vol. 24; no. 15; pp. 4354 - 4361
• Main Authors: Theivendran, Shevanuja, Xian, He, Qu, Jingjing, Song, Yaping, Sun, Bing, Song, Hao, Yu, Chengzhong
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 17.04.2024
• Subjects: Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer-Associated Fibroblasts; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Female; Humans; Nanoparticles; Pioglitazone - pharmacology; Pioglitazone - therapeutic use; Tumor Microenvironment; mesoporous organosilica nanoparticles; cancer-associated fibroblast; pioglitazone; tumor microenvironment; doxorubicin
• ISSN: 1530-6984; 1530-6992; 1530-6992
• DOI: 10.1021/acs.nanolett.3c04706

The recent focus of cancer therapeutics research revolves around modulating the immunosuppressive tumor microenvironment (TME) to enhance efficacy. The tumor stroma, primarily composed of cancer-associated fibroblasts (CAFs), poses significant obstacles to therapeutic penetration, influencing resistance and tumor progression. Reprogramming CAFs into an inactivated state has emerged as a promising strategy, necessitating innovative approaches. This study pioneers the design of a nanoformulation using pioglitazone, a Food and Drug Administration-approved anti-diabetic drug, to reprogram CAFs in the breast cancer TME. Glutathione (GSH)-responsive dendritic mesoporous organosilica nanoparticles loaded with pioglitazone (DMON-P) are designed for the delivery of cargo to the GSH-rich cytosol of CAFs. DMON-P facilitates pioglitazone-mediated CAF reprogramming, enhancing the penetration of doxorubicin (Dox), a therapeutic drug. Treatment with DMON-P results in the downregulation of CAF biomarkers and inhibits tumor growth through the effective delivery of Dox. This innovative approach holds promise as an alternative strategy for enhancing therapeutic outcomes in CAF-abundant tumors, particularly in breast cancer.