Delivery of nitric oxide with a nanocarrier promotes tumour vessel normalization and potentiates anti-cancer therapies

• Published in: Nature nanotechnology Vol. 14; no. 12; pp. 1160 - 1169
• Main Authors: Sung, Yun-Chieh, Jin, Pei-Ru, Chu, Li-An, Hsu, Fu-Fei, Wang, Mei-Ren, Chang, Chih-Chun, Chiou, Show-Jen, Qiu, Jiantai Timothy, Gao, Dong-Yu, Lin, Chu-Chi, Chen, Yu-Sing, Hsu, Yi-Chiung, Wang, Jane, Wang, Fu-Nien, Yu, Pei-Lun, Chiang, Ann-Shyn, Wu, Anthony Yan-Tang, Ko, John Jun-Sheng, Lai, Charles Pin-Kuang, Lu, Tsai-Te, Chen, Yunching
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2019; Nature Publishing Group
• Subjects: 631/61/350; 631/61/350/354; Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - therapeutic use; Angiogenesis; Animals; Apoptosis; Blood vessels; Cancer; Cancer therapies; Cancer vaccines; Carcinoma, Hepatocellular - blood supply; Carcinoma, Hepatocellular - drug therapy; Chemistry and Materials Science; Controlled release; Delayed-Action Preparations - chemistry; Drug delivery systems; Hepatocellular carcinoma; Homeostasis; Humans; Immunostimulation; Immunotherapy; Liver cancer; Liver Neoplasms - blood supply; Liver Neoplasms - drug therapy; Male; Materials Science; Metastases; Mice; Microenvironments; Nanoparticles - chemistry; Nanotechnology; Nanotechnology and Microengineering; Neovascularization, Pathologic - drug therapy; Nitric oxide; Nitric Oxide - administration & dosage; Nitric Oxide - therapeutic use; Phenotypes; Sustained release; Therapy; Tumor microenvironment; Tumor Microenvironment - drug effects; Tumor necrosis factor; Tumors
• ISSN: 1748-3387; 1748-3395; 1748-3395
• DOI: 10.1038/s41565-019-0570-3

Abnormal tumour vasculature has a significant impact on tumour progression and response to therapy. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis and, thus, can be delivered to normalize tumour vasculature. However, a NO-delivery system with a prolonged half-life and a sustained release mechanism is currently lacking. Here we report the development of NanoNO, a nanoscale carrier that enables sustained NO release to efficiently deliver NO into hepatocellular carcinoma. Low-dose NanoNO normalizes tumour vessels and improves the delivery and effectiveness of chemotherapeutics and tumour necrosis factor-related, apoptosis-inducing, ligand-based therapy in both primary tumours and metastases. Furthermore, low-dose NanoNO reprogrammes the immunosuppressive tumour microenvironment toward an immunostimulatory phenotype, thereby improving the efficacy of cancer vaccine immunotherapy. Our findings demonstrate the ability of nanoscale NO delivery to efficiently reprogramme tumour vasculature and immune microenvironments to overcome resistance to cancer therapy, resulting in a therapeutic benefit. Nitric oxide delivered and released by a nanoscale carrier improves the therapeutic effectiveness of chemotherapeutics and immunotherapy by normalizing tumour vasculature.