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

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...

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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:	England Nature Publishing Group 01.12.2019
Subjects:	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 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 Metastases Mice Microenvironments Nanoparticles - chemistry 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
Online Access:	Get full text
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Abstract	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.
AbstractList	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.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. 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.
Author	Gao, Dong-Yu Wang, Fu-Nien Hsu, Fu-Fei Hsu, Yi-Chiung Chu, Li-An Lin, Chu-Chi Chen, Yu-Sing Wang, Jane Chiang, Ann-Shyn Chen, Yunching Qiu, Jiantai Timothy Wu, Anthony Yan-Tang Sung, Yun-Chieh Wang, Mei-Ren Lu, Tsai-Te Chiou, Show-Jen Lai, Charles Pin-Kuang Yu, Pei-Lun Ko, John Jun-Sheng Jin, Pei-Ru Chang, Chih-Chun
Author_xml	– sequence: 1 givenname: Yun-Chieh surname: Sung fullname: Sung, Yun-Chieh organization: Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan – sequence: 2 givenname: Pei-Ru surname: Jin fullname: Jin, Pei-Ru organization: Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan – sequence: 3 givenname: Li-An orcidid: 0000-0002-4092-3024 surname: Chu fullname: Chu, Li-An organization: Brain Research Center, National Tsing Hua University, Hsinchu, Taiwan – sequence: 4 givenname: Fu-Fei surname: Hsu fullname: Hsu, Fu-Fei organization: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan – sequence: 5 givenname: Mei-Ren surname: Wang fullname: Wang, Mei-Ren organization: Department of Chemistry, Chung Yuan Christian University, Taoyuan, Taiwan – sequence: 6 givenname: Chih-Chun surname: Chang fullname: Chang, Chih-Chun organization: Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan – sequence: 7 givenname: Show-Jen surname: Chiou fullname: Chiou, Show-Jen organization: Department of Applied Chemistry, National Chiayi University, Chiayi, Taiwan – sequence: 8 givenname: Jiantai Timothy surname: Qiu fullname: Qiu, Jiantai Timothy organization: Department of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, Taiwan – sequence: 9 givenname: Dong-Yu surname: Gao fullname: Gao, Dong-Yu organization: Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan – sequence: 10 givenname: Chu-Chi orcidid: 0000-0001-9017-5004 surname: Lin fullname: Lin, Chu-Chi organization: Department of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, Taiwan – sequence: 11 givenname: Yu-Sing surname: Chen fullname: Chen, Yu-Sing organization: Department of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, Taiwan – sequence: 12 givenname: Yi-Chiung orcidid: 0000-0002-8712-8714 surname: Hsu fullname: Hsu, Yi-Chiung organization: Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan – sequence: 13 givenname: Jane orcidid: 0000-0003-3957-4485 surname: Wang fullname: Wang, Jane organization: Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan – sequence: 14 givenname: Fu-Nien surname: Wang fullname: Wang, Fu-Nien organization: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan – sequence: 15 givenname: Pei-Lun surname: Yu fullname: Yu, Pei-Lun organization: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan – sequence: 16 givenname: Ann-Shyn orcidid: 0000-0001-9668-7115 surname: Chiang fullname: Chiang, Ann-Shyn organization: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan – sequence: 17 givenname: Anthony Yan-Tang surname: Wu fullname: Wu, Anthony Yan-Tang organization: Department and Graduate Institute of Pharmacology, National Taiwan University, Taipei, Taiwan – sequence: 18 givenname: John Jun-Sheng orcidid: 0000-0003-1368-3982 surname: Ko fullname: Ko, John Jun-Sheng organization: Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, Taiwan – sequence: 19 givenname: Charles Pin-Kuang orcidid: 0000-0001-8050-7060 surname: Lai fullname: Lai, Charles Pin-Kuang organization: Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan – sequence: 20 givenname: Tsai-Te orcidid: 0000-0001-6977-2568 surname: Lu fullname: Lu, Tsai-Te email: ttlu@mx.nthu.edu.tw, ttlu@mx.nthu.edu.tw organization: Department of Chemistry, Chung Yuan Christian University, Taoyuan, Taiwan. ttlu@mx.nthu.edu.tw – sequence: 21 givenname: Yunching orcidid: 0000-0001-6228-5169 surname: Chen fullname: Chen, Yunching email: yunching@mx.nthu.edu.tw organization: Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan. yunching@mx.nthu.edu.tw
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Snippet	Abnormal tumour vasculature has a significant impact on tumour progression and response to therapy. Nitric oxide (NO) regulates angiogenesis and maintains...
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SubjectTerms	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 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 Metastases Mice Microenvironments Nanoparticles - chemistry 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
Title	Delivery of nitric oxide with a nanocarrier promotes tumour vessel normalization and potentiates anti-cancer therapies
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