TY - JOUR
T1 - Nanoparticle Delivery of miR-122 Inhibits Colorectal Cancer Liver Metastasis
AU - Sendi, Hossein
AU - Yazdimamaghani, Mostafa
AU - Hu, Mengying
AU - Sultanpuram, Nikhila
AU - Wang, Jie
AU - Moody, Amber S.
AU - McCabe, Ellie
AU - Zhang, Jiajie
AU - Graboski, Amanda
AU - Li, Liantao
AU - Rojas, Juan D.
AU - Dayton, Paul A.
AU - Huang, Leaf
AU - Wang, Andrew Z.
N1 - Funding Information:
Research reported in this manuscript was supported by the NCI/NIH U54CA198999, University of North Carolina Research Opportunity Initative, and University Cancer Research Fund. H. Sendi was supported by NIH T32CA196589. The authors thank Charlene Santos and her team at UNC Animal Core Facility for their help with animal surgeries and procedures.
Funding Information:
Health, grants from National Institutes of Health, and grants from University of North Carolina Research Opportunity Initiative during the conduct of the study; other support from Capio Biosciences and other support from Archimmune Therapeutics outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
H. Sendi reports grants from National Cancer Institute and grants from National Cancer Institute during the conduct of the study. J.D. Rojas reports other support from SonoVol during the conduct of the study and other support from SonoVol outside the submitted work. P.A. Dayton reports grants and other support from SonoVol, Inc. during the conduct of the study; other support from SonoVol, Inc., other support from Triangle Biotechnology, Inc., and other support from Sonovascular outside the submitted work; in addition, P.A. Dayton has a patent for WO2016/118947A1 pending, issued, licensed, and with royalties paid from SonoVol, Inc. and a patent for US9532769 issued, licensed, and with royalties paid from SonoVol, Inc. A.Z. Wang reports grants from National Institutes of
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Liver metastasis is a leading cause of cancer morbidity and mortality. Thus, there has been strong interest in the development of therapeutics that can effectively prevent liver metastasis. One potential strategy is to utilize molecules that have broad effects on the liver microenvironment, such as miR-122, a liver-specific miRNA that is a key regulator of diverse hepatic functions. Here we report the development of a nanoformulation miR-122 as a therapeutic agent for preventing liver metastasis. We engineered a galactose-targeted lipid calcium phosphate (Gal-LCP) nanoformulation of miR-122. This nanotherapeutic elicited no significant toxicity and delivered miR-122 into hepatocytes with specificity and high efficiency. Across multiple colorectal cancer liver metastasis models, treatment with Gal-LCP miR-122 treatment effectively prevented colorectal cancer liver metastasis and prolonged survival. Mechanistic studies revealed that delivery of miR-122 was associated with downregulation of key genes involved in metastatic and cancer inflammation pathways, including several proinflammatory factors, matrix metalloproteinases, and other extracellular matrix degradation enzymes. Moreover, Gal-LCP miR-122 treatment was associated with an increased CD8+/CD4+ T-cell ratio and decreased immunosuppressive cell infiltration, which makes the liver more conducive to antitumor immune response. Collectively, this work presents a strategy to improve cancer prevention and treatment with nanomedicine-based delivery of miRNA.
AB - Liver metastasis is a leading cause of cancer morbidity and mortality. Thus, there has been strong interest in the development of therapeutics that can effectively prevent liver metastasis. One potential strategy is to utilize molecules that have broad effects on the liver microenvironment, such as miR-122, a liver-specific miRNA that is a key regulator of diverse hepatic functions. Here we report the development of a nanoformulation miR-122 as a therapeutic agent for preventing liver metastasis. We engineered a galactose-targeted lipid calcium phosphate (Gal-LCP) nanoformulation of miR-122. This nanotherapeutic elicited no significant toxicity and delivered miR-122 into hepatocytes with specificity and high efficiency. Across multiple colorectal cancer liver metastasis models, treatment with Gal-LCP miR-122 treatment effectively prevented colorectal cancer liver metastasis and prolonged survival. Mechanistic studies revealed that delivery of miR-122 was associated with downregulation of key genes involved in metastatic and cancer inflammation pathways, including several proinflammatory factors, matrix metalloproteinases, and other extracellular matrix degradation enzymes. Moreover, Gal-LCP miR-122 treatment was associated with an increased CD8+/CD4+ T-cell ratio and decreased immunosuppressive cell infiltration, which makes the liver more conducive to antitumor immune response. Collectively, this work presents a strategy to improve cancer prevention and treatment with nanomedicine-based delivery of miRNA.
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U2 - 10.1158/0008-5472.CAN-21-2269
DO - 10.1158/0008-5472.CAN-21-2269
M3 - Article
C2 - 34753773
AN - SCOPUS:85122342686
VL - 82
SP - 105
EP - 113
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 1
ER -