TY - JOUR
T1 - Multivalent rubber-like RNA nanoparticles for targeted co-delivery of paclitaxel and MiRNA to silence the drug efflux transporter and liver cancer drug resistance
AU - Wang, Hongzhi
AU - Ellipilli, Satheesh
AU - Lee, Wen Jui
AU - Li, Xin
AU - Vieweger, Mario
AU - Ho, Yuan Soon
AU - Guo, Peixuan
N1 - Funding Information:
The work was supported by NIH grant CA207946 to P.G. and CA016058 to OSU campus Microscopy and Imaging Facility. We thank the Analytical Cytometry Shared Resource, the Campus Microscopy and Imaging Facility, and the University Laboratory Animal Resources Facilitates at The Ohio State University Comprehensive Cancer Center for supporting flow cytometry analysis, confocal microscopy, and animal facility, respectively. We appreciate Dr. Daniel Binzel and Nicolas Burns in manuscript preparation. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funding to Peixuan Guo's Endowed Chair in Nanobiotechnology position is from the William Fairish Endowment Fund.
Funding Information:
The work was supported by NIH grant CA207946 to P.G. and CA016058 to OSU campus Microscopy and Imaging Facility. We thank the Analytical Cytometry Shared Resource , the Campus Microscopy and Imaging Facility , and the University Laboratory Animal Resources Facilitates at The Ohio State University Comprehensive Cancer Center for supporting flow cytometry analysis, confocal microscopy, and animal facility, respectively. We appreciate Dr. Daniel Binzel and Nicolas Burns in manuscript preparation. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH . The funding to Peixuan Guo's Endowed Chair in Nanobiotechnology position is from the William Fairish Endowment Fund .
Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2021/2/10
Y1 - 2021/2/10
N2 - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Analogous to the border customs, liver mainly functions as a filter to detoxify chemicals and metabolite administered orally or intravenously. Besides, the liver cancer cells overexpress the drug exporters which cause high drug effluxion from liver cancer cells, leading to chemoresistance and a diminished chemotherapeutic effect on liver cancer. Recently, we found that RNA nanoparticles display rubber-like property that can rapidly deliver therapeutics to tumor site efficiently and the rest of the RNA nanoparticle were cleared by renal excretion within half hour after systemic injection. Therefore, we designed a new multivalent RNA nanoparticle harboring three copies of hepatocyte targeting-ligands, one copy of miR122, and 24 copies of Paclitaxel to overcome the drug effluxion and chemoresistance thus, synergistically treating HCC. The hepatocyte targeting ligands introduce tumor specificity to the RNA nanoparticles as they selectively bind and internalize into liver cancer cells. The rubber-like RNA nanoparticles allow for enhanced targeting ability to the HCC tumors. The RNA nanoparticles carrying miR122 and PTX were delivered to the liver cancer cells efficiently due to their rubber-like property to enhance their EPR as well as the receptor-mediated endocytosis by hepatocyte targeting-ligands. The miR122 efficiently silenced the drug exporters and the oncogenic proteins. The synergistic effect between miR122 and PTX was confirmed by HSA (Highest Single Agent) synergy model. IC50 was determined to be 460 nM. In vivo studies on mice xenografts revealed that the RNA nanoparticle predominantly accumulated in HCC tumor sites and efficiently inhibited the tumor growth after multiple IV injection. This demonstrates the potential of the rubber-like multivalent RNA nanoparticles to conquest the liver cancer, a currently incurable lethal disease.
AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Analogous to the border customs, liver mainly functions as a filter to detoxify chemicals and metabolite administered orally or intravenously. Besides, the liver cancer cells overexpress the drug exporters which cause high drug effluxion from liver cancer cells, leading to chemoresistance and a diminished chemotherapeutic effect on liver cancer. Recently, we found that RNA nanoparticles display rubber-like property that can rapidly deliver therapeutics to tumor site efficiently and the rest of the RNA nanoparticle were cleared by renal excretion within half hour after systemic injection. Therefore, we designed a new multivalent RNA nanoparticle harboring three copies of hepatocyte targeting-ligands, one copy of miR122, and 24 copies of Paclitaxel to overcome the drug effluxion and chemoresistance thus, synergistically treating HCC. The hepatocyte targeting ligands introduce tumor specificity to the RNA nanoparticles as they selectively bind and internalize into liver cancer cells. The rubber-like RNA nanoparticles allow for enhanced targeting ability to the HCC tumors. The RNA nanoparticles carrying miR122 and PTX were delivered to the liver cancer cells efficiently due to their rubber-like property to enhance their EPR as well as the receptor-mediated endocytosis by hepatocyte targeting-ligands. The miR122 efficiently silenced the drug exporters and the oncogenic proteins. The synergistic effect between miR122 and PTX was confirmed by HSA (Highest Single Agent) synergy model. IC50 was determined to be 460 nM. In vivo studies on mice xenografts revealed that the RNA nanoparticle predominantly accumulated in HCC tumor sites and efficiently inhibited the tumor growth after multiple IV injection. This demonstrates the potential of the rubber-like multivalent RNA nanoparticles to conquest the liver cancer, a currently incurable lethal disease.
KW - 6-way junction
KW - Hepatocyte targeting ligands
KW - Liver cancer therapy
KW - Paclitaxel, MiRNA 122
KW - RNA nanotechnology
UR - http://www.scopus.com/inward/record.url?scp=85098216073&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098216073&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2020.12.007
DO - 10.1016/j.jconrel.2020.12.007
M3 - Article
C2 - 33316298
AN - SCOPUS:85098216073
SN - 0168-3659
VL - 330
SP - 173
EP - 184
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -
