Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy

Sijin Guo; Mario Vieweger; Kaiming Zhang; Hongran Yin; Hongzhi Wang; Xin Li; Shanshan Li; Shuiying Hu; Alex Sparreboom; B. Mark Evers; Yizhou Dong; Wah Chiu; Peixuan Guo

doi:10.1038/s41467-020-14780-5

Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy

Sijin Guo, Mario Vieweger, Kaiming Zhang, Hongran Yin, Hongzhi Wang, Xin Li, Shanshan Li, Shuiying Hu, Alex Sparreboom, B. Mark Evers, Yizhou Dong, Wah Chiu, Peixuan Guo

Research output: Contribution to journal › Article › peer-review

78 Scopus citations

Abstract

Paclitaxel is widely used in cancer treatments, but poor water-solubility and toxicity raise serious concerns. Here we report an RNA four-way junction nanoparticle with ultra-thermodynamic stability to solubilize and load paclitaxel for targeted cancer therapy. Each RNA nanoparticle covalently loads twenty-four paclitaxel molecules as a prodrug. The RNA-paclitaxel complex is structurally rigid and stable, demonstrated by the sub-nanometer resolution imaging of cryo-EM. Using RNA nanoparticles as carriers increases the water-solubility of paclitaxel by 32,000-fold. Intravenous injections of RNA-paclitaxel nanoparticles with specific cancer-targeting ligand dramatically inhibit breast cancer growth, with nearly undetectable toxicity and immune responses in mice. No fatalities are observed at a paclitaxel dose equal to the reported LD₅₀. The use of ultra-thermostable RNA nanoparticles to deliver chemical prodrugs addresses issues with RNA unfolding and nanoparticle dissociation after high-density drug loading. This finding provides a stable nano-platform for chemo-drug delivery as well as an efficient method to solubilize hydrophobic drugs.

Original language	English
Article number	972
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14780-5
State	Published - Dec 1 2020

Bibliographical note

Funding Information:
This research was supported by the National Institutes of Health grants R01EB019036 and U01CA207946 to P.G., R01CA195573 to B.M.E. and P.G., and The Ohio State University Comprehensive Cancer Center and the National Institutes of Health grant P30CA016058. The cryo-EM study was supported by P41GM103832 and S10OD021600 to W.C. 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 trials, respectively. We are grateful to Wen-Jui Lee and Yuan-Soon Ho at Taipei Medical University for supporting the in vivo bio-distribution study in Fig. 6a, b, and Supplementary Figure 11. We thank Zhefeng Li from The Ohio State University for helping confocal microscopy experiments, and Catherine Hunt and Lora E. McBride for manuscript preparation. P.G.’s Sylvan G. Frank Endowed Chair position in Pharmaceutics and Drug Delivery is supported by the CM Chen Foundation.

Publisher Copyright:
© 2020, The Author(s).

ASJC Scopus subject areas

Chemistry (all)
Biochemistry, Genetics and Molecular Biology (all)
Physics and Astronomy (all)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-020-14780-5

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title = "Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy",

abstract = "Paclitaxel is widely used in cancer treatments, but poor water-solubility and toxicity raise serious concerns. Here we report an RNA four-way junction nanoparticle with ultra-thermodynamic stability to solubilize and load paclitaxel for targeted cancer therapy. Each RNA nanoparticle covalently loads twenty-four paclitaxel molecules as a prodrug. The RNA-paclitaxel complex is structurally rigid and stable, demonstrated by the sub-nanometer resolution imaging of cryo-EM. Using RNA nanoparticles as carriers increases the water-solubility of paclitaxel by 32,000-fold. Intravenous injections of RNA-paclitaxel nanoparticles with specific cancer-targeting ligand dramatically inhibit breast cancer growth, with nearly undetectable toxicity and immune responses in mice. No fatalities are observed at a paclitaxel dose equal to the reported LD50. The use of ultra-thermostable RNA nanoparticles to deliver chemical prodrugs addresses issues with RNA unfolding and nanoparticle dissociation after high-density drug loading. This finding provides a stable nano-platform for chemo-drug delivery as well as an efficient method to solubilize hydrophobic drugs.",

author = "Sijin Guo and Mario Vieweger and Kaiming Zhang and Hongran Yin and Hongzhi Wang and Xin Li and Shanshan Li and Shuiying Hu and Alex Sparreboom and Evers, {B. Mark} and Yizhou Dong and Wah Chiu and Peixuan Guo",

note = "Funding Information: This research was supported by the National Institutes of Health grants R01EB019036 and U01CA207946 to P.G., R01CA195573 to B.M.E. and P.G., and The Ohio State University Comprehensive Cancer Center and the National Institutes of Health grant P30CA016058. The cryo-EM study was supported by P41GM103832 and S10OD021600 to W.C. 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 trials, respectively. We are grateful to Wen-Jui Lee and Yuan-Soon Ho at Taipei Medical University for supporting the in vivo bio-distribution study in Fig. 6a, b, and Supplementary Figure 11. We thank Zhefeng Li from The Ohio State University for helping confocal microscopy experiments, and Catherine Hunt and Lora E. McBride for manuscript preparation. P.G.{\textquoteright}s Sylvan G. Frank Endowed Chair position in Pharmaceutics and Drug Delivery is supported by the CM Chen Foundation. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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AU - Guo, Sijin

AU - Vieweger, Mario

AU - Zhang, Kaiming

AU - Yin, Hongran

AU - Wang, Hongzhi

AU - Li, Xin

AU - Li, Shanshan

AU - Hu, Shuiying

AU - Sparreboom, Alex

AU - Evers, B. Mark

AU - Dong, Yizhou

AU - Chiu, Wah

AU - Guo, Peixuan

N1 - Funding Information: This research was supported by the National Institutes of Health grants R01EB019036 and U01CA207946 to P.G., R01CA195573 to B.M.E. and P.G., and The Ohio State University Comprehensive Cancer Center and the National Institutes of Health grant P30CA016058. The cryo-EM study was supported by P41GM103832 and S10OD021600 to W.C. 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 trials, respectively. We are grateful to Wen-Jui Lee and Yuan-Soon Ho at Taipei Medical University for supporting the in vivo bio-distribution study in Fig. 6a, b, and Supplementary Figure 11. We thank Zhefeng Li from The Ohio State University for helping confocal microscopy experiments, and Catherine Hunt and Lora E. McBride for manuscript preparation. P.G.’s Sylvan G. Frank Endowed Chair position in Pharmaceutics and Drug Delivery is supported by the CM Chen Foundation. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

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N2 - Paclitaxel is widely used in cancer treatments, but poor water-solubility and toxicity raise serious concerns. Here we report an RNA four-way junction nanoparticle with ultra-thermodynamic stability to solubilize and load paclitaxel for targeted cancer therapy. Each RNA nanoparticle covalently loads twenty-four paclitaxel molecules as a prodrug. The RNA-paclitaxel complex is structurally rigid and stable, demonstrated by the sub-nanometer resolution imaging of cryo-EM. Using RNA nanoparticles as carriers increases the water-solubility of paclitaxel by 32,000-fold. Intravenous injections of RNA-paclitaxel nanoparticles with specific cancer-targeting ligand dramatically inhibit breast cancer growth, with nearly undetectable toxicity and immune responses in mice. No fatalities are observed at a paclitaxel dose equal to the reported LD50. The use of ultra-thermostable RNA nanoparticles to deliver chemical prodrugs addresses issues with RNA unfolding and nanoparticle dissociation after high-density drug loading. This finding provides a stable nano-platform for chemo-drug delivery as well as an efficient method to solubilize hydrophobic drugs.

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Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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