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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.

Authors:
ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [2]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [3]; ORCiD logo [1]; ORCiD logo [4]; ORCiD logo [1]
  1. The Ohio State Univ., Columbus, OH (United States)
  2. Stanford Univ., CA (United States)
  3. Univ. of Kentucky, Lexington, KY (United States)
  4. Stanford Univ., CA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States)
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1608801
Grant/Contract Number:  
AC02-76SF00515; R01CA195573; U01CA207946; R01EB019036; S10OD021600; P41GM103832
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Guo, Sijin, Vieweger, Mario, Zhang, Kaiming, Yin, Hongran, Wang, Hongzhi, Li, Xin, Li, Shanshan, Hu, Shuiying, Sparreboom, Alex, Evers, B. Mark, Dong, Yizhou, Chiu, Wah, and Guo, Peixuan. Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy. United States: N. p., 2020. Web. doi:10.1038/s41467-020-14780-5.
Guo, Sijin, Vieweger, Mario, Zhang, Kaiming, Yin, Hongran, Wang, Hongzhi, Li, Xin, Li, Shanshan, Hu, Shuiying, Sparreboom, Alex, Evers, B. Mark, Dong, Yizhou, Chiu, Wah, & Guo, Peixuan. Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy. United States. doi:https://doi.org/10.1038/s41467-020-14780-5
Guo, Sijin, Vieweger, Mario, Zhang, Kaiming, Yin, Hongran, Wang, Hongzhi, Li, Xin, Li, Shanshan, Hu, Shuiying, Sparreboom, Alex, Evers, B. Mark, Dong, Yizhou, Chiu, Wah, and Guo, Peixuan. Thu . "Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy". United States. doi:https://doi.org/10.1038/s41467-020-14780-5. https://www.osti.gov/servlets/purl/1608801.
@article{osti_1608801,
title = {Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy},
author = {Guo, Sijin and Vieweger, Mario and Zhang, Kaiming and Yin, Hongran and Wang, Hongzhi and Li, Xin and Li, Shanshan and Hu, Shuiying and Sparreboom, Alex and Evers, B. Mark and Dong, Yizhou and Chiu, Wah and Guo, Peixuan},
abstractNote = {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.},
doi = {10.1038/s41467-020-14780-5},
journal = {Nature Communications},
number = 1,
volume = 11,
place = {United States},
year = {2020},
month = {2}
}

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