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 journalArticlepeer-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 languageEnglish
Article number972
JournalNature Communications
Volume11
Issue number1
DOIs
StatePublished - 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)

Fingerprint

Dive into the research topics of 'Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy'. Together they form a unique fingerprint.

Cite this