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 | |
| State | Published - Dec 1 2020 |
Bibliographical note
Publisher Copyright:© 2020, The Author(s).
Funding
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.
| Funders | Funder number |
|---|---|
| CM Chen Foundation | |
| Ohio State University Comprehensive Cancer Center | P30CA016058 |
| National Institutes of Health (NIH) | R01CA195573, R01EB019036 |
| Foundation for the National Institutes of Health | |
| National Childhood Cancer Registry – National Cancer Institute | U01CA207946 |
| National Institute of General Medical Sciences | S10OD021600, P41GM103832 |
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy
