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.
Highlights
Paclitaxel is widely used in cancer treatments, but poor water-solubility and toxicity raise serious concerns
We previously discovered a thermodynamically stable phi[29] pRNA three-way junction (3WJ) motif which has been used as a scaffold to construct multifunctional RNA nanoparticles[25]
As a means to improve RNA nanotechnologies’ capability in delivering high payloads of chemotherapeutic drugs, we intentionally evolved our nanostructure from pRNA-3WJ25 to 4WJ28 to maximize its thermodynamic stability as well as its drug loading capacity
Summary
Paclitaxel is widely used in cancer treatments, but poor water-solubility and toxicity raise serious concerns. RNA nanoparticles can be tuned not to trigger immunostimulation, or to induce strong immune responses that can be potentially used for cancer immunotherapy or as vaccine adjuvant[22,23,24] Taking these advantages into consideration, small chemotherapeutic drugs utilizing RNA nanoparticles as a drug delivery platform could exhibit tumor-specific therapeutic effects and reduce the side effects and toxicity that is currently observed. We previously discovered a thermodynamically stable phi[29] pRNA three-way junction (3WJ) motif which has been used as a scaffold to construct multifunctional RNA nanoparticles[25] This multivalent RNA can be modified with various chemical moieties[26], which makes the covalent conjugation of chemo-drugs to RNA nanoparticles achievable[27]. The limited drug loading capacity can be caused by steric hindrance that interferes with assembly, unfolding of RNA 2D or 3D structures after conjugation, or disassociation of RNA nanoparticles due to reduction of thermostability
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