Talk abstracts
Talk on Saturday 10:45-11:00am submitted by Kai Jin
Construction of RNA four-way junction to co-deliver RNAi and chemical drugs for efficient treatment of colon cancer lung metastasis with undetectable toxicity
Kai Jin (Division of Pharmaceutics & Pharmacology, College of Pharmacy; Center for RNA Nanotechnology and Nanomedicine; The Ohio State University, Columbus, OH, United States.), Xin Li (Division of Pharmaceutics & Pharmacology, College of Pharmacy; Center for RNA Nanotechnology and Nanomedicine; The Ohio State University, Columbus, OH, United States.), Peixuan Guo (Division of Pharmaceutics & Pharmacology, College of Pharmacy; Center for RNA Nanotechnology and Nanomedicine; The Ohio State University, Columbus, OH, United States.)
Abstract:
RNA therapeutics emerge as the third milestone in pharmaceutical drugs. Here is to report the in vitro and in vivo assessments of the pathology and safety aspects of various RNA nanoparticles, encompassing RNA three-way junction (3WJ) containing 2-F modified pyrimidine, folic acid, and survivin siRNA, as well as RNA four-way junction (4WJ) with 2-F modified pyrimidine and 24 copies of SN38. The investigation involved animal models and patient serum. In vitro studies include hemolysis, platelet aggregation, complement activation, plasma coagulation, and interferon induction. In vivo examinations include hematoxylin and eosin (H&E) staining, hematological and biochemical analysis, serum profiling, and organ weight analysis. The extensive safety evaluations revealed that no significant toxicity, side effects, or immune responses were observed for RNA nanoparticles. The physicochemical foundation guiding the strategic construction of a branched RNA four-way junction (4WJ) nanoparticle was also investigated. The use of the 4WJ leads to enhanced high thermostability and drug payload for cancer therapy, particularly targeting metastatic tumors in the lung. The therapeutic effect of the 4WJ nanostructure functionalized with the anti-cancer chemical drug SN38 and tested in two distinct cancer models: colorectal cancer xenograft and orthotopic lung metastasis of colon cancer. The 4WJ RNA drug complex exhibited effective and spontaneous cancer targeting, demonstrating cancer inhibition. The 4WJ showed swift renal excretion, rapid body clearance, and minimal organ accumulation, with no detectable toxicity or immunogenicity. These findings underscore RNA nanoparticles as effective and safe drug delivery vehicles poised for future clinical translations.
References:
1. Kai Jin, Mitch A. Phelps, et al Yuan-Soon Ho, Peixuan Guo. In Vitro and In Vivo Evaluation of the Pathology and Safety Aspects of Three- and Four-Way Junction RNA Nanoparticles. Molecular Pharmaceutics. 2024, https://doi.org/10.1021/acs.molpharmaceut.3c00845
2. Xin Li, Kai Jin, Mitch A. Phelps, et al Yuan Soon Ho, Peixuan Guo. RNA four-way junction (4WJ) for spontaneous cancer-targeting, effective tumor-regression, metastasis suppression, fast renal excretion and undetectable toxicity. Biomaterials, 2024: 305, 122432, https://doi.org/10.1016/j.biomaterials.2023.122432.
Keywords: RNA Based Therapeutics, RNA Interactions, RNA Drug Conjugation