PI-103 modification and pH-sensitive linkage to 3WJ-pRNA for folate guided drug delivery into cancer cells
T2019-179 Modification to PI3K/mTOR inhibitor, PI-103, for conjugation to RNA nanoparticles for targeted drug delivery to cancer cells via folate receptor targeting.
Emerging nanotechnologies promise new treatment approaches for patients with metastatic cancer. However, since the approval of Doxil over 20 years ago, the possibility of engineering nanoparticles that selectively detect and destroy cancer cells in the body remains only a concept and the clinical potential of nanotechnology has not been fully realized. Polyvalent RNA nanoparticles have demonstrated metastatic tumor homing without accumulation in normal organ tissues surrounding metastatic tumors; the flexibility in constructing trimers also enables the assembly of polyvalent nanoparticles to carry drug molecules for therapeutic purposes. The activation of the phosphoinositide 3-kinase (PI3K)/mTOR signaling pathway is one the most frequent genetic events in colorectal cancer cells (CRC). Given the importance of PI3K signaling in cancer, pharmacological inhibition of PI3K is considered to be among the most promising strategies in drug development for cancer therapy.
Researchers at Ohio State have developed a novel pH-sensitive, cell-specific dual PI3K/mTOR inhibitor, PI-103, drug delivery methodology that enables the targeting therapeutic drugs to folate receptor-expressing cancer cells. Modifications to PI-103 have allowed for conjugation to RNA nanoparticles. An improvement was the addition of pH-sensitive intracellular drug delivery by folate receptor targeting (FA)-3WJ-PI-103 nanoparticles in cancer cells. RNA-PI-103 cancer cell-specific drug delivery has the potential to provide a clinically relevant tool to address the problems associated with traditional chemotherapy. The RNA-PI-103 metastasis treatment platform is expected to outperform current treatment approaches in several aspects. First, pRNA-PI-103 nanoparticles have defined size, structure and stoichiometry. Unpredictable side effects arising from heterogeneous materials can thus be avoided. Second, FA-pRNA-PI-103 has improved potency and effectiveness to target and deliver a toxic payload to the selected diseased tissue through receptor mediated drug delivery. The reasoning for the combination of the unique targeting abilities of pRNA with PI-103 is to reduce toxicity associated with PI3K/Akt pathway inhibition through receptor-specific drug delivery. Finally, pH-sensitive PI-103 drug release from FA-pRNA-PI-103 nanoparticles is superior to current methods. Solid tumors have an acidic extracellular environment and an altered pH gradient across their cell compartments. Nanoparticles responsive to the pH gradients are promising for cancer drug delivery; pH-responsive nanoparticles have therapeutic advantages over the conventional pH-insensitive counterparts.
- Drug Delivery
- Unpredictable side effects avoided due to consistent size of nanoparticles
- Improved potency and effectiveness to target and deliver toxic payload to disease tissue
- pH-sensitive drug release from nanoparticles