A dual therapeutic system based on corrole-siRNA conjugates

Abstract

Corrole molecules are a new generation of photosensitizers (PS) due to their ease of tunability for different medical applications. Their ability to initiate cellular death using a wide range of non-toxic wavelengths allows for the creation of non-invasive treatments. This work focuses on creating potent and non-invasive treatments by advancing siRNA therapeutics by directly conjugating siRNAs with the photosensitizer, corrole. Combining gene silencing with photodynamic therapy (PDT) creates a non-invasive dual therapy system. Basic synthetic designs were explored to create novel corrole-phosphoramidites and from these, a small library of corrole-functionalized short interfering RNAs (corrole-siRNAs) were synthesized. Corrole-siRNA conjugates showed promising results when evaluated for gene silencing and PDT therapy in vitro. Gene silencing effects were evaluated in cells by measuring the knockdown activity of the firefly luciferase reporter gene. Gene silencing studies from four siRNAs showed promising dose dependent knockdown with IC₅₀s of 387.8, 77.8, 60.0, and 49.4 pM in the absence of red light, and 101.0, 57.2, 55.3, and 23.8 pM in the presence of red light. Furthermore, PDT showed approximately a 50% decrease in cell viability for red-light irradiated cells treated with corrole-siRNAs, demonstrating the effective role of corrole to act as a photosensitizer while still maintaining robust siRNA activity. In conclusion, corrole-siRNAs show a promising path for developing novel siRNA combination therapy.