Ionizing radiation has unlimited tissue penetration and has already become a part of routine cancer therapy. Recent advances in the delivery of γ-radiation therapy (RT) such as 3-dimensional conformal (3-DCRT), intensity-modulated (IMRT), image-guided (IGRT), and stereotactic (i.e. SAbR, CyberKnife, Gamma Knife etc.) radiosurgery allow for highly localized dosing within tumor tissue anywhere in the body, while sparing the surrounding healthy tissue. When combined, these features make targeted drug release and/or activation using ionizing radiation highly tractable and desirable. Targeted activation of therapeutics by RT is still a relatively nascent field. In addition, the avenue of synergistic combination of these activated therapeutics with the body’s immune response to radiotherapy is still unknown. To that end, we have been investigating drug and RNA release from a non-infectious virus-like particle (VLP) called Qβ and found that RT can trigger the release of the clinically relevant drug doxorubicin, as well as shed fragments of RNA, which we believe will synergistically generate a local immune response in the tumor environment.
Our central hypothesis is that optimized macromolecular single-stranded RNA can be degraded under very low doses of RT to release small immunogenic strands of RNA as well as small molecule drugs from the inside of a porous VLP capsid that are linked to the capsid via tRNA.
This ongoing project is essential because it exploits advancing technologies on focused RT to create nanoscopic drug carriers that can be activated at any tissue depth. Further, ionizing radiation is being applied for the first time to activate RNA degradation for drug release from a novel drug delivery tool, and has been used for potential role in immunomodulation.