The feasibility of using DNA enzyme functionalized liposomes to sensitize hypoxic prostate cancer for radiotherapy
Dr. Runqing Jiang, PhD, MCCPM, Grand River Regional Cancer Centre; University of Waterloo; University of Guelph
Ubiquitously observed low oxygen-level, hypoxia, in solid tumors induces resistance to radiation therapy (RT), because the efficacy of the ionization radiation on deactivating tumor cells is highly dependent on the oxygen level in tumor tissues. Tumor oxygenation can mitigate this resistance, thus improving the effectiveness of RT. Recently, enzymes such as catalase and peroxidase that decompose the high concentration of hydrogen peroxide in tumors to generate oxygen were demonstrated promising in overcoming the hypoxia-induced resistance in solid tumors; however, these proteinaceous enzymes are chemically unstable, costly, and have short shelf-lives. In this project, we will test the feasibility of using a peroxidase-like DNAzyme, instead of the proteinaceous enzyme. The DNAzyme is made from guanine-rich oligoDNA sequences that bind hemin, the same cofactor as in the proteinaceous enzymes, and thus exhibit similar enzymatic activity; however, the DNAzyme is more stable, easier to synthesize, and more cost-effective than peroxidase. We will test the effectiveness of DNAzymes that are encapsulated within liposome nanoparticles for sensitizing RT in a prostate cancer cell model, in contrast to various controls. The new knowledge developed in this project will benefit both the researchers for further tests and the patients in the future.
Hypoxia-associated radiotherapy resistance is a significant challenge that prevents effective treatment of various solid tumors, e.g., prostate cancer, by ionizing radiation. We hypothsize that the G4-DNAzymes may be effective in tumor oxygenation thus sensitizing radiotherapy towards hypoxic solid tumor. Therefore, the objective of this project is to test if G4-DNAzymes could be used to sensitize hypoxic prostate cancer for more effective radiotherapy. To evaluate the effectiveness of the nanocomposites on overcoming the hypoxia issue, cell will be cultured under hypoxic conditions in a “Hypoxia Incubator Chamber” (from Stemcell Technologies Inc.). We plan to use liposomes, a US FDA approved drug-delivery nanomaterial, as the delivery vehicle to encapsulate hemin/G4-DNAzyme that will be anchored to gold nanoparticles (AuNPs), forming a spherical hemin/G4@AuNP@liposome core-shell composite. By combining the high-Z value of the AuNPs to enhance the radiation ionization capability with the peroxidise-like activity of the G4-DNAzyme to overcome tumor hypoxia, the nano-composite may enhance radiotherapy effectiveness for solid prostate cancer. We will focus on evaluation of the efficacy of these hemin/G4@AuNP@liposomes for radiotherapy in human prostate cancer cellular models (cell line PC-3 from American Type Culture Collection). Further testing with animal models may be performed in the future.
Impact on prostate cancer patients:
The overall objective of my research program is to achieve long term survival and less radiotoxicity associated with the health tissue with targeted radiation therapy. The current nanotechnology project is proposed to enhance the efficacy of the radiotherapy towards hypoxic prostate cancer. The results of the research may provide important insights into the development of biocompatible and cost-effective nanomedicine to facilitate precision prostate cancer treatment.