Combination Therapy Utilizing Prodrugs with Protoporphyrin IX Photodynamic Therapy

Posted June 22, 2022

Kelly Standifer, Ph.D., University of Oklahoma Health Science Center
Youngjae You1, Ph.D., The State University of New York, University at Buffalo

Dr. Youngjae You Dr. Youngjae You
Dr. Kelly Standifer Dr. Kelly Standifer

Surgery is a common treatment for people diagnosed with non-invasive bladder cancer; however, there is a high rate of cancer recurrence. To combat this, surgery is often coupled with adjuvant therapies like chemotherapy and bacillus Calmette-Guerin therapy. Both treatments involve direct instillation into the bladder with a catheter. Even with administration of these treatments, issues remain with recurrence and disease progression, as well as off-target effects that may damage healthy tissue, resulting in a need for more selective and effective treatments. Protoporphyrin IX (PpIX) photodynamic therapy (PDT) is a Food and Drug Administration-approved treatment using light-activated compounds to treat tumor cells. PpIX is a light-activated compound that is preferentially formed in the mitochondria of cancer cells, and contains fluorescence properties that can be utilized for imaging and treatment purposes.

With a fiscal year 2016 Peer Reviewed Cancer Research Program Idea Award with Special Focus, Dr. Youngjae You and his team worked to develop a more effective and selective light-based strategy for treatment of early stage bladder cancers targeting cancer cells. Dr. You hypothesized that mitochondria-localizing singlet oxygen (SO)-activatable prodrugs could be activated within cancer cells using PDT, and that this would be a more efficacious treatment with less damage to the bladder. Using clinically available drugs, Dr. You’s team developed several prodrugs that can be activated by SO generated in the mitochondria (PTX, MMC, SN-38, and CA-4). Prodrugs are inactive forms of a drug activated inside the body. These prodrugs were combined with the PpIX-PDT. Dr. You and team administrated the combination therapy in vitro to cancer cells and in a rat model of bladder cancer to determine the uptake of the prodrugs as well as the cytotoxicity and the antitumor properties.

Dr. You found when prodrugs were combined with PpIX-PDT, the cell-killing effects and antitumor responses improved. The team found that the prodrugs only demonstrated cytotoxic effects when coupled with illumination, and these effects are targeted specifically to tumor cells, which reduced off target toxicity. They also determined that to obtain better results, mitochondria targeting is needed, although it is not essential for achieving positive outcomes. The team predicts that improving diffusion in the tumor mass is also important for improving the anti-tumor effects. Continued investigation of these combination therapies could maximize the anti-tumor effect; however, the research team believes their proposed combination strategy could be readily adoptable for clinical application. As PpIX is also used in other cancer types, there are implications that the team’s prodrugs could treat other cancer types in the future.

1 While the terminal administration of this award was handled by Dr. Standifer, Dr. You has been responsible for completion of all scientific work related to the award. This award has resulted in several presentations and a 2019 journal publication in Bioorganic & Medicinal Chemistry Letters titled, “Singlet oxygen-activatable Paclitaxel prodrugs via intermolecular activation for combined PDT and chemotherapy.”

Moses, B, Kazi, M, Irene, L, et al. 2019. Singlet oxygen-activatable Paclitaxel prodrugs via intermolecular activation for combined PDT and chemotherapy. Bioorganic & Medicinal Chemistry Letters 29(12):1537-1540.

Public and Technical Abstracts: Visible Light-Controlled Combination Strategy for Treating Nonmuscle Invasive Bladder Cancers

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Last updated Wednesday, June 22, 2022