Singlet Oxygen Activatable Prodrugs of Paclitaxel, SN‐38, MMC and CA4: Nonmitochondria‐Targeted Prodrugs†
Abstract
We established a light‐activatable prodrug strategy that produces the combination effect of photodynamic therapy (PDT) and site‐specific chemotherapy. Prodrugs are activated by singlet oxygen (SO), generated from PS and visible or near IR light, in either intra‐ or inter‐molecular manner. The goal of this study is to evaluate cytotoxic effects of nonmitochondria‐targeted prodrugs of a number of anticancer drugs with different mechanisms of action. They were tested in both 2D and 3D in vitro conditions via inter‐molecular activation of prodrugs by SO generated in mitochondria by protoporphyrin IX‐PDT (PpIX‐PDT). Prodrugs of anticancer drugs (paclitaxel, SN‐38, combretastatin A4 and mitomycin C) were synthesized using facile and high‐yielding reactions. Nonmitochondria‐targeted prodrugs showed limited dark toxicity while all of them showed greatly enhanced phototoxicity compared to PpIX‐PDT in the 2D culture model. Prodrugs generated up to about 95% cell killing at 2.5 μM when administered with hexyl‐aminolevulinate (HAL) to produce Protoporphyrin IX in cancer cells in both 2D monolayer and 3D spheroids model. The data demonstrate that mitochondria‐targeting of prodrugs is not fully essential for our inter‐molecular activation prodrug strategy. The prodrug strategy also worked for anticancer drugs with diverse MOAs.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 11, 2022
- Source ID
- 10.1111/php.13589
Entities
People
- Kazi Md Mahabubur Rahman
- Pritam Thapa
- Robert Hurst
- Sukyung Woo
- Youngjae You
Organizations
- United States Department of Defense
- University at Buffalo
- University of Oklahoma Health Sciences Center