Photodynamic molecular beacon as an activatable photosensitizer based on protease-controlled singlet oxygen quenching and activation.
Molecular beacons are FRET-based target-activatable probes. They offer control of fluorescence emission in response to specific cancer targets, thus are useful tools for in vivo cancer imaging. Photodynamic therapy (PDT) is a cell-killing process by light activation of a photosensitizer (PS) in the presence of oxygen. The key cytotoxic agent is singlet oxygen ((1)O(2)). By combining these two principles (FRET and PDT), we have introduced a concept of photodynamic molecular beacons (PMB) for controlling the PS's ability to generate (1)O(2) and, ultimately, for controlling its PDT activity. The PMB comprises a disease-specific linker, a PS, and a (1)O(2) quencher, so that the PS's photoactivity is silenced until the linker interacts with a target molecule, such as a tumor-associated protease. Here, we report the full implementation of this concept by synthesizing a matrix metalloproteinase-7 (MMP7)-triggered PMB and achieving not only MMP7-triggered production of (1)O(2) in solution but also MMP7-mediated photodynamic cytotoxicity in cancer cells. Preliminary in vivo studies also reveal the MMP7-activated PDT efficacy of this PMB. This study validates the core principle of the PMB concept that selective PDT-induced cell death can be achieved by exerting precise control of the PS's ability to produce (1)O(2) by responding to specific cancer-associated biomarkers. Thus, PDT selectivity will no longer depend solely on how selectively the PS can be delivered to cancer cells. Rather, it will depend on how selective a biomarker is to cancer cells, and how selective the interaction of PMB is to this biomarker.
Zheng
Gang
G
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 1L7. gang.zheng@uhnres.utoronto.ca
Chen
Juan
J
Stefflova
Klara
K
Jarvi
Mark
M
Li
Hui
H
Wilson
Brian C
BC
D045744:Cell Line, Tumor; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry / Q000627:therapeutic use*; D026082:Singlet Oxygen / Q000378:metabolism*; D012996:Solutions
D017319:Photosensitizing Agents; D012996:Solutions; D026082:Singlet Oxygen; D020783:Matrix Metalloproteinase 7