Photodynamic therapy (
PDT) is an established treatment modality for
cancer.
ADPM06 is an emerging non-
porphyrin PDT agent which has been specifically designed for therapeutic application. Recently, we have demonstrated that ADPM06-PDT is well tolerated in vivo and elicits impressive complete response rates in various models of
cancer when a short
drug-light interval is applied. Herein, the mechanism of action of ADPM06-PDT in vitro and in vivo is outlined. Using a
drug and light combination that reduces the clonogenicity of MDA-MB-231 cells by >90%, we detected a well-orchestrated apoptotic response accompanied by the activation of various
caspases in vitro. The generation of
reactive oxygen species (ROS) upon
photosensitizer irradiation was found to be the key instigator in the observed apoptotic response, with the endoplasmic reticulum (ER) found to be the intracellular site of initial
PDT damage, as determined by induction of a rapid ER stress response post-
PDT.
PDT-induced apoptosis was also found to be independent of p53
tumor suppressor status. A robust therapeutic response in vivo was demonstrated, with a substantial reduction in
tumor proliferation observed, as well as a rapid induction of apoptosis and initiation of ER stress, mirroring numerous aspects of the mechanism of action of
ADPM06 in vitro. Finally, using a combination of (18) F-labeled
3'-deoxy-3'-fluorothymidine ((18) F-FLT) nuclear and optical imaging, a considerable decrease in
tumor proliferation over 24-hr in two models of human
cancer was observed. Taken together, this data clearly establishes
ADPM06 as an exciting novel
PDT agent with significant potential for further translational development.