RE:Enhancing cancer immunotherapy with photodynamic therapyThis article would be much improved if only the authors were familiar with Dr. McFarland's work. Dr. McFarland has done a lot to overcome the challenges to effective PDT noted by the authors.
2.3.4 Challenges in translating PDT into clinical practice
The advancement of PDT into clinical application will confront several challenges that necessitate further development and optimization of PSs. Currently, innovative approaches are enhancing the safety and efficacy of PDT in treating malignancies, with research focused on three main strategies (169).
Firstly, there is an effort to create PSs that can effectively produce ROS even in the low-oxygen environments of tumors, thereby overcoming the limitations posed by TME hypoxia.
Secondly, the development of PSs that are selectively activated in TME and the use of tumor-targeted nanocarriers aim to improve the precision of PDT.
Lastly, enhancing the penetration depth of the excitation light is critical for the effectiveness of PDT
Dr. McFarland's group dealt with the first limitation using both osmium and ruthenium photosensitizers:
Breaking the barrier: an osmium photosensitizer with unprecedented hypoxic phototoxicity for real world photodynamic therapy
This paper reports the first metal-based photosensitizer that approaches the ideal properties for a phototherapy agent...These normoxic and hypoxic activities are the largest reported to date, demonstrating the utility of osmium for phototherapy applications. Moreover, Os-4T had a maximum tolerated dose (MTD) in mice that was >200 mg kg-1, which positions this photosensitizer as an excellent candidate for in vivo applications.
Anticancer Agent with Inexplicable Potency in Extreme Hypoxia: Characterizing a Light-Triggered Ruthenium Ubertoxin
This study introduces a ruthenium compound as a light-responsive anticancer agent that is water-soluble, has minimal dark cytotoxicity, is active at concentrations as low as 170 pM in ∼18.5% O2 normoxia and near 10 nM in 1% O2 hypoxia, and exhibits phototherapeutic indices as large as >500,000 in normoxia and >5,800 in 1% O2 hypoxia using broadband visible and monochromatic blue light treatments. These are the largest values reported to date for any compound class.
The second limitation has been dealt with by the development of Rutherrin, which allows TLD1433 to piggyback on transferrin so it can be selectively delivered to cancer cells which over-express transferrin receptors on their surfaces because of their need for the iron normally delivered to them by transferrin.
Dr. McFarland has also been working with Dr. Lilge on radiation activated PDT using nanoparticles which allows far more effective depth of penetration.
High quantum efficiency ruthenium coordination complex photosensitizer for improved radiation-activated Photodynamic Therapy
The third limitation - depth of penetration - has been dealt with by way of Theralase's radiation-activated PDT which can be enhanced with the use of nanoparticles described in the above article.
Dr. McFarland has also continued to develop photosensitizers which are activated by NIR light for greater depth of penetration than green or red light.
Discovery of immunogenic cell death-inducing ruthenium-based photosensitizers for anticancer photodynamic therapy
We report a new class of ruthenium (Ru)-based photosensitizers that induce potent cytotoxicity in melanoma cells following activation with NIR light. In addition to the direct cytotoxic effect, this Ru-based photodynamic therapy induces immunogenic cell death in melanoma cells that can be therapeutically exploited to establish protective antitumor immunity.