RE:Why was TLD1433 preferred over TLD1633?Well, found this for starters, not quite what I remember, but then again forgetting things seems to be getting easier and easier the older I get. This is excerpt from August 22, 2017 news release from TLT . I will keep looking, but I think the highlighted part should be known by every oncologist in the world.
The most advanced PDC, TLD-1433, developed by McFarland and Theralase, has successfully achieved the primary, secondary and exploratory endpoints in the first part of a Phase 1b human clinical trial, at the Maximum Recommended Starting Dose (0.35 mg/cm2) (“MRSD”) in the first 3 patients treated, for Non-Muscle Invasive Bladder Cancer (“NMIBC”), evaluated at 90 days post treatment.
The elegant computational Study on the family of PDCs, which includes TLD-1433, has used the orthogonal approach of Time-Dependent Density Functional Theory (“TDDFT”) to quantum-mechanically validate McFarland’s experimental findings with regard to Type I/II dual-mode PDT effects and highly specialized excited states.
The Study highlights the ability of TLD-1433, and its associated family of PDCs. to invoke PDT effects even at low oxygen concentrations by exploiting multiple PDT pathways and further validates, on a very sophisticated level, the criteria McFarland previously outlined for producing these unique effects. The unprecedented PDT potencies and unique dual-mode mechanisms of the McFarland-Theralase PDCs are well positioned to finally bring PDT to the forefront of cancer therapy.
Currently, McFarland and Theralase continue to push the boundaries of PDC development by introducing PDC supercatalysts. These so-called supercatalysts maintain dual-mode Type I/II photoreactivity and produce femtomolar PDT effects with no sacrificial co-catalysts. These first-of-their-kind PDCs exploit the fundamental principles of photophysics and supercatalysis to achieve extraordinarily large therapeutic effects.
In comparative analysis evaluations completed by McFarland, the Theralase PDCs are approximately a billion times more potent than a commonly used anti-cancer chemotherapy drug, Cisplatin, when laser light activated.
Eoganacht wrote: The answer is in
Dr. McFarland's (and
Dr. Lilge's) paper describing the development of
TLD1433. The entire text is available online at:
Transition Metal Complexes and Photodynamic Therapy from a Tumor-Centered Approach: Challenges, Opportunities, and Highlights from the Development of TLD1433 "...Our current hypothesis is that TLD1433 and TLD1633 act as supercatalysts, producing more than one ROS or other reactive species per photon absorbed per molecule when electron-transfer reactions are involved ...
Considering the potency of TLD1633, it may seem odd that TLD1433 was selected instead. TLD1433 was prioritized over the other compound for a number of reasons, including:
(1) there were more synthetic steps required for producing TLD1633, and those steps were low yielding (unoptimized at that time) and required expensive catalysts,
(2) there was more batch-to-batch variability with TLD1633,
(3) the theranostic capacity of TLD1433 was greater (i.e., its luminescence quantum yield was higher), and
(4) we were relatively far along in our pre-clinical studies with TLD1433 by the time the synthesis of TLD1633 was optimized to produce the larger batches required for in vivo studies...."