The use of pulsed versus continuous-wave (CW) lasers was investigated in the early days of PDT and the consensus reached was that pulsed lasers did not offer any significant advantage over CW lasers. It is now very exceptional to find PDT studies with pulsed lasers because CW lasers are more affordable and simpler to use. However, the comparison between pulsed and CW lasers in PDT was empirical rather than based on the design of the best approach for each type of laser. Here, we show that when the use of pulsed and CW lasers is compared using the maximum tolerated doses allowed for each type of laser, rather than compared using the same light dose, pulsed lasers promote safer treatments of larger tumors.
We show that, when photosensitizers with high absorption cross-sections are employed, pulsed lasers saturate absorption over a depth of 1 cm, and can be dosed to obtain a selectivity towards tumor tissue matching the biodistribution of the photosensitizer. The increased selectivity offered by pulsed lasers allows for the use of higher light doses. Using the same laser wavelength, we show that the light dose delivered by pulsed lasers, expressed in J/cm2, can be increased one order of magnitude relative to the light dose that leads to lethality in mice when CW lasers are employed. The increase the light dose without phototoxicity enabled by pulsed lasers, allows for the delivery of more photons deeper in the tumor tissue. This will change the paradigm of PDT and we name this new modality as Flash-PDT.
Acknowledgments
We thank the Portuguese Science Foundation (UID/QUI/00313/2020, PTDC/QUI-OUT/0303/2021) and European Regional Development Fund (CENTRO-01-0145-FEDER-181218) for financial support.