Flash Photodynamic Therapy - How the Saturation of Photosensitizer Absorption Enables Selective and Deeper Tumor Treatments

Sep 29, 2026

Flash photodynamic therapy (FLASH-PDT) is highlighted for its ability to spare normal tissues while preserving tumor-destroying efficacy compared with continuous radiation delivery. A theoretical model explains how pulsed lasers, together with photosensitizers, can achieve selective and deeper tumor ablation when photosensitizer absorption is saturated. Pulse number requirements for tumor destruction and normal-tissue sparing are validated in CT26 and 4T1 tumor models, including improved survival with redaporfin, supporting higher drug or light doses without harming healthy tissues.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Introduction

Flash therapies in radiotherapy and PDT selectivity

PDT mechanism and photosensitizer roles

Comparison of continuous-wave and pulsed laser PDT studies

Rationale for saturation and modeling approach

RESEARCH ARTICLE [www.advancedscience.com](www.advancedscience.com) Flash Photodynamic Therapy – How the Saturation of Photosensitizer Absorption Enables Selective and Deeper Tumor Treatments Luis G. Arnaut,* Fábio A. Schaberle, José Sereno, and Lígia C. Gomes-da-Silva FLASH therapies are attracting tremendous interest because they spare normal tissues while maintaining tumor-destroying eﬃcacy, when compared with continuous delivery of radiation. In Photodynamic Therapy (PDT), it has been noted that continuous-wave and pulsed lasers give comparable results for a variety of tumors, but the conditions for increased tumor-to-peritumoral tissue selectivity have never been reported. This work presents a model that explains how pulsed lasers, in combination with photosensitizers, can oﬀer selective and in-depth tumor ablation. It is shown that the photosensitizer absorption must be saturated to obtain the FLASH eﬀect. The importance of the number of laser pulses to destroy tumor tissue and spare normal tissue is demonstrated. The predictions of the model and the superiority of FLASH-PDT are validated with the treatment of subcutaneous CT26 and orthotopic 4T1 tumors models. Notably, FLASH-PDT with redaporﬁnsigniﬁcantly increases the overall survival of mice with 4 mm orthotopic 4T1 tumors and lung metastasis. FLASH-PDT allows for the use of order-of-magnitude higher drug or light doses without aﬀecting healthy tissues, while promoting selective and deeper tumor treatments. probability curves. In radiotherapy (RT), the radiation dose that kills normal tissues in only 1.5 to 3 times higher than that required to kill tumor cells. [1] The delivery of ultrahigh dose-rate radiation, named FLASHRT,[2] was shown to damage tumor cells with the same eﬃciency as the conventional delivery of radiation, but to spare ~~more~~ normal tissue, allowing for the use of 20–30% higher doses with the same toxicity.[3] Differences in reactive oxygen species (ROS) seem to account for diﬀerences in FLASH and conventional radiotherapies, but this is still a matter of debate. [4] ROS also mediates the photodynamic eﬀect. Continuous and pulsed laser sources have been investigated in PDT, but FLASH selectivity in PDT has never been reported. PDT uses red/infrared light to excite a photosensitizer molecule in the presence of molecular oxygen (3 O2 ), to generate ROS and trigger cell death. Photosensitizer development was driven by the maximization of intense electronic 1. Introduction Continuous sources used in radiotherapy (electrons, protons, ionizing photons) or in photodynamic therapy (non-ionizing photons) are associated with narrow separations between the tumor control probability and the normal tissue complication L. G. Arnaut, F. A. Schaberle, L. C. Gomes-da-Silva CQC-IMS Department of Chemistry University of Coimbra Coimbra 3004-535, Portugal E-mail: [lgarnaut@ci. uc.pt](lgarnaut@ci. uc.pt) J. Sereno Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT) University of Coimbra Coimbra 3000-548, Portugal The ORCID identiﬁcation number(s) for the author(s) of this article can be found under [https://doi.org/10.1002/advs.202513199](https://doi.org/10.1002/advs.202513199)[ ](https://doi.org/10.1002/advs.202513199)© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. DOI: 10.1002/advs.202513199 transitions in the phototherapeutic window (650–850 nm), where photons with suﬃcient energy to generate ROS penetrate more deeply in human tissues. [5] Singlet states have lifetimes (􀀂S ) that are too short to react with 3 O2 , and ROS precursors are the photosensitizers triplet states. Solid tumor responses to PDT with continuous-wave (CWPDT) or pulsed lasers were typically compared using the sa

FAQs

What key condition enables the FLASH effect in photodynamic therapy?

Photosensitizer absorption must be saturated to obtain the FLASH effect.

How does FLASH-PDT differ from conventional delivery in terms of treatment depth and selectivity?

FLASH-PDT enables selective and deeper tumor treatments while sparing normal tissue compared with continuous delivery.

Which tumor models were used to validate the model predictions?

The model predictions and the superiority of FLASH-PDT were validated using subcutaneous CT26 and orthotopic 4T1 tumor models, with redaporfin increasing overall survival in 4 mm orthotopic 4T1 tumors and lung metastasis.

Sep 29, 2026

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