| Autor: |
Dick M; Princess Margaret Cancer Centre at University Health Network, Toronto, Ontario, Canada., Jamal H; Princess Margaret Cancer Centre at University Health Network, Toronto, Ontario, Canada., Liu YR; Department of Physics, University of Massachusetts Boston, Boston, Massachusetts, USA., Celli JP; Department of Physics, University of Massachusetts Boston, Boston, Massachusetts, USA., Lilge L; Princess Margaret Cancer Centre at University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Electronic address: lothar.lilge@uhnresearch.ca. |
| Jazyk: |
angličtina |
| Zdroj: |
Photodiagnosis and photodynamic therapy [Photodiagnosis Photodyn Ther] 2023 Mar; Vol. 41, pp. 103263. Date of Electronic Publication: 2022 Dec 29. |
| DOI: |
10.1016/j.pdpdt.2022.103263 |
| Abstrakt: |
In vitro dose escalation experiments are one of the first gatekeepers in therapeutic evaluation and development. This also holds for evaluating novel photosensitizers (PS) and Photodynamic Therapy (PDT) co-therapies as needed to provide dose response guidelines before engaging in further pre-clinical studies. The dose needed to achieve 50% cell kill (LD 50 ) is a standard metric to report the potency of a therapeutic agents that is widely accepted for single-drug therapies. In reporting results of PDT experiments, which involve delivery of both drug and light, it is inherently more complicated to identify such a convenient dose response metric that actually captures the larger space of treatment parameters. In addition to ubiquitous sources of biological variability that apply broadly in biomedical research, PDT treatment efficacy is determined by multiple key parameters that may or may not have been documented, including PS concentration and light fluence, where the latter is itself a function of the spectral properties of the light source used (often not described), not to mention dose rate, fractionation and other parameters that potentially vary between individual studies. It is impossible to compare results between two study when, for example one reports LD 50 PS concentration without providing essential light dosimetry details. Motivated by this challenge in comparing outcomes and establishing reproducibility of in vitro PDT studies, we endeavored to perform a meta-analysis of the reporting of PDT results by converting, where possible, the disparately reported experimental details into a consistent metric that could be used to compare across studies. In this context we adopt here the number of photons absorbed by photosensitizers per unit volume to affect a 50% decline in cell survival as a standardized metric. By choosing this metric one can acknowledge the quantum-based generation of cytotoxins. While this metric does not cover every possible source of variability between any two studies, for a PS with known optical properties, this does encapsulate PS concentration as well as irradiance and spectral properties of light delivered. For the sake of focus we adopt this approach for study of reported results with two photosensitizers, Protoporphyrin IX, either synthesized in the cells by aminolevulinic acid or administered exogenously, and Chlorin e6. A literature search was performed to identify in vitro studies with these two photosensitizers and collect necessary information to calculate the absorbed photon LD 50 threshold for each study. Only approximately 1/10 of the manuscripts reporting on in vitro studies provide the minimum required information to calculate the threshold values. While the majority of the determined threshold values are within a factor of 10, the range of threshold values spanned close to 7 orders of magnitude for both photosensitizers. To contrast with single-agent therapies, a similar exercise was performed for chemotherapeutic drugs targeting cellular mitosis or tyrosine kinase inhibitors resulted in an LD 50 or IC 50 range of 1-2 orders of magnitude, with LD 50 or IC 50 values for a single cell line being within a factor of 5. This review underscores challenges in the reporting of in vitro PDT efficacy. In many cases it takes considerable effort to extract the necessary methodology information to make meaningful comparison between PDT studies. Only when results between studies can be compared is it possible to begin to assess reproducibility which, as shown here, can be a major issue. Hence, guidelines need to be developed and enforced through the peer review process for meaningful reporting of preclinical PDT results in order for the most promising sensitizers and co-therapies to be identified and translated into the clinic.
Competing Interests: Declaration of Competing Interest The authors do not declare any conflict of interest with this study.
(Copyright © 2022. Published by Elsevier B.V.) |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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