Annals of photodynamic therapy: Publish and/or Perish?

The current situation with regard to journal publishing is markedly different from the days when everything was done by mail and subscriptions paid the costs. In even earlier times, i.e., the era of Darwin, scientists tended to publish their findings in book form only after prolonged investigations. Now, publishing is Big Business, scavengers troll the internet for evidence of questionable data to report, significant numbers of CHF can be exchanged for access to journals and reviewing can be hazardous. In the era of the internet, appearance of a report with significant errors missed by reviewers can lead to 'publish AND perish'.

Highways and detours in the realm of photodynamic therapy for cancer control.

Critical elements of photodynamic therapy are a photosensitizing agent, light at a wavelength corresponding to an absorbance band of the agent, and sufficient oxygenation to create a cytotoxic concentration of reactive oxygen species. Other factors may promote efficacy, but these are critical.

Highways and Detours in the Realm of Photodynamic Therapy.

Photodynamic therapy (PDT) has been a topic of interest since the first report in 1900 but has yet to become a 'mainstream' treatment protocol in the medical field. There are clear indications for which PDT might be the 'method of choice', but it is unlikely that there will be protocols for the treatment of systemic disease. This report discusses recent developments for promoting PDT efficacy, in the context of what is already known. Factors that can limit the scope of these applications are also indicated. Among the more interesting of these developments is the use of formulation techniques to target specific organelles for photodamage. This can enhance responses to PDT and circumvent situations where an impaired death pathway interferes with PDT efficacy.

Sites of sub-cellular photodamage: Apoptotic and autophagic responses.

Log dose-response curves relating to the effect of mitochondrial photodamage on clonogenic survival using benzoporphyrin derivative. With wild-type cells, autophagy produces a "shoulder" on the curve which is absent when an ATG5 knockdown is examined. Loss of ATG5 prevents the process of autophagy, which is seen to be cytoprotective.

Critical PDT theory: Viability, cytotoxicity, proliferation and clonogenicity-Is there a difference?

Comparison of MTT versus clonogenic effects of photodynamic therapy in MCF-7c3 breast cancer cells in culture. Left: MTT data; right clonogenic data. A collection of photosensitizers was used to produce these results.

Critical PDT Theory V: What it Takes.

First evidence for an apoptotic response to photodamage provided by Oleinick's group in 1991.

Critical PDT theory VII: The saga of ruthenium.

Recent studies involving photosensitizing agents containing ruthenium (Ru) are interpreted as an indication that this approach might be useful for treatment of bladder cancer. The absorbance spectrum of such agents tends to be limited to wavelengths < 600 nm. While this can spare underlying tissues from photodamage, this will limit applications to instances where only a thin layer of malignant cells is present. Among the more potentially interesting results is a protocol that uses only Ru nanoparticles. Other issues in Ru-based photodynamic therapy are discussed including the limited absorbance spectrum, questions relating to methodology and a general lack of details concerning localization and death pathways.

Critical PDT Theory VII: Preclinical Translation.

The translation of photodynamic effects into clinical practice is a complex process that involves the pharmacokinetics of photosensitizing agents, light dosimetry and oxygenation levels. But even the 'translation' of basic photobiology into meaningful preclinical information can be challenging. Some thoughts on directions for progress in clinical trials are suggested.

Adventures in Photodynamic Therapy: Location, Location, Location.

In the context of photodynamic therapy, reports periodically turn up in journals where reviewers are apparently unacquainted with the essentials. Bizarre procedures and results can thereby appear. This appears to be a byproduct of the publishing industry, especially for some of the "pay to play" options.

Critical PDT Theory VI: Detection of Reactive Oxygen Species: Trials and Errors.

Fluorescence intensity of DCFH-DA in hepatoma 1c1c7 cells after 10 min incubations.

Photodynamic Therapy: Critical PDT Theory.

Photodynamic therapy can be useful for the eradication of malignant cells at sites that are accessible to light delivery. There are few adverse effects, with many clinical reports indicating that PDT has curative potential. Patients with minimal disease, where success is more likely, are also sought by those promoting other protocols. New photosensitizing agents that initiate light-catalyzed reactions continue to be discovered. Reports describing advances in understanding fundamental aspects of photobiology are always of interest. But, implications for treatment of neoplasia and other diseases are not always justified, especially when poorly penetrating wavelengths of light are employed, often at very high light doses. Efficacy is sometimes estimated by protocols that may not accurately measure photokilling. Many reports claiming potential clinical relevance for in vitro observations are based on a limited understanding of the determinants of clinical efficacy. The future of photodynamic therapy depends on an appreciation of what can be accomplished, especially when used with other modalities, but will also depend on the goals and interests of granting agencies, pharmaceutical groups, and clinical personnel. This commentary is intended to provide some thoughts on current research efforts, especially where clinical implications are suggested, hinted at or otherwise implied.

Critical PDT Theory IV: The Strange Case of "KillerRed".

"Nobody expects the Spanish Inquisition." The color red has often been associated with danger and other adverse events. In the recent literature, the protein "KillerRed" has been proposed as a means for lethally sensitizing neoplastic cells and tissues to light. A somewhat different perspective on the feasibility of this approach is offered.

Photochemical Targeting of Mitochondria to Overcome Chemoresistance in Ovarian Cancer †.

Ovarian cancer is the most lethal gynecologic malignancy with a stubborn mortality rate of ~65%. The persistent failure of multiline chemotherapy, and significant tumor heterogeneity, has made it challenging to improve outcomes. A target of increasing interest is the mitochondrion because of its essential role in critical cellular functions, and the significance of metabolic adaptation in chemoresistance. This review describes mitochondrial processes, including metabolic reprogramming, mitochondrial transfer and mitochondrial dynamics in ovarian cancer progression and chemoresistance. The effect of malignant ascites, or excess peritoneal fluid, on mitochondrial function is discussed. The role of photodynamic therapy (PDT) in overcoming mitochondria-mediated resistance is presented. PDT, a photochemistry-based modality, involves the light-based activation of a photosensitizer leading to the production of short-lived reactive molecular species and spatiotemporally confined photodamage to nearby organelles and biological targets. The consequential effects range from subcytotoxic priming of target cells for increased sensitivity to subsequent treatments, such as chemotherapy, to direct cell killing. This review discusses how PDT-based approaches can address key limitations of current treatments. Specifically, an overview of the mechanisms by which PDT alters mitochondrial function, and a summary of preclinical advancements and clinical PDT experience in ovarian cancer are provided.

Paul K Strudler: The Oracle of RAD.

Paul Strudler who facilitated the support of photodynamic therapy by an NIH study section.

Critical PDT Theory III: Events at the Molecular and Cellular Level.

Photodynamic therapy (PDT) is capable of eradicating neoplastic cells that are accessible to sufficient light and oxygen. There is adequate information now available for assessing conditions where PDT might be the therapy of choice, but limited access to clinical facilities and impediments to regulatory approval of new agents have limited clinical usage. Early reports mainly involved clinical data with few thoughts towards finding death pathways. In 2022, there is a clear understanding of the determinants of successful tumor eradication. While PDT may be the optimal method for many clinical indications, support for this approach has lagged. This report provides a commentary on some elements of recent progress in PDT at the molecular and cellular levels, along with a discussion of some of the limitations in current research efforts.

Detection of Paraptosis After Photodynamic Therapy.

Photodynamic therapy (PDT) is a procedure for the selective photosensitization of neoplastic tissues. Subsequent irradiation with visible light can lead to cell death along with vascular shutdown and other responses that lead to selective eradication of malignant cells. Among the cellular responses to PDT are necrosis, apoptosis, and autophagy. These pathways have generally been associated with cell death, although autophagy can also be cytoprotective. A fourth effect that has hitherto been somewhat neglected is termed "paraptosis," a lethal response that can be identified by detecting an extensive collection of cytoplasmic vacuoles. Unlike autophagy, these vacuoles are bound by single membranes. Paraptosis has been characterized as a response to misfolded endoplasmic reticulum proteins that must be "cleared" if the affected cell is to survive. At present, there is no simple biochemical test for paraptosis. This chapter describes the procedure for detection of paraptosis using phase-contrast microscopy, along with some confirmatory approaches.